Patent Grant
9802012
The present disclosure relates to dry powder inhalation systems including dry powder inhalers, cartridges and pharmaceutical compositions for delivering one or more drugs to the pulmonary tract and pulmonary circulation for the treatment of local and/or systemic diseases or disorders.
Drug delivery systems for disease treatment which introduce active ingredients into the circulation are numerous and include oral, transdermal, inhalation, subcutaneous and intravenous administration. Drugs delivered by inhalation are typically delivered using positive pressure relative to atmospheric pressure in air with propellants. Such drug delivery systems deliver drugs as aerosols, nebulized or vaporized. More recently, drug delivery to lung tissue has been achieved with dry powder inhalers. Dry powder inhalers can be breath activated or breath-powered and can deliver drugs by converting drug particles in a carrier into a fine dry powder which is entrained into an air flow and inhaled by the patient. Drugs delivered with the use of a dry powder inhaler are no longer only intended to treat pulmonary disease, but can also be absorbed into the systemic circulation so they can be used to treat many conditions, including, but not limited to diabetes and obesity.
Dry powder inhalers, used to deliver medicaments to the lungs, contain a dose system of a powder formulation usually either in bulk supply or quantified into individual doses stored in unit dose compartments, like hard gelatin capsules or blister packs. Bulk containers are equipped with a measuring system operated by the patient in order to isolate a single dose from the powder immediately before inhalation. Dosing reproducibility requires that the drug formulation is uniform and that the dose can be delivered to the patient with consistent and reproducible results. Therefore, the dosing system ideally operates to completely discharge all of the formulation effectively during an inspiratory maneuver when the patient is taking his/her dose. However, complete discharge is not generally required as long as reproducible dosing can be achieved. Flow properties of the powder formulation, and long term physical and mechanical stability in this respect, are more critical for bulk containers than they are for single unit dose compartments. Good moisture protection can be achieved more easily for unit dose compartments such as blisters. However, materials used to manufacture blisters allow air into the drug compartment and subsequently formulations can lose viability with long storage. Additionally, dry powder inhalers which use blisters to deliver a medicament by inhalation can suffer with inconsistency of dose delivery to the lungs due to variations in the air conduit architecture resulting from puncturing films or peeling films of the blisters.
Dry powder inhalers in the art can generate drug particles or suitable inhalation plumes during an inspiratory maneuver by deagglomerating the powder formulation within a cartridge or capsule. The amount of fine powder discharged from the inhaler's mouthpiece during inhalation is largely dependent on, for example, interparticulate forces in the powder formulation and efficiency of the inhaler to separate those particles so that they are suitable for inhalation. One important inhaler characteristic is the ability of the inhaler to discharge effectively and repeatedly all of its powder content in order to deliver an accurate dose. Also the inhaler should be designed with internal conduits that avoid retaining powder and thus induce costly loss of the active agent to be delivered, which can be typical of, for example, amorphous and/or cohesive powders, and/or crystalline powders. Thus, the inhaler structural design must provide air conduits which effectively deliver the powder from its reservoir during use. The benefits of delivering drugs via the pulmonary circulation are numerous and can include rapid entry into the arterial circulation, avoidance of drug degradation by liver metabolism, ease of use, i.e., lack of discomfort of administration by other routes of administration.
Dry powder inhaler products developed for pulmonary delivery have met with limited success to date, due to lack of practicality and/or cost of manufacture. Some of the persistent problems observed with prior art inhalers, include lack of ruggedness, inconsistency in dosing, inconvenience of the equipment, poor deagglomeration, problems with delivery in light of divorce from propellant use, reduced powder discharge or loss of the powder due to powder retention within an inhaler, and/or lack of patient compliance. In some cases, efficient powder delivery from an inhaler is also dependent on the type of powder, i.e., crystalline versus amorphous powder. Certain types of amorphous powders tend to cake and smear while tumbling, which leads to a decrease inhaler emptying or deagglomeration efficiency and ultimately in drug delivery to a user. Therefore, an inhaler has been designed and manufactured with consistent powder delivery properties, which is easy to use without discomfort, and has discrete inhaler configurations which can allow for better patient compliance.
Described herein generally are dry powder inhalation systems for pulmonary delivery, wherein the systems include dry powder inhalers and containers including cartridges for dry powder inhalers for rapid and effective delivery of dry powder formulations to the pulmonary tract. The dry powder formulations of the inhalation systems comprise active agents for the treatment of one or more diseases. These diseases can include, but are not limited to local or systemic diseases or disorders, including, but not limited to diabetes, obesity, pain, headaches such as migraines, central or peripheral nervous system and immune disorders and the like, as well as for delivery of a vaccine formulation. The dry powder inhalers can be breath-powered, compact, reusable or disposable systems, which can have various shapes and sizes, and comprise a system of airflow conduit pathways for the effective and rapid delivery of dry powder medicaments.
In one embodiment, the inhaler can be a unit dose, reusable or disposable inhaler that can be used with or without a cartridge. By use without a cartridge we refer to systems in which cartridge-like structures are provided that are integral to the inhaler and the inhaler is for a single use and disposable. Alternatively, in some embodiments, the systems comprise a cartridge which is provided separately and installed in the inhaler for use by, for example, the user. In this embodiment, the inhaler can be a reusable inhaler and a new cartridge is installed in the inhaler at every use. In another embodiment, the inhaler can be a multidose inhaler, disposable or reusable, that can be used with single unit dose cartridges installed in the inhaler or cartridge-like structures built-in or structurally configured as part of the inhaler.
In further embodiments, the dry powder inhalation system comprises a dry powder inhalation device or inhaler with or without a cartridge, and a pharmaceutical formulation comprising an active ingredient or active agent for pulmonary delivery. In some embodiments, powder delivery is to the deep lung, including, to the alveolar region, and in some of these embodiments, one or more active agents are delivered to the lungs and absorbed into the pulmonary circulation for systemic delivery. The system can also comprise a dry powder inhaler with or without a unit dose cartridge, and a drug delivery formulation comprising, for example, a pharmaceutically acceptable carrier or substance, for example, a diketopiperazine and an active ingredient such as small molecules, peptides, polypeptides and proteins, including insulin, oxyntomodulin, oxytocin, peptide YY, parathyroid hormone, glucagon-like peptide 1 and the like. In alternate embodiments, the pharmaceutically acceptable carriers and/or excipients, including polyethylene glycol, polyvinylpyrrolidone, saccharides, oligosaccharides, polysaccharides, including lactose, trehalose, mannose, mannitol, sorbitol, and the like; amino acids including, leucine, lysine, isoleucine, trileucine, arginine, cysteine, cystine, histidine and methionine; and/or derivatives thereof.
In one exemplary embodiment, a dry powder inhaler is provided comprising: a) a first element comprising a mouthpiece; b) a second element comprising a container; and c) at least two rigid air conduits; wherein one of the at least two rigid air conduits in use is configured to have a deflector or stem to direct powder movement within a powder container in a substantially U-shaped configuration from an air intake port through a container void and through a dispensing or air exit port to reach a second airflow conduit in the mouthpiece of the inhaler prior to delivery to a user. In this an other embodiments herewith the dry powder inhaler comprises a predetermined air flow balance distribution in use through the air conduit through the powder container and through the air conduit in the mouth piece. The inhaler system also comprises high resistance air flow pathways as described below.
In one embodiment, the dry powder inhaler comprises a housing, a moveable member, and a mouthpiece, wherein the moveable member is operably configured to move a container from a powder containment position to a powder dosing position. In this and other embodiments, the moveable member can be a sled, a slide tray, or a carriage which is moveable by various mechanisms.
In another embodiment, the dry powder inhaler comprises a housing and a mouthpiece, structurally configured to have an open position and a closed position, and a mechanism operably configured to receive, hold, and reconfigure a cartridge from a containment position to a dispensing, dosing or dose delivery position upon movement of the inhaler from the open position to the closed position. In versions of this embodiment, the mechanism can also reconfigure a cartridge installed in the inhaler from the dosing position to an alternate position after use when the inhaler is opened to unload a used cartridge, thereby indicating to a user that the cartridge has been spent. In one embodiment, the mechanism can reconfigure a cartridge to a disposable or discarding configuration after use. In such embodiments, the housing is structurally configured to be moveably attached to the mouthpiece by various mechanisms including, a hinge. The mechanism can be configured to receive and reconfigure a cartridge installed in the inhaler from a containment position to the dosing position and can be designed to operate manually or automatically upon movement of the inhaler components, for example, by closing the device from an open configuration. In one embodiment, the mechanism for reconfiguring a cartridge comprises a slide tray or sled attached to the mouthpiece and movably attached to the housing. In another embodiment, the mechanism is mounted or adapted to the inhaler and comprises a geared mechanism integrally mounted within, for example, a hinge of the inhaler device. In yet another embodiment, the mechanism operably configured to receive and reconfigure the cartridge from a containment position to a dosing position comprises a cam that can reconfigure the cartridge upon rotation of, for example, the housing or the mouthpiece.
In an alternate embodiment, the dry powder inhaler can be made as a single use, unit dose disposable inhaler, which can be provided with a container configured to hold a powder medicament and the container is moveable from a containment configuration to a dosing configuration by a user, wherein the inhaler can have a first and a second configuration in which the first configuration is a containment configuration and the second configuration is a dosing of dispensing configuration. In this embodiment, the inhaler can be provided with or without a mechanism for reconfiguring the powder container. According to aspects of the latter embodiment, the container can be reconfigured directly by the user. In some aspects of this embodiment, the inhaler and container can be manufactured as a two piece inhalation system wherein the powder medicament is provided to the container prior to assembling the device in a containment configuration. In this embodiment, the container is attached or inserted into to the inhaler body and is moveable from the containment configuration to a dosing configuration, for example, by sliding relative to the top portion of the inhaler comprising a mouthpiece.
In yet another embodiment, an inhaler is described comprising a container mounting area configured to receive a container, and a mouthpiece having at least two inlet apertures and at least one exit aperture. In one embodiment, one inlet aperture of the at least two inlet apertures is in fluid communication with the container area, and the other of the at least two inlet apertures is in fluid communication with the at least one exit aperture via a flow path configured to bypass the container area.
In one embodiment, the inhaler has opposing ends such as a proximal end for contacting a user's lips or mouth and a distal end, and comprises a mouthpiece and a medicament container; wherein the mouthpiece comprises a top surface and a bottom or undersurface. The mouthpiece undersurface has a first area configured relatively flat to maintain a container in a sealed or containment configuration, and a second area adjacent to the first area which is raised relative to the first area. In this embodiment, the container is movable from the containment configuration to the dosing configuration and vice versa, and in the dosing configuration, the second raised area of the mouthpiece undersurface and the container form or define an air inlet passageway to allow ambient air to enter the internal volume of the container or expose the interior of the container to ambient air. In one embodiment, the mouthpiece can have a plurality of openings, for example, an inlet port, an outlet port and at least one port for communicating with a medicament container in a dispensing or dosing position, and can be configured to have integrally attached panels extending from the bottom surface sides of the inhaler and having flanges protruding towards the center of the inhaler mouthpiece, which serve as tracks and support for the container on the mouthpiece so that the container can move along the tracks from the containment position to a dispensing or dosing position and back to containment if desired. In one embodiment, the medicament container is configured with wing-like projections or winglets extending from its top border to adapt to the flanges on the mouthpiece panels. In one embodiment, the medicament container can be moved manually by a user from containment position to a dosing position and back to the containment position after dosing, or by way of a sled, a slide tray, or a carriage.
In another embodiment, a single use, unit dose, disposable inhaler can be constructed to have a sled incorporated and operably configured to the mouthpiece. In this embodiment, a bridge on the sled can abut or rest on an area of the medicament container to move the container along the mouthpiece panel tracks from the containment position to the dispensing or dosing position. In this embodiment, the sled can be operated manually to move the container on the mouthpiece tracks.
In a particular embodiment, a single use, unit dose disposable inhaler is structurally configured to have a powder containment configuration and a powder dosing configuration, the inhaler comprises two elements and has a top surface, bottom surface, a proximal end and a distal end; a first element and a second element; the first element has at least three openings and comprises a mouthpiece at the proximal end; a body, an undersurface configured to adapt to the second element and has a protruding structure or stem configured to extending downwardly into the second element; the first element further configured to have a first flow pathway having an air inlet, and an air outlet for delivering an airstream into a subject's mouth during an inhalation; and a third opening configured to form an air conduit and a second flow pathway with the second element in the powder dosing configuration; the second element is configured to adapt to the undersurface of the first element and is moveable relative to the first element to form an inhaler containment configuration or a dosing configuration; the second element comprises a container or reservoir, has an opening configured to receive and retain a powder and form an air inlet and an air conduit or a second flow pathway with the first element in the dosing configuration; wherein in the powder dispensing configuration a powder is exposed to ambient air to be dispensed or discharged during an inhalation. In this and other embodiments, a dry powder inhaler in a dosing configuration comprises a stem-like or protruding structure extending downwardly into the container void or chamber and serves to deflect powder. In this embodiment, airflow entering the container or powder reservoir travels primarily in a pathway closely related to the shape of the container which is structurally configured in the shape substantially of the letter U having the portion of the air conduit extending from the air inlet in the form of an open letter s on its side, and powder is lifted and translated or transported from this second airstream to the first airstream into a subject's mouth and airways.
In one embodiment, the dry powder inhaler comprises one or more air inlets and one or more air outlets. When the inhaler is closed, at least one air inlet can permit flow to enter the inhaler and at least one air inlet allows flow to enter a cartridge compartment or the interior of the cartridge or container adapted for inhalation. In one embodiment, the inhaler has an opening structurally configured to communicate with the cartridge placement area and with a cartridge inlet port when the cartridge container is in a dosing position. Flow entering the cartridge interior can exit the cartridge through an exit or dispensing port or ports; or flow entering the container of an inhaler can exit through at least one of the dispensing apertures. In this embodiment, the cartridge inlet port or ports is/are structurally configured so that all, or a portion of the air flow entering the interior of the cartridge is directed at the exit or dispensing port or ports.
The medicament container or powder reservoir can be structurally configured to have two opposing, relatively curvilinear sides which can direct airflow. In one embodiment, flow entering the air inlet during an inhalation enters the container or powder reservoir and can circulate within the interior of the container about an axis relatively perpendicular to the axis of the dispensing ports, and thereby, flow can lift, tumble and effectively fluidize a powder medicament contained in the cartridge or reservoir prior to exiting through dispensing ports or outlets. In another embodiment, flow entering the air inlet during an inhalation can lift powder from the container of powder reservoir and translate or transport the powder particles entrained in the airstream into a second stream in the inhaler. In this and other embodiments, fluidized powder in the air conduit can be further deagglomerated into finer powder particles by a change in direction or velocity, i.e., acceleration or deceleration of the particles in the flow pathway. In certain embodiments, the change in acceleration or deceleration can be accomplished by changing the angle and geometries of, for example, the dispensing port or ports, the mouthpiece conduit and/or its interfaces. In the inhalers described herewith, the mechanism of fluidization and acceleration of particles as they travel through the inhaler are methods by which deagglomeration and delivery of a dry powder formulation is effectuated.
In particular embodiments, a method for deagglomerating and dispersing a dry powder formulation comprises one or more steps such as tumbling within a primary container region started and enhanced by flow entering the container; a rapid acceleration of powder in the flow through the dispensing ports leaving the container; further accelerating the powder induced by a change in direction or velocity as the powder exits the dispensing port; shearing of powder particles caught within a flow gradient, wherein the flow on the top of the particle is faster than flow on bottom of the particle; deceleration of flow due to expansion of cross-sectional area within the mouthpiece air conduit; expansion of air trapped within a particle due to the particle moving from a higher pressure region to a lower pressure region, or collisions between particles and flow conduit walls at any point in the flow passageways.
In another embodiment, a dry powder inhaler comprises a mouthpiece; a sled, slide tray, or a carriage; a housing, a hinge, and a gear mechanism configured to effectuate movement of the sled or slide tray; wherein the mouthpiece and the housing are moveably attached by the hinge.
Cartridges for use with the dry powder inhaler can be manufactured to contain any dry powder medicament for inhalation. In one embodiment, the cartridge is structurally configured to be adaptable to a particular dry powder inhaler and can be made of any size and shape, depending on the size and shape of the inhaler to be used with, for example, if the inhaler has a mechanism which allows for translational movement or for rotational movement. In one embodiment, the cartridge can be configured with a securing mechanism, for example, having a beveled edge on the cartridge top corresponding to a matching beveled edge in an inhaler so that the cartridge is secured in use. In one embodiment, the cartridge comprises a container and a lid or cover, wherein the container can be adapted to a surface of the lid and can be movable relative to the lid or the lid can be movable on the container and can attain various configurations depending on its position, for example, a containment configuration, a dosing configuration or after use configuration. Alternatively, the lid can be removable.
An exemplary embodiment can comprise an enclosure to hold medicament configured having at least one inlet aperture to allow flow into the enclosure; at least one dispensing aperture to allow flow out of the enclosure; the inlet aperture configured to direct at least a portion of the flow at the dispensing aperture or at the particles approaching the dispensing aperture within the enclosure in response to a pressure gradient. The dispensing aperture or apertures and the intake gas aperture each independently can have a shape such as oblong, rectangular, circular, triangular, square and oval-shaped and can be in close proximity to one another. In one embodiment and during inhalation, a cartridge adapted to the inhaler in a dosing position allows airflow to enter the enclosure and mix with the powder to fluidize the medicament. The fluidized medicament can move within the enclosure such that medicament gradually exits the enclosure through the dispensing aperture, wherein the fluidized medicament exiting the dispensing aperture is sheared and diluted by a secondary flow not originating from within the enclosure. In one embodiment, the flow of air in the internal volume rotates in a circular manner so as to lift a powder medicament in the container or enclosure and recirculate the entrained powder particles or powder mass in the internal volume of the container promoting the flow to tumble prior to the particles exiting dispensing ports of the container or one or more of the inhaler inlet ports or air outlet or dispensing apertures, and wherein the recirculating flow, can cause tumbling, or non-vortical flow of air in the internal volume acts to deagglomerate the medicament. In one embodiment, the axis of rotation is mostly perpendicular to gravity. In another embodiment the axis of rotation is mostly parallel to gravity. The secondary flow not originating from within the enclosure further acts to de-agglomerate the medicament. In this embodiment, the pressure differential is created by the user's inspiration. A cartridge for a dry powder inhaler, comprising: an enclosure configured to hold a medicament; at least one inlet port to allow flow into the enclosure, and at least one dispensing port to allow flow out of the enclosure; the at least one inlet port is configured to direct at least a portion of the flow entering the at least one inlet port at the at least one dispensing port within the enclosure in response to a pressure differential.
A unit dose cartridge for an inhaler is described comprising: a substantially flat cartridge top, arrow-like in configuration, having one or more inlet apertures, one or more dispensing apertures, two side panels extending downwardly and each of the two side panels having a track; and a container moveably engaged to the track of the side panels of the cartridge top, and comprising a chamber configured to have a relatively cup-like shape with two relatively flat and parallel sides and a relatively rounded bottom, and interior surface defining an internal volume; the container configurable to attain a containment position and a dosing position with the cartridge top; wherein in use with a dry powder inhaler during an inhalation a flow entering the internal volume diverges as it enters the internal volume with a portion of the flow exiting through the one or more dispensing apertures and a portion of the flow rotating inside the internal volume and lifting a powder in the internal volume before exiting through the dispensing apertures.
In one embodiment, an inhalation system for pulmonary drug delivery is provided, comprising: a dry powder inhaler comprising a housing and a mouthpiece having an inlet and an outlet port, an air conduit between the inlet and the outlet, and an opening structurally configured to receive a cartridge; a cartridge mounting mechanism such as a sled; a cartridge configured to be adapted to the dry powder inhaler and containing a dry powder medicament for inhalation; wherein the cartridge comprises a container and a lid having one or more inlet ports or one or more dispensing ports; the dry powder inhaler system in use has a predetermined airflow balance distribution through the cartridge relative to total flow delivered to the patient.
In embodiments disclosed herewith, the dry powder inhaler system comprises a predetermined mass flow balance within the inhaler. For example, a flow balance of approximately 20% to 70% of the total flow exiting the inhaler and into the patient is delivered by the dispensing ports or passed through the cartridge, whereas approximately 30% to 80% is generated from other conduits of the inhaler. Moreover, bypass flow or flow not entering and exiting the cartridge can recombine with the flow exiting the dispensing port of the cartridge within the inhaler to dilute, accelerate and ultimately deagglomerate the fluidized powder prior to exiting the mouthpiece.
In embodiments described herein, the dry powder inhaler is provided with relatively rigid air conduits or a plumbing system and high flow resistance levels to maximize deagglomeration of powder medicament and facilitate delivery. Inhalation systems disclosed herein comprise conduits which exhibit resistance to flow in use maintaining low flow rates which minimize high inertial forces on powder particles discharged from the inhaler, preventing throat deposition or impaction of the powder particles in the upper respiratory tract, and thereby, maximizing powder particle deposition in the lungs. Accordingly, the present inhalation systems provide effective and consistent powder medicament discharge from the inhalers after repeated use since the inhalers are provided with air conduit geometries which remain the constant and cannot be altered. In some embodiments, the dry powder medicament is dispensed with consistency from an inhaler in less than about 3 seconds, or generally less than 1 second. In some embodiments, the inhaler system can have a high resistance value of, for example, approximately 0.065 to about 0.200 (√kPa)/liter per minute. Therefore, in the inhalation systems, peak inhalation pressures drop offs between 2 and 20 kPa produce resultant peak flow rates of about between 7 and 70 liters per minute. These flow rates result in greater than 75% of the cartridge contents dispensed in fill masses between 1 and 30 mg or greater. In some embodiments, these performance characteristics are achieved by end users within a single inhalation maneuver to produce cartridge dispense percentages greater than 90%. In certain embodiments, the inhaler and cartridge system are configured to provide a single dose by discharging powder from the inhaler as a continuous flow of powder delivered to a patient.
In one embodiment, a method for effectively deagglomerating a dry powder formulation during an inhalation in a dry powder inhaler is provided. The method can comprise the steps of providing a dry powder inhaler comprising a container having an air inlet, dispensing ports communicating with a mouthpiece air conduit and containing and delivering a formulation to a subject in need of the formulation; generating an airflow in the inhaler by the subject's inspiration so that about 20 to about 70% of the airflow entering the inhaler enters and exits the container; allowing the airflow to enter the container inlet, circulate and tumble the formulation in an axis perpendicular to the dispensing ports to fluidize the formulation so as to yield a fluidized formulation; accelerating metered amounts of fluidized formulation through the dispensing ports and in the air conduit, and decelerating the airflow containing fluidized formulation in the mouthpiece air conduit of the inhaler prior to reaching the subject. In some specific embodiments, 20% to 60% of the total flow through the inhaler goes through the cartridge during dose delivery.
In another embodiment, a method for deagglomerating and dispersing a dry powder formulation for inhalation is provided, comprising the steps of: generating an airflow in a dry powder inhaler comprising a mouthpiece and a container having at least one inlet port and at least one dispensing port and containing a dry powder formulation; the container forming an air passage between at least one inlet port and at least one dispensing port and the inlet port directs a portion of the airflow entering the container to at least one dispensing port; allowing airflow to tumble powder within the container in a substantially perpendicular axis to the at least one dispensing port so as to lift and mix the dry powder medicament in the container to form an airflow medicament mixture; and accelerating the airflow exiting the container through at least one dispensing port. In one embodiment, the inhaler mouthpiece is configured to have a gradual expanding cross-section to decelerate flow and minimize powder deposition inside the inhaler and promote maximal delivery of powder to the patient. In one embodiment, for example, the cross-sectional area of the oral placement region of an inhaler can be from about 0.05 cm2 to about 0.25 cm2 over an approximate length of about 3 cm. These dimensions depend on the type of powder used with the inhaler and the dimensions of the inhaler itself.
In one embodiment, a cartridge for a dry powder inhaler is provided, comprising: a cartridge top and a container defining an internal volume; wherein the cartridge top has an undersurface that extends over the container; the undersurface configured to engage the container, and comprising an area to contain the internal volume and an area to expose the internal volume to ambient air. In one aspect of this embodiment, the container can optionally have one or more protrusions, or stems extending from the undersurface or inner surface of the top into void of the container. The protrusions can be of any shape or size as long as they can direct or deflect flow, particularly downwardly in the container in use. In particular embodiments, the protrusion can be configured in the lid of a cartridge extending from the surface facing the internal volume of the container in proximity to an air inlet in the dosing configuration. Alternatively, the protrusion can be designed in the surface of the mouthpiece for contacting the internal volume of a container and in proximity to the air inlet formed by the container in the dosing configuration.
In an alternate embodiment, a method for particle delivery through a dry powder delivery device is provided, comprising: inserting into the delivery device a cartridge for the containment and dispensing of particles comprising an enclosure enclosing the particles, a dispensing aperture and an intake gas aperture; wherein the enclosure, the dispensing aperture, and the intake gas aperture are oriented such that when an intake gas enters the intake gas aperture, the particles are deagglomerated by at least one mode of deagglomeration as described herein to separate the particles, and the particles along with a portion of intake gas are dispensed through the dispensing aperture; concurrently forcing a gas through a delivery conduit in communication with the dispensing aperture thereby causing the intake gas to enter the intake gas aperture, deagglomerate the particles, and dispense the particles along with a portion of intake gas through the dispensing aperture; and, delivering the particles through a delivery conduit of the device, for example, in an inhaler mouthpiece. In embodiments described herein, to effectuate powder deagglomeration, the dry powder inhaler can be structurally configured and provided with one or more zones of powder deagglomeration, wherein the zones of deagglomeration during an inhalation maneuver can facilitate tumbling of a powder by air flow entering the inhaler, acceleration of the air flow containing a powder, deceleration of the flow containing a powder, shearing of a powder particles, expansion of air trapped in the powder particles, and/or combinations thereof.
In another embodiment, the inhalation system comprises a breath-powered dry powder inhaler, a cartridge containing a medicament, wherein the medicament can comprise, for example, a drug formulation for pulmonary delivery such as a composition comprising a carrier, for example, a saccharide, oligosaccharide, polysaccharide, or a diketopiperazine and an active agent. In some embodiments, the active agent comprises peptides and proteins, such as insulin, glucagon-like peptide 1, oxyntomodulin, peptide YY, exendin, parathyroid hormone, analogs thereof, vaccines, small molecules, including anti-asmatics, vasodilators, vasoconstrictors, muscle relaxants, neurotransmitter agonist or antagonists, and the like.
The inhalation system can be used, for example, in methods for treating conditions requiring localized or systemic delivery of a medicament, for example, in methods for treating diabetes, pre-diabetes conditions, respiratory track infection, osteoporosis, pulmonary disease, pain including headaches including, migraines, obesity, central and peripheral nervous system conditions and disorders and prophalactic use such as vaccinations. In one embodiment, the inhalation system comprises a kit comprising at least one of each of the components of the inhalation system for treating the disease or disorder.
In one embodiment, there is provided a method for the effective delivery of a formulation to the blood stream of a subject, comprising an inhalation system comprising an inhaler including a cartridge containing a formulation comprising a diketopiperazine, wherein the inhalation system delivers a powder plume comprising diketopiperazine microparticles having a volumetric median geometric diameter (VMGD) ranging from about 2.5 μm to 10 μm. In an example embodiment, the VMGD of the microparticles can range from about 2 μm to 8 μm. In an example embodiment, the VMGD of the powder particles can be from 4 μm to about 7 μm in a single inhalation of the formulation of fill mass ranging between 3.5 mg and 10 mg of powder. In this and other embodiments, the inhalation system delivers greater than about 90% of the dry powder formulation from the cartridge.
In another embodiment, there is provided a dry powder inhaler comprising: a) a mouthpiece configured to deliver a dry powder to a subject by oral inhalation; b) a container housing, and c) rigid air conduits extending between the container housing and the mouthpiece and configured to communicate with ambient air; wherein the dry powder inhaler is configured to emit greater than 75% of a dry powder as powder particles from a container oriented in the container housing in a single inhalation and the powder particles emitted have a volumetric median geometric diameter (VMGD) of less than about 5 microns, when a user inhales through the mouthpiece to generate a peak inspiratory pressure of about 2 kPa within two seconds and an area under the curve (AUC) within 1 second for a pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec. In another embodiment, the AUC within 1 second for a pressure versus time curve is between about 1.0 and about 15 kPa*sec.
In some embodiments, there is also provided a method of delivering a dose of a dry powder medication using a high resistance dry powder inhaler comprising, providing a high resistance dry powder inhaler containing a dose of a dry powder medicament and inhaling from the inhaler with sufficient force (or effort) to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and generating an area under the curve in the first second (AUC0-1sec) of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than 75% of the dry powder dose is discharged or emitted from the inhaler as powder particles. In some embodiments the VMGD of the emitted particles is less than about 5 microns.
In another embodiment, a method of delivering an adequately de-agglomerated dose of a dry powder medication using a high resistance dry powder inhaler comprising, providing a high resistance dry powder inhaler containing a dose of a dry powder medicament; inhaling from the inhaler with sufficient force to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and generating an area under the curve in the first second (AUC0-1sec) of a inspiratory pressure-time curve of at least about 1.0, 1.1, or 1.2 kPa*second; wherein VMGD (×50) of the emitted powder is less than about 5 um. In an alternative embodiment, the dry powder is composed of microparticles with a median particle size and the VMGD (×50) of the emitted powder particles is not greater than 1.33 times the median particle size when the inhaler is used optimally, for example, at about 6 kPa.
In another embodiment, described is a use of a high resistance dry powder inhaler for the delivery of a dry powder wherein the dry powder inhaler having an airflow resistance value ranging from about 0.065 (√kPa)/liter per minute to about 0.200 (√kPa)/liter per minute, and containing the dose of the dry powder, wherein sufficient force is applied to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and wherein an area under the curve in the first second (AUC0-1sec) of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec is generated; and wherein greater than 75% of the dose of the dry powder is discharged or emitted from the inhaler as powder particles.
In some embodiments the inhalation systems described herein are used to treat patients in need of treatment of a disease or disorder described herein using a medicament as described.
In still another embodiment, a high resistance dry powder inhaler for use to deliver a dry powder medicament to a patient is described, characterized in that the dry powder inhaler is provided having an airflow resistance value ranging from about 0.065 (√kPa)/liter per minute to about 0.200 (√kPa)/liter per minute, and containing a dose of the dry powder medicament, wherein in use sufficient force is applied to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and an area under the curve is generated in the first second (AUC0-1sec) of an inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec; and wherein greater than 75% of the dose of the dry powder is discharged or emitted from the inhaler as powder particles.
In another embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles; wherein the diketopiperazine microparticles deliver a plasma level (exposure) of diketopiperazine having an AUC0-2 hr between 1,300 ng*min/mL and 3,200 ng*min/mL per mg of diketopiperazine emitted in a single inhalation. In another exemplary embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles; wherein the diketopiperazine microparticles deliver a plasma level (exposure) of diketopiperazine having an AUC0-∞ greater than 2,300 ng*min/mL per mg of powder emitted in a single inhalation. In an aspect of such embodiments the DKP is FDKP. In this and other embodiments, the diketopiperazine microparticles do not cause a reduction in lung function as assessed by pulmonary function tests and measured as forced expiratory volume in one second (FEV1). In certain embodiments, the measured plasma exposure of FDKP in a subject can be greater than 2,500 ng*min/mL per mg of FDKP powder emitted in a single inhalation. In alternate embodiments, the measured plasma exposure, AUC0-∞ of FDKP of a subject can be greater than 3,000 ng*min/mL per mg of FDKP powder emitted in a single inhalation. In yet another embodiment, the measured plasma exposure of FDKP AUC0-∞ in a subject can be less than or about 5,500 ng*min/mL per mg of FDKP emitted in a single inhalation of a dry powder composition comprising FDKP. In some embodiments, the stated level of exposure represents an individual exposure. In alternate embodiments, the stated level of exposure represents a mean exposure. Active agent quantities, including contents and exposures may be express alternatively in units of activity or mass.
In these and other embodiments, the microparticles can further comprise an active ingredient. In particular embodiments, the active ingredient is insulin. In another exemplary embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles containing insulin; wherein the diketopiperazine microparticles deliver a plasma level (exposure) of insulin with an AUC0-2 hr greater than 160 μU*min/mL per units of insulin in the powder formulation emitted in a single inhalation. In an aspect of this embodiment, the inhalation system is configured to deliver and attain an insulin plasma level or exposure wherein the measured insulin AUC0-2 hr ranges from about 100 to 1,000 μU*min/mL per units of insulin in the powder formulation emitted in a single inhalation. In some embodiments, the stated level of exposure represents an individual exposure. In alternate embodiments, the stated level of exposure represents a mean exposure.
In another exemplary embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles comprising insulin; wherein the diketopiperazine microparticles deliver a plasma level (exposure) of insulin with an AUC0-4 hr greater than 100 μU*min/mL per U of insulin filled emitted in a single inhalation. In an aspect of this embodiment, the inhalation system is configured to deliver to a patient a formulation of insulin and fumaryl diketopiperazine which attains a plasma exposure of insulin having measured AUC0-4 hr in the range of 100 to 250 μU*min/mL per U of insulin filled dose, emitted in a single inhalation. In aspects of these embodiments, the AUC0-4 hr can be greater than 110, 125, 150 or 175 μU*min/mL per U of insulin filled, emitted in a single inhalation. In this and other embodiments, the insulin content of the formulation comprises from about 10 to about 20% (w/w) of the formulation
In still another exemplary embodiment, an inhalation system is provided comprising an inhaler, a cartridge containing a dry powder formulation for delivery to the systemic circulation comprising diketopiperazine microparticles containing insulin; wherein the diketopiperazine microparticles deliver a plasma level of insulin with a Cmax over 10 μU/mL per mg of powder emitted in a single inhalation, within 30 minutes of administration. In an aspect of this embodiment, the insulin formulation administered generates a Cmax ranging from about 10 to 20 μU/mL per mg of powder emitted in a single inhalation, and within 30 minutes after administration. In further aspects of this embodiment, insulin Cmax can be attained within 25, 20, or 15 minutes of administration. In alternatives of these Cmax embodiments, the Cmax attained after pulmonary inhalation of the formulation is greater than 3 μU/mL per U of insulin filled into a cartridge, or in the range of 3 U to 6 U, or 4 U to 6 μU/mL per U of insulin in a cartridge dose.
In another embodiment, an inhalation system, comprising: a dry powder inhaler; and a dry powder formulation comprising a plurality of powder particles of a diketopiperazine is provided, wherein the inhalation system is configured to deliver the diketopiperazine to the pulmonary circulation of a subject, and the diketopiperazine can be measured in the subject's plasma having a mean exposure or AUC0-∞ greater than 2,300 ng*min/mL per mg of diketopiperazine content in the dry powder formulation administered in a single inhalation. In one embodiment, the inhalation system further comprises a cartridge configured to adapt to a breath powered dry powder inhaler. In this and other embodiments, the diketopiperazine in the formulation is 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine (FDKP).
In embodiments wherein FDKP is used in the formulation, the system can deliver the FDKP into the systemic circulation at a Tmax of less than 1 hour. In some embodiments, the Tmax for FDKP can be less than 15 or 30 minutes after administration of the FDKP in a single inhalation. In this an other embodiments, the AUC is measured from 0 to 2 hours, 0 to 4 hrs or 0 to ∞.
In another embodiment, an inhalation system, comprising: a breath-powered dry powder inhaler, and a dry powder formulation comprising a plurality of diketopiperazine particles is provided; wherein the inhalation system is operably configured to emit a powder plume comprising the diketopiperazine microparticles having a volumetric median geometric diameter ranging from 2 μm to 8 μm and a geometric standard deviation of less than 4 μm.
In yet another embodiment, an inhalation system for pulmonary delivery of a drug, comprising: a breath-powered dry powder inhaler, and a dry powder formulation comprising a plurality of diketopiperazine particles is provided; wherein the inhalation system is operably configured to emit more than 90% of the powder particles that dissolve and are absorbed into the blood in less than 30 minutes or less than 25 minutes yield a peak concentration of the diketopiperazine after a single inhalation of the dry powder formulation. In some embodiments, the system emits more than 95% of the powder particles in a single inhalation, which particles are absorbed into the circulation.
In one embodiment, an inhalation system, comprising: a dry powder inhaler; and a dry powder formulation comprising a plurality of dry powder particles comprising insulin is provided; wherein the inhalation system is configured to deliver the insulin to the pulmonary circulation of a subject, and the insulin can be measured in a subject's plasma at an exposure having a mean AUC0-2 hr greater than 160 uU*min/mL per unit of insulin emitted in the dry powder formulation administered in a single inhalation.
In one embodiment, the inhalation system, the dry powder formulation is administered to a subject by oral inhalation and the formulation comprises powder particles of insulin which can deliver the insulin to the subject systemic circulation, wherein a Cmax for insulin is measured in less than 30 minutes after administration to a patient in a single inhalation.
In an embodiment, there is provided an inhalation system, comprising: a breath-powered dry powder inhaler, and a powder formulation comprising a plurality of diketopiperazine particles; wherein the inhalation system is operably configured to emit a powder plume comprising the diketopiperazine microparticles having a volumetric median geometric diameter ranging from 2 μm to 8 μm and a geometric standard deviation of less than 4 μm.
In yet another embodiment, an inhalation system for pulmonary delivery of a drug is provided, comprising: a breath-powered dry powder inhaler, and a powder formulation comprising a plurality of diketopiperazine particles; wherein the inhalation system is operably configured to emit powder particles that are absorbed into the blood to yield a peak concentration of the drug in less than or equal to 30, 25, 20, or 15 minutes.
In one embodiment, a dry powder inhaler comprising a mouthpiece configured to deliver a dry powder to a subject by oral inhalation, a container configured to hold a dry powder, and air conduits extending between the container and the mouthpiece and configured to communicate with ambient air, wherein the dry powder inhaler is configured to emit greater than 75% of the dry powder as powder particles in a single inhalation and the powder particles emitted have a volumetric median geometric diameter of less than 5 microns, when a user inhales through the mouthpiece to generate a peak inspiratory pressure of about 2 kPa within two seconds, and an AUC0-1sec of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than 75% of the dry powder dose is discharged or emitted from the inhaler as powder particles.
In yet another embodiment, a method of delivering a dose of a dry powder medication to a subject is disclosed using a high resistance dry powder inhaler comprising the steps of providing a dry powder inhaler having a resistance value to airflow ranging from about 0.065 (√kPa)/liter per minute to about 0.200 (√kPa)/liter per minute and containing a dose of a dry powder medicament; inhaling from the inhaler with sufficient force to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and generating an AUC0-1sec of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than 75% of the dry powder dose is discharged or emitted from the inhaler as powder particles.
Disclosed herein generally are dry powder inhalers, cartridges for a dry powder inhalers and inhalation systems for delivering one or more pharmaceutical medicaments to a patient via pulmonary inhalation. In one embodiment, an inhalation system comprises a breath-powered dry powder inhaler, and a cartridge containing a pharmaceutical formulation comprising a pharmaceutically active substance or active ingredient and a pharmaceutically acceptable carrier. The dry powder inhaler is provided in various shapes and sizes, and can be reusable or for single use, easy to use, is inexpensive to manufacture and can be produced in high volumes in simple steps using plastics or other acceptable materials. In addition to complete systems, inhalers, filled cartridges and empty cartridges constitute further embodiments disclosed herein. The present inhalation system can be designed to be used with any type of dry powder. In particular, the inhaler system is used alone comprising a container, or can be configured to use replaceable containers for multiple use. Alternatively, the inhaler system can include designs including multi-use inhaler comprising a plurality of integrally built-in containers which hold individual powder doses for dispensing one at a time. Methods for the effective and consistent delivery of a pharmaceutical formulation to the systemic circulation using inhalers described herewith are also disclosed.
The present disclosure also includes inhaler system designs exemplary for use with any type of dry powders, in particular, certain amorphous dry powder medicament compositions. In one embodiment, the amorphous dry powder comprises particles which are highly dispersible and prone to smearing and/or pasting upon repeated tumbling action, including particle to particle interactions, or particle to container surface collisions. The smearing and/or pasting of the powder particles can lead to unwanted and increased retention of the dry powder to be delivered by the inhaler system, leading a decrease in delivered powder mass from the inhaler system.
As used herein “dry powder” refers to a fine particulate composition that is not suspended or dissolved in a propellant, or other liquid. It is not meant to necessarily imply a complete absence of all water molecules.
As used herein, “amorphous powder” refers to dry powders lacking a definite repeating form, shape, or structure, including all non-crystalline powders.
In one embodiment, the dry powder is a relatively cohesive powder which requires optimal deagglomeration condition. In one embodiment, the inhalation system provides a re-useable, miniature breath-powered inhaler in combination with single-use cartridges containing pre-metered doses of a dry powder formulation.
As used herein the term “a unit dose inhaler” refers to an inhaler that is adapted to receive a single container a dry powder formulation and delivers a single dose of a dry powder formulation by inhalation from container to a user. It should be understood that in some instance multiple unit doses will be required to provide a user with a specified dosage.
As used herein the term “a multiple dose inhaler” refers to an inhaler having a plurality of containers, each container comprising a pre-metered dose of a dry powder medicament and the inhaler delivers a single dose of a medicament powder by inhalation at any one time.
As used herein a “container” is an enclosure configured to hold or contain a dry powder formulation, a powder containing enclosure, and can be a structure with or without a lid. This container can be provided separately from the inhaler or can be structurally integrated within the inhaler (e.g. non-removable). Further, the container can be filled with a dry powder. A cartridge can also include a container.
As used herein a “powder mass” is referred to an agglomeration of powder particles or agglomerate having irregular geometries such as width, diameter, and length.
As used herein, the term “microparticle” refers to a particle with a diameter of about 0.5 to about 1000 μm, irrespective of the precise exterior or interior structure. However four pulmonary delivery microparticles that are less than 10 μm are generally desired, especially those with mean particles sizes of less than about 5.8 μm in diameter.
As used herein a “rigid air conduit” refers to an air conduit that is associated with the pathway of air through the inhalation system that does not change in geometry or remains constant, for example, in a reusable inhaler the air conduits remain the same after repeated use. The rigid air conduit can be associated with a mouthpiece, container, inhaler housing, container, container housing or the like.
As used herein a “unit dose” refers to a pre-metered dry powder formulation for inhalation. Alternatively, a unit dose can be a single container having multiple doses of formulation that can be delivered by inhalation as metered single amounts. A unit dose cartridge/container contains a single dose. Alternatively it can comprise multiple individually accessible compartments, each containing a unit dose.
As used herein “U-shaped” refers to the trajectory of a flow traversing the internal volume of a cartridge which is substantially shaped in the form of the letter u, and wherein an airflow entering the container at a substantially perpendicular angle and parallel to the mouthpiece of the inhaler is deflected in a substantially downward direction and exiting at a substantially perpendicular angle to the mouthpiece.
As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.
In embodiments herewith, the present devices can be manufactured by several methods, however, in one embodiment, the inhalers and cartridges are made, for example, by injection molding techniques, thermoforming, using various types of plastic materials, including, polypropylene, cyclicolephin co-polymer, nylon, polyesters such as polyethylenes, and other compatible polymers and the like. In certain embodiments, the dry powder inhaler can be assembled using top-down assembly of individual component parts. In some embodiments, the inhalers are provided in compact and discrete sizes, such as from about 1 inch to about 5 inches in dimension, and generally, the width and height are less than the length of the device. In certain embodiments the inhaler is provided in various shapes including, relatively rectangular bodies, cylindrical, oval, tubular, squares, oblongs, and circular forms.
In embodiments described and exemplified herewith, the inhalation system comprises inhaler, cartridge or container, and a dry powder formulation, wherein the inhalers are configured with the cartridge to effectively fluidize, deagglomerate or aerosolize a dry powder formulation by using at least one relatively rigid flow conduit pathway for allowing a gas such as air to enter the inhaler. For example, the inhaler is provided with a first air/gas pathway for entering and exiting a cartridge containing the dry powder, and a second air pathway which can merge with the first air flow pathway exiting the cartridge. The flow conduits, for example, can have various shapes and sizes depending on the inhaler configuration. General examples of inhalers and cartridges that can be used in the present inhalation system are disclosed in, for example, U.S. patent application Ser. Nos. 12/484,125 (US 2009/0308390), 12/484,129 (US 2009/0308391), 12/484,137 (US 2009/0308392, U.S. Pat. No. 8,424,518), 12/717,884 (US 2010/0197565) and PCT/US2011/041303, all of which are incorporated herein by reference in their entirety for all they disclose regarding inhalation systems.
In embodiments exemplified herewith, each inhaler can be used with a suitable cartridge. However, the inhalation system can perform more efficiently when inhaler and cartridge are designed to correspond to one another. For example, the cartridge mounting area of an inhaler can be designed to house only a specific cartridge and therefore, structural configurations of the openings of cartridge and inhaler match or fit one another, for example, as keying areas or surfaces which can aid as safety parameter for users. Examples of a corresponding inhaler and cartridge follows herewith as inhaler 302 which can be used with cartridge 170, 981 and inhaler 900 which can be used with cartridge 150. These inhalers and cartridges have been disclosed in U.S. patent application Ser. Nos. 12/484,125; 12/484,129, and 12/484,137 (U.S. Pat. No. 8,424,518), all of which are incorporated by reference herein in their entirety for all they disclose regarding inhalers and cartridges, and where appropriate, for teachings of additional or alternative details, features, and/or technical background.
An embodiment of a dry powder inhaler is exemplified in
Gear mechanism or rack 319 which is part of sled 317 and pinion 363 are configured with the mouthpiece as part of the hinge mechanism to engage housing 320, which housing can also be configured to house sled 317. In this embodiment, sled 317 is configured as a separate part and has a portion configured as a rack which engages the gearwheel configured on the hinge mechanism. Hinge mechanism 363 allows movement of mouthpiece 330 to an open or cartridge loading configuration, and close configuration or position of inhaler 302 in an angular direction. Gear mechanism 363 in inhalers 300, 302 can actuate the sled to allow concurrent movement of sled 317 within housing 320 when the inhaler is effectuated to open and close by movement of mouthpiece 330, which sled 317 is integrally configured with rack 319 as part of gear mechanism 363. In use with a cartridge, the inhaler's gear mechanism 363 can reconfigure a cartridge by movement of sled 317 during closing of the inhaler, from a cartridge containment configuration after a cartridge is installed on the inhaler housing or mounting area to a dosing configuration when the inhaler is closed. Movement of the mouthpiece 330 to an open inhaler configuration after inhalation with a cartridge 170, or to a disposable configuration after a subject has effectuated dosing of a dry powder formulation. In the embodiment illustrated herein, the hinge and gear mechanism are provided at the distal end of the inhaler, however, other configurations can be provided so that the inhaler opens and closes to load or unload a cartridge as a clam-like configuration.
As shown in
In one embodiment, housing 320 comprises one or more component parts, for example, a top portion 316 and a bottom portion 318. The top and bottom portions are configured to adapt to one another in a tight seal, forming an enclosure which houses sled 317 and the hinge and/or gear mechanisms 363. Housing 320 is also configured to have one or more openings 309 to allow air flow into the interior of the housing, a locking mechanism 313, such as protrusions or snap rings to engage and secure mouthpiece cover portion 308 in the closed position of inhaler 302. Housing 320 is also configured to have a cartridge holder or cartridge mounting area 315 which is configured to correspond to the type of cartridge to be used with the inhaler. In this embodiment, the cartridge placement area or holder is an opening in the top portion of housing 320 which opening also allows the cartridge bottom portion or container to lie on sled 317 once a cartridge is installed in inhaler 302. The housing can further comprise grasping areas 304, 307 configured to aid a user of the inhaler to firmly or securely grip the inhaler to open it to load or unload a cartridge. Housing 320 can further comprise flanges configured to define an air channel or conduit, for example, two parallel flanges 303 which are also configured to direct air flow into the inhaler air inlet 310 and into a cartridge air inlet of the cartridge air conduit positioned in the inhaler. Flanges 310 are also configured to prevent a user from obstructing inlet port 310 of inhaler 302.
In one particular embodiment illustrated in
Inhaler 302 can further include a mouthpiece cap 342 to protect the oral placement portion of the mouthpiece.
In embodiments disclosed herein, inhaler apertures, for example, 355, 955 can be provided with a seal, for example, crushed ribs, conformable surfaces, gaskets, and o-rings to prevent air flow leakage into the system so that the airflow only travels through the cartridge. In other embodiment, to effectuate the seal, the seal can be provided to the cartridge. The inhalers are also provided with one or more zones of deagglomeration, which are configured to minimize build-up of powder or deposition. Deagglomeration zones are provided, for example, in the cartridge, including, in the container and the dispensing ports, and at one or more locations in the air conduit of the mouthpiece.
Cartridge embodiments for use with the inhalers are describe above, such as cartridges 150, 170, illustrated, respectively, in
In certain embodiments, the cartridge comprises a lid or top and a container having one or more apertures, a containment configuration and dosing configuration, an outer surface, an inner surface defining an internal volume; and the containment configuration restricts communication to the internal volume and the dispensing configuration forms an air passage through the internal volume to allow an air flow to enter and exit the internal volume in a predetermined manner. For example, the cartridge container can be configured so that an airflow entering the cartridge air inlet is directed across the air outlets within the internal volume to meter the medicament leaving the cartridge so that rate of discharge of a powder is controlled; and wherein airflow in the cartridge can tumble substantially perpendicular to the air outlet flow direction, mix and fluidize a powder in the internal volume prior to exiting through dispensing apertures.
In one embodiment, the cartridge can be coded with one or more indicators, including, label, etching, color, frostings, flanges, ridges, and the like. For example, if color is selected, color pigments of various types, which are compatible with plastics and pharmaceutical formulations or that are pharmaceutically-acceptable, can be incorporated during manufacturing of the cartridge. In this and other embodiments, the color can denote a specific active ingredient or dose strength, for example, a green lid can be indicative of 6 units of an FDKP and insulin formulation. Pharmaceutically acceptable colors can be green, blue, teal, poppy, violet, yellow, orange, etc.
In another embodiment, a translational cartridge 170 is illustrated in
In other embodiments of the cartridge, the cartridge can be adapted to the dry powder inhalers which are suitable for use with an inhaler with a rotatable mechanism for moving the inhaler or cartridge from a containment configuration to a dosing position, wherein the cartridge top is movable relative to the container, or for moving the container relative to the top in achieving alignment of the dispensing ports with the container to a dosing position, or moving either the container or the top to the containment configuration.
In embodiments described herein, cartridges can be configured to deliver a single unit, pre-metered dose of a dry powder medicament in various amounts depending on the dry powder formulation used. Cartridge examples such as cartridge 150, 170 can be structurally configured to contain a dose of, for example, from 0.1 mg to about 50 mg of a dry powder formulation. Thus the size and shape of the container can vary depending on the size of the inhaler and the amount or mass of powder medicament to be delivered. For example, the container can have a relatively cylindrical shape with two opposing sides relatively flat and having an approximate distance between of from about 0.4 cm to about 2.0 cm. To optimize the inhaler performance, the height of the inside of the cartridge along the Y axis may vary depending on the amount of powder that is intended to be contained within the chamber. For example, a fill of 5 mg to 15 mg of powder may optimally require a height of from about 0.6 cm to about 1.2 cm.
In an embodiment, a medicament cartridge for a dry powder inhaler is provided, comprising: an enclosure configured to hold a medicament; at least one inlet port to allow flow into the enclosure, and at least one dispensing port to allow flow out of the enclosure; the at least one inlet port is configured to direct at least a portion of the flow entering the at least one inlet port at the at least one dispensing port within the enclosure in response to a pressure differential. In one embodiment, the inhaler cartridge is formed from a high density polyethylene plastic. The cartridge has a container which has an internal surface defining an internal volume and comprising a bottom and side walls contiguous with one another, and having one or more openings. The can have a cup-like structure and has one opening with a rim and it is formed by a cartridge top and a container bottom which are configurable to define one or more inlet ports and one or more dispensing ports. The cartridge top and container bottom are configurable to a containment position, and a dispensing or dosing position.
In embodiments described herein, a dry powder inhaler and cartridge form an inhalation system which can be structurally configured to effectuate a tunable or modular airflow resistance, as the system can be effectuated by varying the cross-sectional area at any section of its airflow conduits. In one embodiment, the dry powder inhaler system can have an airflow resistance value of from about 0.065 to about 0.200 (√kPa)/liter per minute. In other embodiments, a check valve may be employed to prevent air flow through the inhaler until a desired pressure drop, such as 4 kPa has been achieved, at which point the desired resistance reaches a value within the range given herewith.
In the embodiments disclosed herein, the dry powder inhaler system is configured to have a predetermined flow balance distribution in use, having a first flow pathway through the cartridge and second flow pathway through, for example, the mouthpiece air conduit.
In an alternate embodiment of a cartridge,
In one aspect of this embodiment, container 977, 983 can optionally have one or more protrusions, or stems extending from the undersurface or inner surface of the cartridge top or lid 976, 982 into void or internal volume 974, 990 of the container 977, 983. The protrusions or deflector 978, 984 can be of any shape or size as long as they can direct or deflect flow, particularly downwardly in the container during an inhalation in the dosing configuration. In particular embodiments, the protrusion 978, 984 can be configured in the lid of a cartridge extending from the surface facing the internal volume of the container 975, 981 in proximity to an air inlet 980, 986 in the dosing configuration. Alternatively, the protrusion 978, 984 can be designed in the surface of the mouthpiece for contacting the internal volume of a container and in proximity to the air inlet formed by the container in the dosing configuration in a single use inhaler (
In a particular embodiment, a single use, unit dose disposable inhaler structurally configured to have a powder containment configuration and a powder dosing configuration, the inhaler comprises two elements and has a top surface, bottom surface, a proximal end and a distal end; a first element and a second element; the first element has at least three openings and comprises a mouthpiece at the proximal end; a body, an undersurface configured to adapt to the second element and has a protruding structure or stem configured to extending downwardly into the second element; the first element further configured to have a first flow pathway having an air inlet, and an air outlet for delivering an airstream into a subject's mouth during an inhalation; and a third opening configured to form an air conduit and a second flow pathway with the second element in the powder dosing configuration; the second element is configured to adapt to the undersurface of the first element and is moveable relative to the first element to form an inhaler containment configuration or a dosing configuration; the second comprises a container or reservoir has an opening configured to receive and retain a powder and form an air inlet and an air conduit or a second flow pathway with the first element in the dosing configuration; wherein in the powder dispensing configuration a powder is exposed to ambient air to be dispensed or discharged during an inhalation. In this and other embodiments, a dry powder inhaler in a dosing configuration comprises a stem-like or protruding structure extending downwardly into the container void or chamber and serves to deflect powder. In this embodiment, and airflow entering the container or powder reservoir travels primarily in a pathway closely related to the shape of the container which is structurally configured in the shape substantially of the letter U having the portion of the air conduit extending from the air inlet in the form of an open letter s on its side, and powder is lifted and translated or transported from this second airstream to the first airstream into a subject's mouth and airways.
In an alternate embodiment, the substantially U configuration of the second flow pathway can be adapted to a multiple use inhaler wherein the inhaler and replaceable cartridge are configured similarly as described above. In this embodiment, a cartridge top can be configured to have a protrusion or stem which extends into the void of the container to deflect an air flow entering a cartridge
The balance of mass flow within an inhaler is approximately 20% to 70% of the volume going through the cartridge flow pathway, and about 30% to 90% through the beginning portion of the mouthpiece conduit. In this embodiment, the airflow distribution through the cartridge mixes the medicament in a tumbling manner to fluidize or aerosolize the dry powder medicament in the cartridge container. Airflow fluidizing the powder within the container then lifts the powder and gradually lets the powder particles exit the cartridge container through the dispensing ports, then shear from the airflow entering the mouthpiece conduit converges with the airflow containing medicament emanating from the cartridge container. Predetermined or metered exiting airflow from the cartridge converge with bypass airflow entering the air conduit of the mouthpiece to further dilute and deagglomerate the powder medicament prior to exiting the mouthpiece outlet port and entering the patient.
In yet another embodiment, an inhalation system for delivering a dry powder formulation to a patient is provided, comprising an inhaler comprising a container mounting area configured to receive a container, and a mouthpiece having at least two inlet apertures and at least one exit aperture; wherein one inlet aperture of the at least two inlet apertures is in fluid communication with the container area, and one of the at least two inlet apertures is in fluid communication with the at least one exit aperture via a flow path configured to bypass the container area to deliver the dry powder formulation to the patient; wherein the flow conduit configured to bypass the container area delivers 30% to 90% of the total flow going through the inhaler during an inhalation.
In another embodiment, an inhalation system for delivering a dry powder formulation to a patient is also provided, comprising a dry powder inhaler comprising a container region and a container; the dry powder inhaler and container combined are configured to have rigid flow conduits in a dosing configuration and a plurality of structural regions that provide a mechanism for powder deagglomeration of the inhalation system in use; wherein at least one of the plurality of mechanisms for deagglomeration is an agglomerate size exclusion aperture in the container region having a smallest dimension between 0.25 mm and 3 mm. The term “rigid flow conduits” denotes air conduits of the inhalation system that do not change in geometry after repeated use, i.e., the conduits remain the same or constant and are not variable from use to use, as opposed to systems which operate with puncturing mechanisms for use with capsules and blisters which may exhibit variability in conduit configuration from capsule to capsule or blister to blister.
In an alternate embodiment, an inhalation system for delivering a dry powder formulation to a patient is provided, comprising a dry powder inhaler comprising a mouthpiece and a container; the dry powder inhaler and container combined are configured to have rigid flow conduits in a dosing configuration and a plurality of structural regions that provide a mechanism for powder deagglomeration of the inhalation system in use; wherein at least one of the plurality of mechanisms for deagglomeration is an air conduit configured in the mouthpiece which directs flow at an exit aperture in fluid communication with the container. In particular embodiments, the inhalation system includes a container further comprising a mechanisms for cohesive powder deagglomeration which comprises a cup-like structure configured to guide a flow entering the container to rotate, re-circulating in the internal volume of the cup-like structure and lifting up a powder medicament so as to entrain the powder agglomerates in the flow until the powder mass is small enough prior to exiting the container. In this embodiment, the cup-like structure has one or more radii configured to prevent flow stagnation.
In embodiments describe herein, the cartridge is structurally configured having the inlet opening in close proximity to the dispensing ports in a horizontal and vertical axis. For example, the proximity of the inlet to the dispensing ports can be immediately next to the air inlet to about within one cartridge width, although this relationship can vary depending on the flow rate, the physical and chemical properties of the powder. Because of this proximity, flow from the inlet crosses the opening to the dispensing ports within the cartridge creating a flow configuration that inhibits fluidized powder or powder entrained within the airflow, from exiting the cartridge. In this manner, during an inhalation maneuver, flow entering the cartridge container can effectuate tumbling of the dry powder formulation in the cartridge container, and fluidized powder approaching the exit or dispensing ports of a cartridge can be impeded by flow entering the inlet port of the cartridge, thereby, flow within the cartridge can be restricted from exiting the cartridge container. Due to differences in inertia, density, velocity, charge interaction, position of the flow, only certain particles can navigate the path needed to exit the dispensing ports. Particles that do not pass through the exit port must continue to tumble until they possess the proper mass, charge, velocity or position. This mechanism, in effect, can meter the amount of medicament leaving the cartridge and can contribute to deagglomeration of powder. To further help meter the exiting fluidized powder, the size and number of dispensing ports can be varied. In one embodiment, two dispensing ports are used, configured to be circular in shape, each 0.10 cm in diameter and positioned near the inlet aperture about middle center line of the container to about 0.2 cm from the centerline towards the air inlet port. Other embodiments can, for example, have dispensing ports of various shapes including rectangular wherein the cross-sectional area of the one or more dispensing ports ranges from 0.05 cm2 to about 0.25 cm2. In some embodiments, the sizes ranging of the dispensing ports can be from about 0.05 cm to about 0.25 cm in diameter. Other shapes and cross-sectional areas can be employed as long as they are similar in cross-sectional area to the values given herewith. Alternatively, for more cohesive powders larger cross sectional area of the dispensing port can be provided. In certain embodiments, the cross sectional area of the dispensing port can be increased depending on the size of the agglomerates relative to the minimum opening dimension of the port or ports so that the length relative to the width of the port remains large. In one embodiment, the intake aperture is wider in dimension than the width of the dispensing port or ports. In embodiments wherein the intake aperture is rectangular, the air inlet aperture comprises a width ranging from about 0.2 cm to about the maximal width of the cartridge. In one embodiment the height is about 0.15 cm, and width of about 0.40 cm. In alternate embodiments, the container can have a height of from about 0.05 cm to about 0.40 cm. In particular embodiments, the container can be from about 0.4 cm to about 1.2 cm in width, and from about 0.6 cm to about 1.2 cm in height. In an embodiment, the container comprise one or more dispensing ports having and each of the ports can have a diameter between 0.012 cm to about 0.25 cm.
In particular inhalation systems, a cartridge for a dry powder inhaler, comprising a cartridge top and a container is provided, wherein the cartridge top is configured relatively flat and having one or more openings and one or more flanges having tracks configured to engage the container; the container having an inner surface defining an internal volume and is moveably attached to the tracks on the one or more flanges on the cartridge top and configurable to attain a containment position and a dispensing or dosing position by moving along the tracks of the one or more flanges.
In another embodiment, the inhalation system comprises an enclosure having one or more exit ports configured to exclude a powder mass of a dry powder composition having a smallest dimension greater than 0.5 mm and less than 3 mm. In one embodiment, a cartridge for a dry powder inhaler, comprising an enclosure having two or more rigid parts; the cartridge having one or more inlet ports and one or more dispensing ports, wherein one or more inlet ports have a total cross-sectional area which is larger than the total cross-sectional area of the dispensing ports, including wherein the total cross-sectional area of one or more dispensing ports ranges from 0.05 cm2 to about 0.25 cm2.
The medicament container or powder reservoir is structurally configured to have two opposing, relatively curvilinear sides which can direct airflow. In one embodiment, flow entering the air inlet during an inhalation enters the container or powder reservoir and can circulate within the interior of the container about an axis relatively perpendicular to the axis of the dispensing ports, and thereby, the flow can lift, tumble and effectively fluidize a powder medicament contained in the cartridge or reservoir prior to exiting through dispensing ports or outlets. In another embodiment, flow entering the air inlet during an inhalation can lift powder from the container of powder reservoir and translate or transport the powder particles entrained in the airstream into a second stream in the inhaler. In this and other embodiments, fluidized powder in the air conduit can be further deagglomerated into finer powder particles by a change in direction or velocity, i.e., acceleration or deceleration of the particles in the flow pathway. In certain embodiments, the change in acceleration or deceleration can be accomplished by changing the angle and geometries of, for example, the dispensing port or ports, the mouthpiece conduit and/or its interfaces. In the inhalers described herewith, the mechanism of fluidization and acceleration of particles as they travel through the inhaler are methods by which deagglomeration and delivery of a dry powder formulation is effectuated.
In one embodiment, a method for deagglomerating and dispersing a dry powder formulation for inhalation, comprising the steps of: generating an airflow in a dry powder inhaler comprising a mouthpiece and a container having at least one inlet port and at least one dispensing port and containing a dry powder formulation; the container forming an air conduit between the at least one inlet port and the at least one dispensing port and the inlet port directs a portion of the airflow entering the container to the at least one dispensing port; allowing airflow to tumble powder within the container so as to lift and mix the dry powder medicament in the container to form an airflow medicament mixture; and accelerating the airflow exiting the container through the at least one dispensing port. In this embodiment, the powder medicament that passes through the dispensing ports can immediately accelerate due to reduction in cross-sectional area of the exit ports relative to the inlet port. This change in velocity may further deagglomerate the fluidized and aerosolized powder medicament during inhalation. Additionally, because of the inertia of the particles or groups of particles in the fluidized medicament, the velocity of the particles leaving the dispensing ports is not the same. The faster moving air flow in the mouthpiece conduit imparts a drag or shear force on each particle or group of particles of the slower moving fluidized powder leaving the exit or dispensing port or ports, which can further deagglomerate the medicament.
The powder medicament that passes through the dispensing port or ports immediately accelerates due to reduction in cross-sectional area of the exit or dispensing ports relative to the container, which are designed to be narrower in cross-sectional area than the air inlet of the container. This change in velocity may further deagglomerate the fluidized powder medicament. Additionally, because of the inertia of the particles or groups of particles in the fluidized medicament, the velocity of the particles leaving the dispensing ports and the velocity of the flow passing the dispensing ports is not the same.
In embodiments described herein, powder exiting the dispensing ports can further accelerate, for example, by an imparted change in direction and/or velocity of the fluidized medicament. Directional change of fluidized powder leaving the dispensing port and entering the mouthpiece conduit can occur at an angle of approximately 0° to about 180°, for example approximately 90°, to the axis of the dispensing port. Change in flow velocity and direction may further deagglomerate the fluidized powder through the air conduits. The change in direction can be accomplished through geometric configuration changes of the air flow conduit and/or by impeding the air flow exiting the dispensing ports with a secondary air flow entering the mouthpiece inlet. The fluidized powder in the mouthpiece conduit expands and decelerates as it enters the oral placement portion of the mouthpiece prior to exiting due to a cross-sectional area increase in the conduit. Gas trapped within agglomerates also expands and may help to break apart the individual particles. This is a further deagglomeration mechanism of the embodiments described herein. Airflow containing medicament can enter the patient's oral cavity and be delivered effectively, for example, into the pulmonary circulation.
Each of the deagglomeration mechanisms described herein and part of the inhalation system represent a multi-stage approach which maximizes powder deagglomeration. Maximal deagglomeration and delivery of powder can be obtained by optimizing the effect of each individual mechanism, including, one or more acceleration/deceleration conduits, drag, or expansion of gas trapped within the agglomerates, interactions of powder properties with those of the inhaler components material properties, which are integral characteristics of the present inhaler system. In the embodiments described herein, the inhalers are provided with relatively rigid air conduits or plumbing system to maximize deagglomeration of powder medicament so that there is consistency of the powder medicament discharge from the inhaler during repeated use. Since the present inhalers are provided with conduits which are rigid or remain the same and cannot be altered, variations in the air conduit architecture resulting from puncturing films or peeling films associated with prior art inhalers using blister packs are avoided.
In one embodiment, there is provided a method of deagglomerating a powder formulation in a dry powder inhalation system, comprising: providing the dry powder formulation in a container having an internal volume to a dry powder inhaler; allowing a flow to enter the container which is configured to direct a flow to lift, entrain and circulate the dry powder formulation until the powder formulation comprises powder masses sufficiently small to pass through one or more dispensing apertures into a mouthpiece. In this embodiment, the method can further comprise the step of accelerating the powder masses entrained in the flow leaving the one or more dispensing apertures and entering the mouthpiece.
In embodiments disclosed herein, a dry powder medicament is dispensed with consistency from the inhaler in less than about 2 seconds. The present inhaler system has a high resistance value of approximately 0.065 to about 0.20 (√kPa)/liter per minute. Therefore, in the inhalation system comprising a cartridge, peak inhalation pressure drops of between 2 and 20 kPa produce resultant peak flow rates of about through the system of between 7 and 70 L/min. In some embodiments, the pressure differential for the inhaler and cartridge system can be below 2 kPa. These flow rates result in greater than 75% of the cartridge contents dispensed in fill masses between 1 and 30 mg of powder or greater amounts. In some embodiments, these performance characteristics are achieved by end users within a single inhalation maneuver to produce cartridge dispense percentage of greater than 90%. In other embodiments, these performance characteristics are achieved by end users within a single inhalation maneuver to produce cartridge dispense percentage of about 100%. In certain embodiments, the inhaler and cartridge system are configured to provide a single dose by discharging powder from the inhaler as a continuous flow of powder delivered to a patient. In some embodiments, it may be possible to configure the inhalation system to deliver powder in use as one or more pulses of powder discharge depending on the particle sizes. In one embodiment, an inhalation system for delivering a dry powder formulation to a patient's lungs is provided, comprising a dry powder inhaler configured to have flow conduits with a total resistance to flow in a dosing configuration ranging in value from about 0.065 to about 0.200 (√kPa)/liter per minute. In this and other embodiments, the total resistance to flow of the inhalation system is relatively constant across a pressure differential range of between 0.5 kPa and 7 kPa.
The structural configuration of the inhalation system allows the deagglomeration mechanism to produce respirable fractions greater than 50% and particles of less than 5.8 μm. The inhalers can discharge greater than 85% of a powder medicament contained within a container during an inhalation maneuver. Generally, the inhalers herein depicted in figures herewith can discharge greater that 90% of the cartridge or container contents in less than 3 seconds at pressure differentials between 2 and 5 kPa with fill masses ranging up to 30 mg.
In another embodiment, the present systems have a lower limit of performance. This performance limit is assigned based on inhalation of a dry powder as described herein where a median particular particle size distribution is attained. A graph of peak inspiratory pressures, PIP versus AUC can be formed where a triangular area exists where PIP values are physically impossible to attain for a device given the AUC values. However, an acceptable area can be formed based on a horizontal and vertical lines representing passing criteria. The inhalation systems described herein have a lower limit for acceptable performance of a PIP of about 2 kPa and an AUC of at least about 1.0, 1.1 or 1.2 kPa*sec.
In other embodiments, a lower limit and an upper limit for AUC exist. For example, AUC can range from about 1.0 to about 15 kPa*sec, from about 1.0 to about 10 kPa*sec, form about 1.1 to about 15 kPa*sec, from about 1.2 to about 10 kPa*sec, from about 1.2 to about 15 kPa*sec, or from about 1.2 to about 10 kPa*sec.
In another embodiment, adequately de-agglomerated doses of a dry powder medicament using a high resistance dry powder inhaler are accomplished by providing a high resistance dry powder inhaler containing a dose of the dry powder medicament; inhaling from the inhaler with sufficient force to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and generating an area under the curve in the first second (AUC0-1sec) of a inspiratory pressure-time curve of at least about 1.0, 1.1, or 1.2 kPa*second; wherein VMGD (×50) of the emitted powder is less than about 5 um. In some embodiments a patient exerts a peak inspiratory pressure in two (2) seconds (PIP2 seconds) of greater than or equal to 2 kPa and less than or equal to 15 or 20 kPa. In another embodiment, the dry powder medicament includes microparticles with a median particle size VMGD (×50) of the emitted powder particles is not greater than 1.33 times the median particle size when the inhaler is used optimally. In this and other embodiments, optimal inhaler use by a patient is when a patient exerts a peak inspiratory pressure in two (2) seconds (PIP2 seconds) of about 6 kPa.
The high resistance dry powder inhaler, in some embodiments, comprises a dose of a dry powder medicament is inhaled by the patient with sufficient force (or effort) to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and generating an area under the curve in the first second (AUC0-1sec) of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec; wherein greater than 75% of the dry powder dose is discharged or emitted from the inhaler as powder particles. In some embodiments the VMGD of the emitted particles is less than about 5 microns.
Adequately de-agglomerated doses of a dry powder medication using a high resistance dry powder inhaler can be achieved by providing a high resistance dry powder inhaler containing a dose of a dry powder medicament; inhaling from the inhaler with sufficient force to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and generating an area under the curve in the first second (AUC0-1sec) of a inspiratory pressure-time curve of at least about 1.0, 1.1, or 1.2 kPa*second; wherein VMGD (×50) of the emitted powder is less than about 5 um. In another embodiment, the dry powder medicament includes microparticles with a median particle size VMGD (×50) of the emitted powder particles is not greater than 1.33 times the median particle size when the inhaler is used optimally.
While the present inhalers are primarily described as breath-powered, in some embodiments, the inhaler can be provided with a source for generating the pressure differential required to deagglomerate and deliver a dry powder formulation. For example, an inhaler can be adapted to a gas powered source, such as compressed gas stored energy source, such as from a nitrogen can, which can be provided at the air inlet ports. A spacer can be provided to capture the plume so that the patient can inhale at a comfortable pace.
In embodiments described herewith, the inhaler can be provided as a reusable inhaler or as a single use inhaler. In alternate embodiments, a similar principle of deagglomeration can be adapted to multidose inhalers, wherein the inhaler can comprise a plurality of, for example, cartridge like structures in a single tray and a single dose can be dialed as needed. In variations of this embodiment, the multidose inhaler can be configured to provide enough doses, for example, for a day, a week or a month's supply of a medication. In the multidose embodiments described herein, end-user convenience is optimized. For example, in prandial regimens, breakfast, lunch and dinner dosing is achieved with a system configured to provide dosing for a course of 7 days in a single device. Additional end-user convenience is provided by a system configured with an indicator mechanism that indicates the day and dosing, for example, day 3 (D3), lunchtime (L).
In one embodiment, the dry powder medicament may comprise, for example, pharmaceutically-acceptable carrier or excipient, for example, a diketopiperazine and a pharmaceutically active ingredient. The dry powder can comprise a diketopiperazine having the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl. In this embodiment, the dry powder composition can comprise a diketopiperazine salt.
In this embodiment, the pharmaceutically active ingredient or active agent can be any type depending on the disease or condition to be treated. In another embodiment, the diketopiperazine can include, for example, symmetrical molecules and asymmetrical diketopiperazines having utility to form particles, microparticles and the like, which can be used as carrier systems for the delivery of active agents to a target site in the body. The particles, microparticles, and the like can comprise a diketopiperazine having the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl. In this embodiment, the dry powder composition can comprise a diketopiperazine salt. The term ‘active agent’ is referred to herein as the therapeutic agent, or molecule such as protein or peptide or biological molecule, to be encapsulated, associated, joined, complexed or entrapped within or adsorbed onto the diketopiperazine formulation. Any form of an active agent can be combined with a diketopiperazine. The drug delivery system can be used to deliver biologically active agents having therapeutic, prophylactic or diagnostic activities.
One class of drug delivery agents that has been used to produce microparticles that overcome problems in the pharmaceutical arts such as drug instability and/or poor absorption, are the 2,5-diketopiperazines. 2,5-diketopiperazines are represented by the compound of the general Formula 1 as shown below wherein the ring atoms E1 and E2 at positions 1 and 4 are either O or N to create the substitution analogs diketomorpholine and diketodioxane, respectively, and at least one of the side-chains R1 and R2 located at positions 3 and 6 respectively contains a carboxylic acid (carboxylate) group. Compounds according to Formula 1 include, without limitation, diketopiperazines, diketomorpholines and diketodioxanes and their substitution analogs.
As used herein, “a diketopiperazine” or “a DKP” includes diketopiperazines and pharmaceutically acceptable salts, derivatives, analogs and modifications thereof falling within the scope of the general Formula 1.
These 2,5 diketopiperazines have been shown to be useful in drug delivery, particularly those bearing acidic R1 and R2 groups (see for example U.S. Pat. Nos. 5,352,461 entitled “Self Assembling Diketopiperazine Drug Delivery System;” 5,503,852 entitled “Method For Making Self-Assembling Diketopiperazine Drug Delivery System;” 6,071,497 entitled “Microparticles For Lung Delivery Comprising Diketopiperazine;” and 6,331,318 entitled “Carbon-Substituted Diketopiperazine Delivery System,” each of which is incorporated herein by reference in its entirety for all that it teaches regarding diketopiperazines and diketopiperazine-mediated drug delivery). Diketopiperazines can be formed into drug adsorbing microparticles. This combination of a drug and a diketopiperazine can impart improved drug stability and/or absorption characteristics. These microparticles can be administered by various routes of administration. As dry powders these microparticles can be delivered by inhalation to specific areas of the respiratory system, including the lung.
The fumaryl diketopiperazine (3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; FDKP) is one preferred diketopiperazine for pulmonary applications:
FDKP provides a beneficial microparticle matrix because it has low solubility in acid but is readily soluble at neutral or basic pH. These properties allow FDKP to crystallize under acidic conditions and the crystals self-assemble to form particles. The particles dissolve readily under physiological conditions where the pH is neutral. In one embodiment, the microparticles disclosed herein are FDKP microparticles loaded with an active agent such as insulin.
FDKP is a chiral molecule having trans and cis isomers with respect to the arrangement of the substituents on the substituted carbons on the diketopiperazine ring. As described in US Patent Application Publication No. 2010/0317574, entitled “Diketopiperazine microparticles with defined isomer contents,” more robust aerodynamic performance and consistency of particle morphology can be obtained by confining the isomer content to about 45-65% trans. Isomer ratio can be controlled in the synthesis and recrystallization of the molecule. Exposure to base promotes ring epimerization leading to racemization, for example during the removal of protecting groups from the terminal carboxylate groups. However increasing methanol content of the solvent in this step leads to increased trans isomer content. The trans isomer is less soluble than the cis isomers and control of temperature and solvent composition during recrystallization can be used to promote or reduce enrichment for the trans isomer in this step.
Microparticles having a diameter of between about 0.5 and about 10 microns can reach the lungs, successfully passing most of the natural barriers. A diameter of less than about 10 microns is required to navigate the turn of the throat and a diameter of about 0.5 microns or greater is required to avoid being exhaled. Diketopiperazine microparticles with a specific surface area (SSA) of between about 35 and about 67 m2/g exhibit characteristics beneficial to delivery of drugs to the lungs such as improved aerodynamic performance and improved drug adsorption.
As described in PCT Publication No. WO2010144789, entitled “Diketopiperazine microparticles with defined specific surface areas,” the size distribution and shape of FDKP crystals are affected by the balance between the nucleation of new crystals and the growth of existing crystals. Both phenomena depend strongly on concentrations and supersaturation in solution. The characteristic size of the FDKP crystal is an indication of the relative rates of nucleation and growth. When nucleation dominates, many crystals are formed but they are relatively small because they all compete for the FDKP in solution. When growth dominates, there are fewer competing crystals and the characteristic size of the crystals is larger.
Crystallization depends strongly on supersaturation which, in turn, depends strongly on the concentration of the components in the feed streams. Higher supersaturation is associated with the formation of many small crystals; lower supersaturation produces fewer, larger crystals. In terms of supersaturation: 1) increasing the FDKP concentration raises the supersaturation; 2) increasing the concentration of ammonia shifts the system to higher pH, raises the equilibrium solubility and decreases the supersaturation; and 3) increasing the acetic acid concentration increases the supersaturation by shifting the endpoint to lower pH where the equilibrium solubility is lower. Decreasing the concentrations of these components induces the opposite effects.
Temperature affects FDKP microparticle formation through its effect on FDKP solubility and the kinetics of FDKP crystal nucleation and growth. At low temperatures, small crystals are formed with high specific surface area. Suspensions of these particles exhibit high viscosity indicating strong inter-particle attractions. A temperature range of about 12° C. to about 26° C. produced particles with acceptable (or better) aerodynamic performance with various inhaler systems including inhaler systems disclosed herein.
These present devices and systems are useful in the pulmonary delivery for powders with a wide range of characteristics. Embodiments of the invention include systems comprising an inhaler, an integral or installable unit dose cartridge, and powder of defined characteristic(s) providing an improved or optimal range of performance. For example, the devices constitute an efficient deagglomeration engine and thus can effectively deliver cohesive powders. This is distinct from the course pursued by many others who have sought to develop dry powder inhalation systems based on free flowing or flow optimized particles (see for example U.S. Pat. Nos. 5,997,848 and 7,399,528, US Patent Application No. 2006/0260777; and Ferrari et al. AAPS PharmSciTech 2004; 5 (4) Article 60). Thus, embodiments include systems plus a cohesive powder.
Cohesiveness of a powder can be assessed according to its flowability or correlated with assessments of shape and irregularity such as rugosity. As discussed in the US Pharmacopeia USP 29, 2006 section 1174 four techniques commonly used in the pharmaceutical arts to assess powder flowability: angle of repose; compressibility (Carr's) index and Hausner ratio; flow through an orifice; and shear cell methods. For the latter two no general scales have been developed due to diversity of methodology. Flow through an orifice can be used to measure flow rate or alternatively to determine a critical diameter that allows flow. Pertinent variables are the shape and diameter of the orifice, the diameter and height of the powder bed, and the material the apparatus is made of. Shear cell devices include cylindrical, annular, and planar varieties and offer great degree of experimental control. For either of these two methods description of the equipment and methodology are crucial, but despite the lack of general scales they are successfully used to provide qualitative and relative characterizations of powder flowability.
Angle of repose is determined as the angle assumed by a cone-like pile of the material relative to a horizontal base upon which it has been poured. Hausner ratio is the unsettled volume divided by the tapped volume (that is the volume after tapping produces no further change in volume), or alternatively the tapped density divided by the bulk density. The compressibility index (CI) can be calculated from the Hausner ratio (HR) as
CI=100×(1−(1/HR)).
Despite some variation in experimental methods generally accepted scales of flow properties have been published for angle of repose, compressibility index and Hausner ratio (Carr, R L, Chem. Eng. 1965, 72:163-168).
The Conveyor Equipment Manufacturers Association (CEMA) code provides a somewhat different characterization of angle of repose.
Powders with a flow character according to the table above that is excellent or good can be characterized in terms of cohesiveness as non- or minimally cohesive, and the powders with less flowability as cohesive and further dividing them between moderately cohesive (corresponding to fair or passable flow character) and highly cohesive (corresponding to any degree of poor flow character). In assessing angle of repose by the CEMA scale powders with an angle of repose ≧30° can be considered cohesive and those ≧40° highly cohesive. Powders in each of these ranges, or combinations thereof, constitute aspects of distinct embodiments of the invention.
Cohesiveness can also be correlated with rugosity, a measure of the irregularity of the particle surface. The rugosity is the ratio of the actual specific surface area of the particle to that for an equivalent sphere:
Methods for direct measurement of rugosity, such as air permeametry, are also known in the art. Rugosity of 2 or greater has been associated with increased cohesiveness. It should be kept in mind that particle size also affects flowability so that larger particles (for example on the order of 100 microns) can have reasonable flowability despite somewhat elevated rugosity. However for particles useful for delivery into the deep lung, such as those with primary particle diameters of 1-3 microns, even modestly elevated rugosity or 2-6 may be cohesive. Highly cohesive powders can have rugosities ≧10 (see Example A below).
Many of the examples below involve the use of dry powders comprising FDKP. The component microparticles are self-assembled aggregates of crystalline plates. Powders comprised of particles with plate-like surfaces are known to have generally poor flowability, that is, they are cohesive. Indeed smooth spherical particles generally have the best flowability, with flowability generally decreasing as the particles become oblong, have sharp edges, become substantially two dimensional and irregularly shaped, have irregular interlocking shapes, or are fibrous. While not wanting to be bound, it is the Applicants' present understanding that the crystalline plates of the FDKP microparticles can interleave and interlock contributing to the cohesiveness (the inverse of flowability) of bulk powders comprising them and additionally making the powder more difficult to deagglomerate than less cohesive powders. Moreover factors affecting the structure of the particles can have effects on aerodynamic performance. It has been observed that as specific surface area of the particles increases past a threshold value their aerodynamic performance, measured as respirable fraction, tends to decrease. Additionally FDKP has two chiral carbon atoms in the piperazine ring, so that the N-fumaryl-4-aminobutyl arms can be in cis or trans configurations with respect to the plane of the ring. It has been observed that as the trans-cis ratio of the FDKP used in making the microparticles departs from an optimal range including the racemic mixture respirable fraction is decreased and at greater departures from the preferred range the morphology of the particles in SEM becomes visibly different. Thus embodiments of the invention include systems of the device plus diketopiperazine powders with specific surface areas within preferred ranges, and the device plus FDKP powders with trans-cis isomer ratios within preferred ranges.
FDKP microparticles either unmodified or containing a drug, for example insulin, constitute highly cohesive powders. FDKP microparticles have been measured to have a Hausner ratio of 1.8, a compressibility index of 47%, and an angle of repose of 40°. Insulin loaded FDKP microparticles (TECHNOSPHERE® Insulin; TI; MannKind Corporation, Valencia, Calif.) have been measured to have a Hausner ratio of 1.57, a compressibility index of 36%, and an angle of repose of 50°±3°. Additionally in critical orifice testing it was estimated that to establish flow under gravity an orifice diameter on the order of 2 to 3 feet (60-90 cm) would be needed (assumes a bed height of 2.5 feet; increased pressure increased the size of the diameter needed). Under similar conditions a free flowing powder would require an orifice diameter on the order of only 1-2 cm (Taylor, M. K. et al. AAPS PharmSciTech 1, art. 18).
Accordingly, in one embodiment, the present inhalation system comprises a dry powder inhaler and a container for deagglomerating cohesive powder is provided, comprising a cohesive dry powder having a Carr's index ranging from 16 to 50. In one embodiment, the dry powder formulation comprises a diketopiperazine, including, FDKP and a peptide or protein including an endocrine hormone such as insulin, GLP-1, parathyroid hormone, oxyntomodulin, and others as mentioned elsewhere in this disclosure.
Microparticles having a diameter of between about 0.5 and about 10 microns can reach the lungs, successfully passing most of the natural barriers. A diameter of less than about 10 microns is required to navigate the turn of the throat and a diameter of about 0.5 microns or greater is required to avoid being exhaled. Embodiments disclosed herein show that microparticles with a SSA of between about 35 and about 67 m2/g exhibit characteristics beneficial to delivery of drugs to the lungs such as improved aerodynamic performance and improved drug adsorption.
Disclosed herein are also FDKP microparticles having a specific trans isomer ratio of about 45 to about 65%. In this embodiment, the microparticles provide improved flyability.
In one embodiment, there is also provided a system for the delivery of an inhalable dry powder comprising: a) a cohesive powder comprising a medicament, and b) an inhaler comprising an enclosure defining an internal volume for containing a powder, the enclosure comprising a gas inlet and a gas outlet wherein the inlet and the outlet are positioned so that gas flowing into the internal volume through the inlet is directed at the gas flowing toward the outlet. In an embodiment, the system is useful for deagglomerating a cohesive powder having a Carr's index of from 18 to 50. The system can also be useful for delivering a powder when the cohesive powder has an angle of repose from 30° to 55°. The cohesive powder can be characterized by a critical orifice dimension of ≦3.2 feet for funnel flow or ≦2.4 feet for mass flow, a rugosity >2. Exemplary cohesive powder particles include particles comprising of FDKP crystals wherein the ratio of FDKP isomers in the range of 50% to 65% trans:cis.
In another embodiment, the inhalation system can comprise an inhaler comprising a mouthpiece and upon applying a pressure drop of ≧2 kPa across the inhaler to generate a plume of particles which is emitted from the mouthpiece wherein 50% of the emitted particles have a VMGD of ≦10 micron, wherein 50% of the emitted particles have a VMGD of ≦8 microns, or wherein 50% of the emitted particles have a VMGD of ≦4 microns.
In yet another embodiment, a system for the delivery of an inhalable dry powder comprising: a) a dry powder comprising particles composed of FDKP crystals wherein the ratio of FDKP isomers in the range of 50% to 65% trans:cis, and a medicament; and b) an inhaler comprising a powder containing enclosure, the chamber comprising a gas inlet and a gas outlet; and a housing in which to mount the chamber and defining two flow pathways, a first flow pathway allowing gas to enter the gas inlet of the chamber, a second flow pathway allowing gas to bypass the chamber gas inlet; wherein flow bypassing the enclosure gas inlet is directed to impinge upon the flow exiting the enclosure substantially perpendicular to the gas outlet flow direction.
In certain embodiments, a system for the delivery of an inhalable dry powder is provided, comprising: a) a dry powder comprising particles composed of FDKP crystals wherein the microparticles have a SSA of between about 35 and about 67 m2/g which exhibit characteristics beneficial to delivery of drugs to the lungs such as improved aerodynamic performance and improved drug adsorption per milligram, and a medicament; and b) an inhaler comprising a powder containing enclosure, wherein the enclosure comprises a gas inlet and a gas outlet; and a housing in which to mount the chamber and defining two flow pathways, a first flow pathway allowing gas to enter the gas inlet of the chamber, a second flow pathway allowing gas to bypass the chamber gas inlet; wherein flow bypassing the chamber gas inlet is directed to impinge upon the flow exiting the enclosure substantially perpendicular to the gas outlet flow direction.
A system for the delivery of an inhalable dry powder is also provided, comprising: a) a dry powder comprising a medicament, and b) an inhaler comprising a powder containing cartridge, the cartridge comprising a gas inlet and a gas outlet, and a housing in which to mount the cartridge and defining two flow pathways, a first flow pathway allowing gas to enter the gas inlet of the cartridge, a second flow pathway allowing gas to bypass the enclosure gas inlet, and a mouthpiece and upon applying a pressure drop of ≧2 kPa across the inhaler plume of particles is emitted from the mouthpiece wherein 50% of the emitted particles have a VMGD of ≦10 microns, wherein flow bypassing the cartridge gas inlet is directed to impinge upon the flow exiting the enclosure substantially perpendicular to the gas outlet flow direction.
Active agents for use in the compositions and methods described herein can include any pharmaceutical agent. These can include, for example, synthetic organic compounds, including, vasodialators, vasoconstrictor molecules, neurotransmitter analogs, neurotransmitter antagonists, steroids, anti-nociceptive agents, peptides and polypeptides, polysaccharides and other sugars, lipids, inorganic compound, and nucleic acid molecules, having therapeutic, prophylactic, or diagnostic activities. Peptides, proteins, and polypeptides are all chains of amino acids linked by peptide bonds.
Examples of active agents that can be delivered to a target or site in the body using the diketopiperazine formulations, include hormones, anticoagulants, immunomodulating agents, vaccines, cytotoxic agents, antibiotics, vasoactive agents, neuroactive agents, anaesthetics or sedatives, steroid molecules such as glucocorticoids including fluticasone, budesonide, mometasone, ciclesonide, flunisolide, betamethasone, and triamcinolone, decongestants, antivirals, antisense, antigens, and antibodies. More particularly, these compounds include insulin, heparin (including low molecular weight heparin), calcitonin, felbamate, sumatriptan, parathyroid hormone and active fragments thereof, growth hormone, erythropoietin, AZT, DDI, granulocyte macrophage colony stimulating factor (GM-CSF), lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, beta-galactosidase, exendin, vasoactive intestinal peptide, argatroban, small molecules, including anticancer and inhibitors or analogs of cell receptors such as neurorecptors, including, anti-nociceptive agents; triptans including, Sumatriptan succinate, Almotriptan malate, Rizatriptan benzoate, Zolmitriptan, Eletriptan hydrobromide, Naratriptan hydrochloride, β2-agonists such as salbutamol fenoterol formoterol terbutaline pirbuterol, bitolterol, indacaterol, and the like, and vaccines. Antibodies and fragments thereof can include, in a non-limiting manner, anti-SSX-241-49 (synovial sarcoma, X breakpoint 2), anti-NY-ESO-1 (esophageal tumor associated antigen), anti-PRAME (preferentially expressed antigen of melanoma), anti-PSMA (prostate-specific membrane antigen), anti-Melan-A (melanoma tumor associated antigen) and anti-tyrosinase (melanoma tumor associated antigen).
In certain embodiments, a dry powder formulation for delivering a pharmaceutical formulation to the pulmonary circulation comprises an active ingredient or agent, including, a peptide, a protein, a hormone, analogs thereof or combinations thereof, wherein the active ingredient is insulin, calcitonin, growth hormone, erythropoietin, granulocyte macrophage colony stimulating factor (GM-CSF), chorionic gonadotropin releasing factor, deoxyribonuclease, luteinizing releasing hormone, follicle stimulating hormone (FSH), oxytocin, vasoactive intestinal peptide, parathyroid hormone (including black bear PTH), parathyroid hormone related protein, glucagon-like peptide-1 (GLP-1), exendin, oxyntomodulin, peptide YY, interleukin 2-inducible tyrosine kinase, Bruton's tyrosine kinase (BTK), inositol-requiring kinase 1 (IRE1), or analogs, active fragments, PC-DAC-modified derivatives, or O-glycosylated forms thereof. In particular embodiments, the pharmaceutical composition or dry powder formulation comprises fumaryl diketopiperazine and the active ingredient is one or more selected from insulin, parathyroid hormone 1-34, GLP-1, oxyntomodulin, peptide YY, heparin and analogs thereof; small molecules, including neurotransmitters, derivatives and/or analogs or inhibitors/antagonists, anti-nociceptive agents such as pain modulators, headache medications, anti-migraine drugs, including vasoactive agents such as triptans, and vaccine and adjuvants thereof; immunosuppressant molecules and anticancer drugs.
In one embodiment, a method of self-administering a dry powder formulation to one's lung with a dry powder inhalation system is also provided, comprising: obtaining a dry powder inhaler in a closed position and having a mouthpiece; obtaining a cartridge comprising a pre-metered dose of a dry powder formulation in a containment configuration; opening the dry powder inhaler to install the cartridge; closing the inhaler to effectuate movement of the cartridge to a dose position; placing the mouthpiece in one's mouth, and inhaling once deeply to deliver the dry powder formulation.
In one embodiment, a method of delivering an active ingredient comprising: a) providing dry powder inhaler containing a cartridge with a dry powder formulation comprising a diketopiperazine and the active agent; and b) delivering the active ingredient or agent to an individual in need of treatment. The dry powder inhaler system can deliver a dry powder formulation such as insulin FDKP having a respirable fraction greater than 50% and particles sizes less than 5.8 μm.
In still yet a further embodiment, a method of treating obesity, hyperglycemia, insulin resistance, and/or diabetes is disclosed. The method comprises the administration of an inhalable dry powder composition or formulation comprising a diketopiperazine having the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl. In this embodiment, the dry powder composition can comprise a diketopiperazine salt. In still yet another embodiment of the present invention, there is provided a dry powder composition or formulation, wherein the diketopiperazine is 2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine, with or without a pharmaceutically acceptable carrier, or excipient.
In one embodiment, the inhalation system for delivering a dry powder formulation to a patient's lungs comprises a dry powder inhaler configured to have flow conduits with a total resistance to flow in a dosing configuration ranging in value from 0.065 to about 0.200 (√kPa)/liter per minute.
In one embodiment, a dry powder inhalation kit is provided comprising a dry powder inhaler as described above, and one or more medicament cartridge comprising a dry powder formulation for treating a disorder or disease such as respiratory tract disease, diabetes and obesity. In this embodiment, the kit can comprise materials with instructions for use.
The improved cartridge emptying and deagglomeration capabilities of the inhalation systems described herein contribute to increased bioavailability of dry powder formulation. In particular embodiments, the dry powders are diketopiperazine containing powders. By bioavailability we refer to the exposure to either the active ingredient (e.g. insulin) or the diketopiperazine (in those embodiments related to diketopiperazine powders) resultant from delivery into a subject's systemic circulation, as commonly assessed by the AUC of a concentration versus time plot. By normalizing such measurements to dosage a characteristic of the system can be revealed. The dosage used in normalizing exposure can be based on filled or emitted dose and can be expressed in unit mass of powder. Alternatively exposure can be normalized to a cartridge of a particular fill mass. Either way exposure can be further adjusted to take into account the specific diketopiperazine or active ingredient content of a particular formulation, that is, the exposure can be normalized to the amount of active agent or the amount of diketopiperazine in the filled or emitted dose. Variables related to the subject, for example fluid volume, can affect the observed exposure so in various embodiments bioavailability of the system will be expressed as a range or limit.
In one embodiment, the powder formulation can comprise microparticles of FDKP and insulin as the active agent for the treatment of diabetes, wherein the insulin content of the formulation can be 3 U/mg, 4 U/mg, 6 U/mg of powder or greater. The amount of insulin or dose to be administered can vary depending on the patient's need. For example, in one embodiment, a single dose for a single inhalation can contain up to about 60 U of insulin for the treatment of hyperglycemia in diabetes.
The pharmacokinetic profile of insulin is an important factor in determining its physiologic effect. With similar insulin exposures an insulin administration of a formulation which provides a pharmacokinetic profile characterized by a rapidly attained peak is more effective at suppressing prandial glucose excursions and hepatic glucose release than is an insulin administration resulting in a slower rise to Cmax and characterized by an extended plateau. Thus, the inhalation systems disclosed herein also result in the more efficient delivery of insulin so that similar Cmax levels can be attained with smaller doses of insulin as compared to prior art systems. Stated otherwise these inhalations systems attain a higher dose normalized Cmax.
Several dry powder inhaler designs were tested to measure their resistance to flow—an important characteristic determined in part by the geometries or configurations of the inhaler pathways. Inhalers exhibiting high resistance require a greater pressure drop to yield the same flow rate as lower resistance inhalers. Briefly, to measure the resistance of each inhaler and cartridge system, various flow rates are applied to the inhaler and the resulting pressures across the inhaler are measured. These measurements can be achieved by utilizing a vacuum pump attached to the mouthpiece of the inhaler, to supply the pressure drop, and a flow controller and pressure meter to change the flow and record the resulting pressure. According to the Bernoulli principle, when the square root of the pressure drop is plotted versus the flow rate, the resistance of the inhaler is the slope of the linear portion of the curve. In these experiments, the resistance of the inhalation system, comprising a dry powder inhaler and cartridge as described herein, were measured in the dosing configuration using a resistance measuring device. The dosing configuration forms an air pathway through the inhaler air conduits and through the cartridge in the inhaler.
Since different inhaler designs exhibit different resistance values due to slight variations in geometries of their air pathways, multiple experiments were conducted to determine the ideal interval for pressure settings to use with a particular design. Based on the Bernoulli principle of linearity between square root of pressure and flow rate, the intervals for assessing linearity were predetermined for the three inhalers used after multiple tests so that the appropriate settings could be used with other batches of the same inhaler design. An exemplary graph for an inhaler can be seen in
The data in Tables 1 show the results of a set of experiments using the inhalation system described in
Table 1 illustrates the resistance of the inhalation system tested herewith is 0.0874 and 0.0894 √kPa/LPM, respectively for DPI 1 and DPI 2. The data show that the resistance of the inhalation system to flow is in part determined by the geometry or configuration of the air conduits within the cartridge.
Measurements of the particle size distribution with a laser diffraction apparatus (Helos Laser Diffraction system, Sympatec Inc.) with an adaptor (MannKind Corp., U.S. patent application Ser. No. 12/727,179, which disclosure is incorporated herein by reference for its teaching of the relevant subject matter) were made of a formulation of various amounts in milligram (mg) of an insulin and fumaryl diketopiperazine particles provided in a cartridge-inhaler system as described herewith (inhaler of
Multiple tests were carried out using different amounts of powders or fill mass in the cartridges. Cartridges were only used once. Cartridge weights were determined before and after powder discharge from the inhaler to determine discharged powder weights. Measurements in the apparatus were determined at various pressure drops and repeated multiple times as indicated in Table 2 below. Once the powder plume is measured, the data is analyzed and graphed. Table 2 depicts data obtained from the experiments, wherein CE denotes cartridge emptying (powder discharged) and Q3 (50%) is the geometric diameter of the 50th percentile of the cumulative powder particle size distribution of the sample, and q3(5.8 μm) denotes the percentage of the particle size distribution smaller than 5.8 μm geometric diameter.
The data in Table 2 showed that 92.9% to 98.4% of the total powder fill mass was emitted from the inhalation system. Additionally, the data indicate that regardless of the fill mass, 50% of the particles emitted from the inhalation system had a geometric diameter of less than 4.7 μm as measured at the various times and pressure drops tested. Moreover, between 60% and 70% of the particles emitted had a geometric diameter of less than 5.8 μm.
The experiments were conducted using the inhalation system described herewith using multiple inhaler prototypes depicted in
The experiments were conducted using an Andersen Cascade Impactor to collect stage plate powder deposits during a simulated dose delivery using flow rates of 28.3 LPM. This flow rate resulted in a pressure drop across the inhalation system (DPI plus cartridge) of approximately 6 kPa. Depositions on the plate stages were analyzed gravimetrically using filters and electronic balances. Fill weights of a cohesive powder in 10 mg, 6.6 mg and 3.1 mg fill mass were evaluated for inhalation system performance. Each impaction test was conducted with five cartridges. The cumulative powder mass collected on stages 2-F was measured in accordance with aerodynamic particle sizes less than 5.8 μm. The ratio of the collected powder mass to the cartridge fill content was determined and is provided as percent respirable fraction (RF) over the fill weight. The data is presented in Table 4.
The data show that a respirable fraction ranging from 50% to 70% was achieved with multiple powder batches. This range represents a normalized performance characteristic of the inhalation system.
The inhaler system performance measurements were repeated 35 times with a different cartridge. Fill mass (mg) and discharge time (seconds) were measured for each inhaler cartridge system used. Additionally, the percent of respirable fraction, i.e., particles suitable for pulmonary delivery, in the powder was also measured. The results are presented in Table 4 below. In the table, the % RF/fill equals the percent of particles having a size (≦5.8 μm) that would travel to the lungs in the powder; CE indicates cartridge emptying or powder delivered; RF indicates respirable fraction. In Table 4, Test Nos. 1-10 were conducted using a second batch of a clinical grade of the insulin-FDKP powder, but the test powder for 11-17 used the same powder as the tests conducted and presented in Table 3.
The data above show that the present inhalation system comprising a dry powder inhaler and a cartridge containing a cohesive powder, i.e., TECHNOSPHERE® Insulin (FDKP particles comprising insulin) can discharge effectively almost all of the powder content, since greater than 85% and in most cases greater than 95% of the total powder content of a cartridge at variable fill masses and pressure drops were obtained with consistency and significant degree of emptying. The Andersen cascade impaction measurements indicated that greater than 50% of the particles are in the respirable range wherein the particles are less than 5.8 μm and ranging from 53.5% to 73% of the total emitted powder.
The rugosity is the ratio of the actual specific surface area of the particle to that for an equivalent sphere. The specific surface area of a sphere is:
where deff=1.2 μm is the surface-weighted diameter of TI particles from Sympatec/RODOS laser diffraction measurements.
An average sphere with the same density as the TI particle matrix (1.4 g/cm3) would therefore have an SSA of
Thus for TI particles with specific surface area (SSA) of approximately 40 m2/g
For similarly sized particles with specific surface area of 50 or 60 m2/g the rugosity would be roughly 14 and 16 respectively.
Laser diffraction of dry powder formulations emitted from dry powder inhalers is a common methodology employed to characterize the level of de-agglomeration subjected to a powder. The methodology indicates a measure of geometric size rather than aerodynamic size as occurring in industry standard impaction methodologies. Typically, the geometric size of the emitted powder includes a volumetric distribution characterized by the median particle size, VMGD. Importantly, geometric sizes of the emitted particles are discerned with heightened resolution as compared to the aerodynamic sizes provided by impaction methods. Smaller sizes are preferred and result in greater likelihood of individual particles being delivered to the pulmonary tract. Thus, differences in inhaler de-agglomeration and ultimate performance can be easier to resolve with diffraction. In these experiments, an inhaler as specified in Example 3 and a predicate inhaler are tested with laser diffraction at pressures analogous to actual patient inspiratory capacities to determine the effectiveness of the inhalation system to deagglomerate powder formulations. Specifically, the formulations included cohesive diketopiperazine powders with an active insulin loaded ingredient and without. These powder formulations possessed characteristic surface areas, isomer ratios, and Carr's indices. Reported in Table 5 are a VMGD and an efficiency of the container emptying during the testing. FDKP powders have an approximate Carr's index of 50 and TI powder has an approximate Carr's index of 40.
These data in Table 5 show an improvement in powder de-agglomeration over a predicate inhaler system as compared to the inhaler system described herein. Diketopiperazine formulations with surface areas ranging from 14-56 m2/g demonstrated emptying efficiencies in excess of 85% and VMGD less than 7 microns. Similarly, formulations possessing an isomer ratio ranging from 45-66% trans demonstrated improved performance over the predicate device. Lastly, performance of the inhaler system with formulations characterized with Carr's indices of 40-50 were shown to be improved over the predicate device as well. In all cases, the reported VMGD values were below 7 microns.
TECHNOSPHERE® formulations have been successfully delivered to patients with MEDTONE® delivery system (MTDS, MannKind Corporation, Valencia, Calif.). This system includes dry powder formulations, pre-metered into single-use cartridges and inserted into a high resistance, breath-powered, re-usable MEDTONE® inhaler. An improved delivery system (DPI 2 as described in Example 1) has been developed as an alternative to MTDS. In vitro powder performance for these systems was compared for various parameter of inhaler performance. For DPI 2 a single discharge per cartridge was used as compared to two discharges per cartridge in the MEDTONE® system.
Particle sizing by laser diffraction and quantification of emitted mass as described above were used in these experiments. A laser diffraction instrument (Sympatec HELOS) was adapted with a novel pressurized inhaler chamber to facilitate analysis of powder plumes. MTDS cartridges were discharged twice per determination versus once with DPI 2. The inhalation systems were used with peak pressures of 4 kPa to assess powder-emptying percentage and volumetric median geometric diameter (VMGD) with TECHNOSPHERE® (FDKP inhalation powder) and TECHNOSPHERE® Insulin (FDKP-insulin inhalation powder) formulations.
The results of the experiments are shown in Table 6 and
To assess the safety and tolerability of various fill weights of TECHNOSPHERE® Inhalation Powder (FDKP-inhalation powder) delivered by DPI 1, described in Example 1 above, measurements were made using the inhalation system, i.e., inhaler and cartridge containing various fill weights of a dry inhalation powder, a modified CQLQ, VAS, and peak flows of the inhalation system. The MEDTONE® inhaler system was used for comparison. Experiments were also conducted to collect data from the systems in used in order to assess the effect of altering inhalation efforts and inhalation times on the pharmacokinetics (PK) of FDKP inhaled as FDKP-Inhalation Powder through the DPI 1 inhaler. Powder used were crystalline powder formulations.
At the onset of the study, subjects were monitored and instructed to practice taking “short” and “long” inhalations with the inhalation system adapted with a pressure sensing device as disclosed in U.S. patent application Ser. No. 12/488,469, which can detect the presence of a dose emitted from the device in use. During an inhalation maneuver, the patient was instructed to maintain a nominal pressure differential of 4-6 kPa combined with a short inhalation of 3-4 seconds or a long inhalation of 6-7 seconds. To generate a “hard” inhalation, the subject provided a nominal inhalation time of about 6.5 seconds and a peak pressure of 7 kPa. Conversely, to generate an “easy” inhalation, the subject provided a nominal inhalation time of about 6.5 seconds and a peak pressure of 5 kPa. Coupled with the inhalation monitoring apparatus, gravimetric assessment of the powder mass discharged from the cartridge was performed. This enabled a linkage between inhalation maneuver during dosing, cartridge discharge mass and pharmacokinetic profile determinations for each subject.
The study was an open-label, crossover, 2-part study in healthy volunteers. In Part 1, a three-way, 3-period crossover study of 10 and 15 mg of FDKP inhalation powder was inhaled through the DPI 1 Inhaler and 10 mg through the MEDTONE® inhaler. Ten subjects were administered a dose of FDKP-inhalation powder and safety and tolerability measurements (CQLQ, VAS, and peak flows) were taken. Blood samples from the subjects were taken prior to dosing and at 5, 10, 15, 25, 30, 60, 120, 240 and 360 minutes after dosing to assess the pharmacokinetics of FDPK with each treatment.
In Part 2, after determining the tolerability of FDKP-inhalation powder in Part 1, 10 mg were then used in Part 2. Part 2 was carried out as a 2-part, 2-way crossover study for evaluating the effect of flow rate (15 versus 30 LPM) and inhalation time (3 versus 6 seconds). For each parameter tested (i.e., flow rate, and inhalation time), ten subjects were crossed over for each parameter with 20 subjects total for all of the parameters. Pharmacokinetics of FDPK was assessed with each treatment from blood samples taken from the subjects. Measurements of pulmonary parameters (FEV1) were performed before and after inhalation of FDKP-inhalation powder. The results from these experiments are shown in the Table 7 and
Representative data of the results of the experiments are shown in Table 7 below which illustrates the mean AUC0-6 hr for FDKP measured for the subjects tested as well as the mean Cmax.
The DPI 1 inhalation system containing 10 mg of FDKP powder delivered almost twice FDKP into the blood as the MEDTONE® inhaler containing 10 mg. The DPI 1 inhalation system containing 15 mg of FDKP-inhalation powder on average did not deliver a dose proportional in exposure as compared to DPI 1 system containing 10 mg of powder, due to several individuals not having good exposure to the powder, as seen in the significantly higher standard deviation. Variations of the data in Part 1 of the experiments may be due to some subjects not using the inhalers in the proper position during dosing.
The DPI 1 10 mg dose results for longer, shorter, harder or easier inhalation data compared to the MEDTONE® inhaler system are listed in Table 8. The study was conducted in three parts as indicated in Table 8. Table 8 illustrates delivery of the FDKP into the pulmonary circulation measured as the mean AUC0-∞ of FDKP values obtained in the experiments. The data is exemplary of the effectiveness and performance of the DPI 1 inhalation system compared to the MEDTONE® inhaler system and shows that DPI 1 was more effective at delivering the FDKP into the systemic circulation, at about 30% better than the MEDTONE® inhaler, wherein the values for DPI 1 ranged from AUC0-∞ 2375 to 5277 ng*min/mL per mg of FDKP emitted in the formulation. AUC0-∞ for MEDTONE® ranged from 1465 to 2403 ng*min/mL per mg of FDKP emitted in the formulation after two inhalations.
FDKP 10 mg as delivered by the DPI 1 device is more efficient at delivering FDKP as measured by FDKP plasma AUC by an almost 2-fold increase over MEDTONE®. The delivery of FDKP is independent of inhalation time and inhalation effort. The data show that DPI 1 has an improved bioavailability and efficiency over MEDTONE® as assessed by FDKP AUC and the effect of altering inhalation parameters on FDKP AUC. The Cmax for FDKP in this study was greater than about 100 ng/mL with DPI 1 (one inhalation) and a lesser value using MEDTONE® (two inhalations), i.e., 96±30 ng/mL.
This study was designed to assess the relative bioavailability of various fill weights of TECHNOSPHERE® insulin inhalation powder (FDKP-insulin) delivered by a pulmonary inhalation delivery system (DPI 2) compared with MEDTONE® inhaler, as determined by the pharmacokinetics (PK) of insulin and FDKP.
This was an open-label, crossover, PK (insulin and FDKP) study in healthy volunteers. C-peptide corrections were used to determine the relative amounts of insulin delivered by inhalation versus insulin of endogenous origin. Twenty four subjects (12 per arm) were administered a dose of 6.7 mg and 7.3 mg of FDKP-insulin inhalation powder (20 U and 22 U insulin, respectively and about 10% insulin w/w) using a DPI 2, and 10 mg FDKP-insulin inhalation powder (30 U insulin) using MEDTONE®. Subsequently, 12 subjects were given 20 U using DPI 2, or 30 U via MEDTONE® in a 3-way crossover arm of the study. Blood samples from the subjects were taken prior to dosing and at 7, 15, 30, 60, 120, 240 and 360 minutes after dosing to assess the pharmacokinetics of FDPK with each treatment.
The data show that 20 U or 22 U insulin using DPI 2 delivered similar exposures of insulin and FDKP compared with 30 U of insulin administered with MEDTONE®. For insulin, results of plasma exposures (AUC0-2hr) were 3407±1460, uU×min/mL vs. 4,154±1,682 uU*min/mL for DPI 2 20 U and MEDTONE® 30 U, respectively, and 4,661±2,218 uU*min/mL vs. 3,957±1,519 uU*min/mL for DPI 2 containing 22 U and MEDTONE® 30 U, respectively. In the 3-way crossover arm, plasma insulin exposures were 4,091±1,189 uU*min/mL and 3,763±1,652 uU*min/mL for DPI 2 and MEDTONE®, respectively.
The results from the 3-way study also showed a reduction in Tmax for insulin from 20.8±18.7 minutes in MEDTONE® to 14.8±8.94 minutes in DPI 2 (20 U) and to 13.6±4.3 minutes using the DPI 2 (22 U) system. In the 3-way cross-over study, wherein 6.7 mg FDKP-insulin was delivered in DPI 2 vs. 10.0 mg of FDKP-insulin powder delivered in MEDTONE®, FDKP plasma exposures (AUC0-2hr) normalized for delivered mass were 2,059 ng*min/mL/mg (average of 16 subjects doses) for DPI 2 compared to 1,324 ng*min/mL/mg for MEDTONE® (average of 17 subjects doses). In this exemplary embodiment, the bioavailability studies were conducted with approximately 10% insulin content in the powder formulation. Accordingly, higher bioavailabilities (not normalized for powder content) can be obtained by providing a higher concentration of the insulin, and similar results can be accomplished with other active ingredients. Similarly, formulations containing higher contents of an active ingredient would yield lower bioavailabilities of FDKP (not normalized for powder content).
In summary, DPI 2 was more efficient at delivering insulin as measured by insulin plasma exposures than MEDTONE®. DPI 2 system delivered similar insulin exposures with 20 U of insulin as that of MEDTONE® with 30 U of insulin.
Further results from the experiments above are presented in the tables below. The study described in the immediately above example was continued in two additional parts. In the second part of this study subjects were given a dose of 10 U of insulin in an FDKP dry powder formulation using DPI 2, or 15 U of insulin in FDKP using the MEDTONE® inhalation system. In the 3rd part of this study, subjects were given 20 U of insulin in FDKP formulation using DPI 2 or 30 U using MEDTONE® in a 3-way crossover. Insulin concentration in blood was measured and the results were analyzed and evaluated.
The plasma insulin and FDKP exposures (AUC0-2 hr) attained from subjects treated using DPI 2 20 U is similar to that obtained from subjects using the MEDTONE® Inhaler. The data are presented in Tables 9. The values presented were obtained from all of the dosing groups that used DPI 2 with 20 U of insulin, part I and III, while the values for the MEDTONE® Inhaler 30 U of insulin were obtained from parts I, Ia and III. Lower than expected AUC plasma exposure of insulin for DPI 2 22 U is most likely secondary to insufficient time points during the terminal elimination phase of insulin. It was recognized that some of the later time points were not contributing to the calculation of AUC and with an amendment were moved up in the timing sequence which gave improved results for AUClast. This change in the insulin pharmacokinetic time points after the DPI 2 22 U insulin cohort was completed improved the subsequent concentration time profiles. The lower doses of DPI 2 10 U and MEDTONE® Inhaler 15 U were also similar. Insulin concentrations from all individuals are plotted in
The data in Table 9 is representative of the inhaler system performance disclosed herein and shows that the average plasma mean AUC0-inf measured for subjects in the experiment ranged from 1,879 to 3,383 ng*min/mL per mg of FDKP emitted with MEDTONE® with two inhalations and for DPI 2 from 2,773 to 5124 ng*min/mL per mg of FDKP emitted in the formulation after a single inhalation. The data also show that the average mean AUC0-inf for FDKP per mg of emitted FDKP mass in the formulation for all subjects was greater 3,500 or 3,568 ng*min/mL.
Plasma insulin average mean AUC0-2hr in this study for DPI 2 ranged from about 96 to 315 μU*min/mL per unit of insulin in the powder formulation administered in a single inhalation, wherein the average mean of insulin ranged from 168 to 216 μU*min/mL per unit of insulin in the powder formulation administered in a single inhalation. The AUC0-inf (AUC0-∞) values for MEDTONE ranged from about 76 to about 239 μU*min/mL per unit of insulin in the powder formulation administered in two inhalations. It has been previously noted that the first inhalation with the MEDTONE® inhaler system provides less than half the total insulin emitted with two inhalations per cartridge typically used (data not shown), and the same characteristic is similarly exhibited for FDKP when used as a delivery agent in the formulation.
Post prandial glucose excursions were evaluated in each subject during the test meal used to establish the insulin C-Peptide relationship, as well as during meal challenges after the administration of insulin with DPI 2 or MEDTONE®. Glucose excursions in each individual comparing between DPI 2 or MEDTONE® are displayed in
The bioavailability of the inhalers was also assessed as compared to the bioavailability of fumaryl diketopiperazine or FDKP administered by intravenous bolus using radiolabeled FDKP and measured as AUC AUC0-∞. The results of this study showed that for the MEDTONE® system bioavailability was calculated to be about 26% and 32% for 10 mg and 20 mg, respectively of FDKP powder delivered. The bioavailable obtained measured using DPI 1 in a model analysis to deliver 10 mg of FDKP was 57% when compared to a 10 mg of FDKP administered by an IV bolus injection. A model analysis of the data obtained using FDKP-insulin formulation was used to assess inhaler system performance or efficiency of powder delivered as measured by AUC0-∞ for FDKP using DPI 2 and a single inhalation of the powder. DPI 2 delivered 64% of the FDKP from a 6.7 mg of total fill into the systemic circulation as compared to 46% for MEDTONE® with two inhalations. For this FDKP-insulin formulation, the FDKP content was about 6 mg.
In an arm of the study conducted as described in Example 9, 46 healthy normal volunteers were studied using a Phase 1, open-label, randomized, crossover study protocol. The studies were conducted to evaluate the bioequivalence of FDKP-insulin formulation administered using DPI 2 inhalers which require a single inhalation to deliver a dose contained in a cartridge, when compared to MEDTONE®, which requires two inhalations per cartridge to deliver a dose. Additionally, the experiments were conducted to evaluate whether a dose of FDKP-insulin inhalation powder of two cartridges containing 10 U doses delivered an insulin concentration to a subject would be bioequivalent to one cartridge containing 20 U dose of insulin using DPI 2 inhalers and FDKP-insulin formulation administered by oral inhalation. Subjects were administered FDKP-insulin by oral inhalation using DPI 2 or MEDTONE®. Subjects received a single dose of 20 U insulin, two 10 U doses of insulin using DPI 2 inhalers or 30 U of insulin using a MEDTONE® inhaler. Blood samples were collected from each individual treated at various times for a period of 2 hours. The samples were analyzed to measure the insulin concentration. Pharmacokinetic parameters for the study were based on C-peptide corrected insulin concentration values. The results obtained from the study are shown in Table 10 below.
The data indicate that using 20 U of insulin administered by oral inhalation to individuals using an FDKP-insulin formulation with a DPI 2 delivery system is bioequivalent statistically to administering 30 U of the same formulation using a MEDTONE® inhaler. The data also indicate that administering two 10 U doses of an FDKP-insulin formulation by oral inhalation with DPI 2 inhaler yields similar systemic exposure of insulin when compared to a single 20 U dose of insulin of an FDKP-insulin formulation using the same inhaler type or DPI 2. Therefore, two 10 U of insulin doses of FDKP-insulin formulation yields bioequivalent insulin concentration in the systemic circulation as a single 20 U dose of FDKP-insulin using the DPI 2 inhaler system and administered by pulmonary inhalation. The bioavailability data also indicate that using DPI 2 to dose patients, at least as exemplified with an insulin/FDKP formulation, that dosing with this inhalation system the dosing appears to be linear and proportional for at least the insulin rages tested, or from a 10 U to 30 U range.
The results also indicate that the DPI 2 delivery system is about 33% more efficient in delivering the same dose of the formulation. Therefore, DPI 2 provides similar exposures of an insulin dose with a dose reduction of 33% when compared to MEDTONE® inhaler.
An inhalation system described herewith consisting of a dry powder inhaler (DPI 2) with a cartridge. The DPI 2 was adapted with a BLUHALE™ apparatus as disclosed in U.S. patent application Ser. No. 12/488,469 (US 2009/0314292, which disclosure is incorporated herein by reference for all it teaches regarding inhalation maneuver and efforts and measurements thereof), which measures the pressure differential generated in an inhaler for a period of time during and after an inhalation maneuver.
DPI 2 type inhalers were used in these experiments. Individual inhalers were loaded with a cartridge containing a dry powder formulation comprising microparticles comprising insulin and FDKP to test performance of the devices. The inhalers had been previously used to collect profiles as exemplified in Example 11 above. After collecting the inhalation profiles with BLUHALE™, the inhalers were adapted to an inhalation simulator as described in Patent Application No. PCT/US2010/055323, which disclosure is incorporated herein by reference for all it teaches regarding inhalation maneuver and efforts and measurements thereof, to reproduce exemplary inhalation by a user. The inhalation profiles using the simulator were then applied to discharge powder from two inhalers into a laser diffraction apparatus as described in Example 2 above to measure the particle size distribution. The laser diffraction apparatus measures the volumetric median geometric diameter (VMGD). Values were considered acceptable if 50% of the particles emitted were less than 4.88 μm in diameter, which was selected based on 33% increase in the average of particle size for a DPI 2 used optimally. Two inhalers with powder doses were loaded into the laser diffraction apparatus and powder discharges or emissions were obtained with the various inhalations profiles, i.e., various PIP (2) and AUC (1) values. The test was repeated 5 times for each inhaler for a total of ten measurements and the data was analyzed and plotted
An inhaler system as exemplified in
The data on Table 11 and
These experiments were conducted to test various inhaler designs in trying to improve percent dose discharge or increase device emptying to acceptable ranges for certain types of powders used. It was found that, for example, amorphous powders tend to not be discharged well from a standard inhaler and loss of active agent in the product is costly to a patient. In these experiments, therefore, two types of dry powder inhalers were designed and built. An O-series (
The microparticles can be assemblages of crystalline plates with irregular surfaces and internal voids as is typical of those made by pH controlled precipitation of the DKP acids. In such embodiments the active agents can be entrapped by the precipitation process or coated onto the crystalline surfaces of the microparticle. The microparticles can also be spherical shells or collapsed spherical shells comprised of DKP salts with the active agent dispersed throughout. Typically such particles can be obtained by spray drying a co-solution of the DKP and the active agent. The DKP salt in such particles can be amorphous. The forgoing descriptions should be understood as exemplary. Other forms of microparticles are contemplated and encompassed by the term.
DKP microparticles can be obtained by pH-based precipitation of the free acid (or base) resulting in self-assembled microparticles comprised of aggregated crystalline plates. The stability of the particle can be enhanced by small amounts of a surfactant, such as polysorbate-80, in the DKP solution from which the particles are precipitated (see for example US Patent Publication No. 2007/0059373 entitled “Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents” which is incorporated herein by reference in its entirety for all that it teaches regarding the formation and loading of DKP microparticles and dry powders thereof). Ultimately solvent can be removed to obtain a dry powder. Appropriate methods of solvent removal include lyophilization and spray drying (see for example US Patent Publication No. 2007/0196503 entitled “A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent” and U.S. Pat. No. 6,444,226 entitled “Purification and stabilization of peptide and protein pharmaceutical agents” each of which is incorporated herein by reference in its entirety for all that it teaches regarding the formation and loading of DKP microparticles and dry powders thereof). Free acid or base microparticles are distinct from microparticles composed of DKP salts. Such particles are typically formed (as opposed to dried) by spray drying, resulting in spheres and/or collapsed spheres of an amorphous salt (as opposed to a free acid or base) so that they are chemically, physically, and morphologically distinct entities.
Methods for synthesizing diketopiperazines are described in, for example, Katchalski, et al. J. Amer. Chem. Soc. 68, 879-880 (1946) and Kopple, et al., J. Org. Chem. 33(2), 862-864 (1968), the teachings of which are incorporated herein by reference in their entirety. 2,5-Diketo-3,6-di(aminobutyl)piperazine (Katchalski et al. refer to this as lysine anhydride) can also be prepared via cyclodimerization of N-.epsilon.-P-L-lysine in molten phenol, similar to the Kopple method, followed by removal of the blocking (P)-groups with an appropriate reagent and conditions. For example, CBz-protecting groups can be removed using 4.3 M HBr in acetic acid. This route can be preferred because it uses a commercially available starting material, it involves reaction conditions that are reported to preserve stereochemistry of the starting materials in the product and all steps can be easily scaled up for manufacture. Methods for synthesizing diketopiperazines are also described in U.S. Pat. No. 7,709,639, entitled, “Catalysis of Diketopiperazine Synthesis,” which is also incorporated by reference herein for its teachings regarding the same.
Illustrative, schematic examples of O-shaped air flow conduits are shown in
The rigid flow conduits as illustrated in
In the inhaler embodiment comprising the U-shaped air flow conduit through the container or reservoir (U-series), the data indicate this inhaler was most suitable for delivering amorphous powders at high content of an active agent as exemplified by the composition comprising Na2FDKP and insulin, wherein the average percent powder delivered from a dose of 25 mg delivered using data collected 5 samplings of the same inhaler were 89.23%+/−3.4% in a single inhalation when compared to 51.63% +/− 10.04% for the inhaler comprising O-shaped conduit (O-series). Low masses of powders also show similar properties. The data also indicate that inhalers with U-shaped air conduits were also effective at deagglomerating the amorphous powders. That is, the particle size distribution is similar for both inhaler types using amorphous powders, e.g., 50% of the discharged powder plume was comprised of particles less than or equal to 2.13 μm (VMGD) for the O-series compared to 2.28 μm for the U-series. The data demonstrate that the U-series inhalers have greater utility with amorphous powders, having at least 50% active agent for peptide content to produce a suitable plume for inhalation with improved discharging/emptying and similar deagglomeration levels as achieved with the O-series inhalers. The data also indicate acceptable discharges of a formulation comprising crystalline particles.
Table 11 also indicates that the O-shaped air flow conduit produced by the container or powder reservoir, was more effective at de-agglomerating crystalline powders such as TECHNOSPHERE® as shown by the smaller particle size distribution (×16, ×50 and ×84) obtained with this inhaler type wherein 50% of the discharged powder plume was comprised of particles having a geometric diameter of 6.86 μm compared to 11.19 μm for the inhalers comprising the U-shaped air flow conduit for the same dose of powder at a pressure differential of 4 kPa.
The preceding disclosures are illustrative embodiments. It should be appreciated by those of skill in the art that the devices, techniques and methods disclosed herein elucidate representative embodiments that function well in the practice of the present disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
The terms “a” and “an” and “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”
Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects those of ordinary skill in the art to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.
Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.
Further, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.
This application claims the benefit under 35 U.S.C. §119(e) from U.S. Provisional Patent Application Ser. No. 61/671,041, filed on Jul. 12, 2012, the contents of which is incorporated herein by reference in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2549303 | Friden | Apr 1951 | A |
| 2754276 | Joseph et al. | Jul 1956 | A |
| D189076 | Altman | Oct 1960 | S |
| 3337740 | Gray et al. | Aug 1967 | A |
| 3407203 | Buijle | Oct 1968 | A |
| 3518340 | Raper | Jun 1970 | A |
| 3622053 | Ryden | Nov 1971 | A |
| 3669113 | Altounyan et al. | Jun 1972 | A |
| 3673698 | Guerard | Jul 1972 | A |
| 3823816 | Controullis et al. | Jul 1974 | A |
| 3823843 | Stephens et al. | Jul 1974 | A |
| 3856142 | Vessalo | Dec 1974 | A |
| 3873651 | Mosley, Jr. et al. | Mar 1975 | A |
| 3906950 | Cocozza | Sep 1975 | A |
| 3921637 | Bennie et al. | Nov 1975 | A |
| 3976773 | Curran et al. | Aug 1976 | A |
| 3980074 | Watt et al. | Sep 1976 | A |
| 3998226 | Harris | Dec 1976 | A |
| 4013075 | Cocozza | Mar 1977 | A |
| 4018619 | Webster et al. | Apr 1977 | A |
| 4022749 | Kuechler | May 1977 | A |
| 4040536 | Schwarz | Aug 1977 | A |
| 4047525 | Kulessa et al. | Sep 1977 | A |
| 4066756 | Orr et al. | Jan 1978 | A |
| 4078128 | Hoyt et al. | Mar 1978 | A |
| 4091077 | Smith et al. | May 1978 | A |
| 4098273 | Glenn | Jul 1978 | A |
| 4102953 | Johnson et al. | Jul 1978 | A |
| 4110240 | Leo et al. | Aug 1978 | A |
| 4148308 | Sayer | Apr 1979 | A |
| 4153689 | Hirai | May 1979 | A |
| D252707 | Besnard | Aug 1979 | S |
| 4168002 | Crosby | Sep 1979 | A |
| 4171000 | Uhle | Oct 1979 | A |
| 4175556 | Freezer | Nov 1979 | A |
| 4187129 | Bost et al. | Feb 1980 | A |
| 4196196 | Tiholiz | Apr 1980 | A |
| 4206758 | Hallworth et al. | Jun 1980 | A |
| 4210140 | James et al. | Jul 1980 | A |
| 4211769 | Okada | Jul 1980 | A |
| 4268460 | Boiarski et al. | May 1981 | A |
| 4272398 | Jaffe | Jun 1981 | A |
| 4275820 | LeBlond | Jun 1981 | A |
| 4289759 | Heavener | Sep 1981 | A |
| 4294829 | Suzuki | Oct 1981 | A |
| 4300546 | Kruber | Nov 1981 | A |
| 4356167 | Kelly | Oct 1982 | A |
| D269463 | Young et al. | Jun 1983 | S |
| 4407525 | Hoppe | Oct 1983 | A |
| 4456007 | Nakao et al. | Jun 1984 | A |
| 4481139 | Folkers et al. | Nov 1984 | A |
| 4483922 | Carpenter | Nov 1984 | A |
| D276654 | Snellman-Wasenius et al. | Dec 1984 | S |
| 4487327 | Grayson | Dec 1984 | A |
| 4524769 | Wetterlin | Jun 1985 | A |
| 4526804 | Escallon | Jul 1985 | A |
| 4534345 | Wetterlin | Aug 1985 | A |
| D282209 | Newell et al. | Jan 1986 | S |
| 4581020 | Mittleman | Apr 1986 | A |
| 4592348 | Waters, IV et al. | Jun 1986 | A |
| 4613500 | Suzuki | Sep 1986 | A |
| 4615817 | McCoy | Oct 1986 | A |
| 4624861 | Yale et al. | Nov 1986 | A |
| 4637996 | Konishi | Jan 1987 | A |
| D288852 | Miyoshi | Mar 1987 | S |
| 4659696 | Hirai et al. | Apr 1987 | A |
| 4668218 | Virtanen | May 1987 | A |
| 4671954 | Goldberg et al. | Jun 1987 | A |
| 4681752 | Melillo | Jul 1987 | A |
| D295321 | Hallworth | Apr 1988 | S |
| 4742156 | Wright | May 1988 | A |
| 4757066 | Shiokari et al. | Jul 1988 | A |
| 4792451 | Kim | Dec 1988 | A |
| 4811731 | Newell et al. | Mar 1989 | A |
| D301273 | Leonard | May 1989 | S |
| 4835312 | Itoh et al. | May 1989 | A |
| 4841964 | Hurka et al. | Jun 1989 | A |
| 4847091 | Illum | Jul 1989 | A |
| 4849227 | Cho | Jul 1989 | A |
| 4861627 | Mathiowitz | Aug 1989 | A |
| 4866051 | Hunt et al. | Sep 1989 | A |
| 4873087 | Morishita et al. | Oct 1989 | A |
| 4887722 | Greenward, Sr. | Dec 1989 | A |
| 4900730 | Miyauchi | Feb 1990 | A |
| 4907583 | Wetterlin | Mar 1990 | A |
| 4925673 | Steiner | May 1990 | A |
| 4926852 | Zoltan et al. | May 1990 | A |
| 4927555 | Colarusso, Jr. | May 1990 | A |
| 4927928 | Shroot et al. | May 1990 | A |
| 4946828 | Markussen | Aug 1990 | A |
| 4981295 | Belman et al. | Jan 1991 | A |
| 4981625 | Rhim et al. | Jan 1991 | A |
| 4983402 | Steiner et al. | Jan 1991 | A |
| 4984158 | Hillsman | Jan 1991 | A |
| 4991605 | Keritsis | Feb 1991 | A |
| 4998624 | Capes et al. | Mar 1991 | A |
| 5006343 | Benson | Apr 1991 | A |
| D316902 | Hoefling | May 1991 | S |
| 5017383 | Ozawa et al. | May 1991 | A |
| 5019400 | Gombotz et al. | May 1991 | A |
| 5021376 | Nienburg et al. | Jun 1991 | A |
| 5027806 | Zoltan et al. | Jul 1991 | A |
| 5042975 | Chien | Aug 1991 | A |
| D321570 | Blasdell et al. | Nov 1991 | S |
| 5067500 | Keritsis | Nov 1991 | A |
| 5069204 | Smith et al. | Dec 1991 | A |
| 5074418 | Buan et al. | Dec 1991 | A |
| 5075027 | Dixit et al. | Dec 1991 | A |
| 5098590 | Dixit et al. | Mar 1992 | A |
| 5105291 | Matsumoto et al. | Apr 1992 | A |
| D326517 | Funai et al. | May 1992 | S |
| 5110007 | Law et al. | May 1992 | A |
| 5110823 | Hamaguchi et al. | May 1992 | A |
| 5118666 | Habener | Jun 1992 | A |
| 5120712 | Habener | Jun 1992 | A |
| 5124291 | Bremer et al. | Jun 1992 | A |
| 5131539 | Karita et al. | Jul 1992 | A |
| 5139878 | Kim | Aug 1992 | A |
| 5145684 | Liversidge et al. | Sep 1992 | A |
| 5152284 | Valentini et al. | Oct 1992 | A |
| D331106 | Fuchs | Nov 1992 | S |
| 5167506 | Kilis et al. | Dec 1992 | A |
| 5170801 | Casper et al. | Dec 1992 | A |
| 5188837 | Domb | Feb 1993 | A |
| 5196049 | Coombs et al. | Mar 1993 | A |
| 5201308 | Newhouse | Apr 1993 | A |
| 5203768 | Haak et al. | Apr 1993 | A |
| 5204108 | Illum | Apr 1993 | A |
| 5208998 | Dyler, Jr. | May 1993 | A |
| 5215739 | Kamishita et al. | Jun 1993 | A |
| D337636 | Kocinski | Jul 1993 | S |
| D338062 | Yair | Aug 1993 | S |
| D338268 | Kobayashi et al. | Aug 1993 | S |
| 5239992 | Bougamont et al. | Aug 1993 | A |
| 5239993 | Evans | Aug 1993 | A |
| 5244653 | Berke et al. | Sep 1993 | A |
| 5250287 | Cocozza | Oct 1993 | A |
| D340975 | Sladek | Nov 1993 | S |
| 5260306 | Boardman et al. | Nov 1993 | A |
| 5270305 | Palmer | Dec 1993 | A |
| 5287850 | Haber et al. | Feb 1994 | A |
| D344796 | Sochon et al. | Mar 1994 | S |
| D344797 | Sochon et al. | Mar 1994 | S |
| D345013 | Huck et al. | Mar 1994 | S |
| 5301666 | Lerk et al. | Apr 1994 | A |
| 5306453 | Shulman | Apr 1994 | A |
| D347057 | Yair | May 1994 | S |
| D348100 | Clarke | Jun 1994 | S |
| 5320094 | Laube et al. | Jun 1994 | A |
| D348928 | Ashley et al. | Jul 1994 | S |
| D348929 | Paton | Jul 1994 | S |
| 5327883 | Williams et al. | Jul 1994 | A |
| 5328464 | Kriesel et al. | Jul 1994 | A |
| 5331953 | Andersson et al. | Jul 1994 | A |
| 5333106 | Lanpher et al. | Jul 1994 | A |
| D349572 | Jagnandan et al. | Aug 1994 | S |
| D350193 | Huck et al. | Aug 1994 | S |
| 5337740 | Armstrong et al. | Aug 1994 | A |
| D350602 | Hobbs | Sep 1994 | S |
| D350821 | Wright et al. | Sep 1994 | S |
| 5351683 | Chiesi et al. | Oct 1994 | A |
| 5352461 | Feldstein et al. | Oct 1994 | A |
| 5354562 | Platz | Oct 1994 | A |
| 5358734 | Lenox et al. | Oct 1994 | A |
| D352107 | Meier et al. | Nov 1994 | S |
| 5360614 | Fox et al. | Nov 1994 | A |
| 5363842 | Mishelevich et al. | Nov 1994 | A |
| 5364838 | Rubsamen | Nov 1994 | A |
| 5372128 | Haber et al. | Dec 1994 | A |
| D355029 | Kinneir et al. | Jan 1995 | S |
| 5385904 | Andersson et al. | Jan 1995 | A |
| 5394868 | Ambrosio et al. | Mar 1995 | A |
| 5401516 | Milstein et al. | Mar 1995 | A |
| D357603 | Wolff | Apr 1995 | S |
| 5404871 | Goodman et al. | Apr 1995 | A |
| D358880 | Mulhauser et al. | May 1995 | S |
| 5413804 | Rhodes | May 1995 | A |
| 5415162 | Casper et al. | May 1995 | A |
| D359153 | Viggiano | Jun 1995 | S |
| D359555 | Funai et al. | Jun 1995 | S |
| 5424286 | Eng | Jun 1995 | A |
| 5437271 | Hodson et al. | Aug 1995 | A |
| 5443841 | Milstein et al. | Aug 1995 | A |
| D362500 | Cook et al. | Sep 1995 | S |
| 5447150 | Bacon | Sep 1995 | A |
| 5447151 | Bruna et al. | Sep 1995 | A |
| 5447728 | Milstein et al. | Sep 1995 | A |
| 5451410 | Milstein et al. | Sep 1995 | A |
| D363775 | Hobbs | Oct 1995 | S |
| 5454871 | Liaw et al. | Oct 1995 | A |
| 5455335 | Kahne et al. | Oct 1995 | A |
| 5458135 | Patton et al. | Oct 1995 | A |
| 5466971 | Higuchi | Nov 1995 | A |
| 5469750 | Lloyd et al. | Nov 1995 | A |
| 5469971 | Chilton et al. | Nov 1995 | A |
| 5476093 | Laniken | Dec 1995 | A |
| 5477285 | Riddle et al. | Dec 1995 | A |
| D365876 | Chawla | Jan 1996 | S |
| 5482032 | Smith et al. | Jan 1996 | A |
| 5482927 | Maniar et al. | Jan 1996 | A |
| 5483954 | Mecikalski | Jan 1996 | A |
| 5484606 | Dhaber et al. | Jan 1996 | A |
| 5487378 | Robertson et al. | Jan 1996 | A |
| 5492112 | Mecikalski et al. | Feb 1996 | A |
| D368364 | Reitano et al. | Apr 1996 | S |
| 5503144 | Bacon | Apr 1996 | A |
| 5503852 | Steiner et al. | Apr 1996 | A |
| 5505194 | Adjei et al. | Apr 1996 | A |
| 5506203 | Backstrom et al. | Apr 1996 | A |
| D370255 | Yamamoto et al. | May 1996 | S |
| 5514646 | Chance et al. | May 1996 | A |
| 5518998 | Backstrom et al. | May 1996 | A |
| 5524613 | Haber et al. | Jun 1996 | A |
| 5532461 | Crummenauer et al. | Jul 1996 | A |
| 5533502 | Piper | Jul 1996 | A |
| 5533505 | Kallstrand et al. | Jul 1996 | A |
| 5541155 | Leone-Bay | Jul 1996 | A |
| 5542411 | Rex | Aug 1996 | A |
| 5542539 | Early | Aug 1996 | A |
| 5545618 | Buckley et al. | Aug 1996 | A |
| 5547929 | Andersson, Jr. et al. | Aug 1996 | A |
| 5562909 | Allcock et al. | Oct 1996 | A |
| 5562918 | Stimpson | Oct 1996 | A |
| 5568884 | Bruna | Oct 1996 | A |
| 5570810 | Lambelet, Jr. et al. | Nov 1996 | A |
| 5571795 | Kahne et al. | Nov 1996 | A |
| 5574008 | Johnson et al. | Nov 1996 | A |
| 5577497 | Mecikalski et al. | Nov 1996 | A |
| 5578323 | Milstein et al. | Nov 1996 | A |
| 5584417 | Graf et al. | Dec 1996 | A |
| D377215 | Rand | Jan 1997 | S |
| D377686 | Waldeck et al. | Jan 1997 | S |
| 5595175 | Malcher et al. | Jan 1997 | A |
| 5596701 | Augusteijn et al. | Jan 1997 | A |
| D377861 | Jacober | Feb 1997 | S |
| 5598835 | von Schrader | Feb 1997 | A |
| 5601846 | Milstein et al. | Feb 1997 | A |
| 5610271 | Dooley et al. | Mar 1997 | A |
| 5614492 | Habener | Mar 1997 | A |
| 5615670 | Rhodes et al. | Apr 1997 | A |
| 5617844 | King | Apr 1997 | A |
| 5619984 | Hodson et al. | Apr 1997 | A |
| 5622164 | Kilis et al. | Apr 1997 | A |
| 5622166 | Eisele et al. | Apr 1997 | A |
| 5623724 | Gurkovich et al. | Apr 1997 | A |
| 5623920 | Bryant | Apr 1997 | A |
| D379506 | Maher | May 1997 | S |
| 5629020 | Leone-Bay | May 1997 | A |
| 5631224 | Efendic et al. | May 1997 | A |
| 5632971 | Yang | May 1997 | A |
| 5634900 | Makino et al. | Jun 1997 | A |
| 5639441 | Sievers et al. | Jun 1997 | A |
| 5641861 | Dooley et al. | Jun 1997 | A |
| D381416 | Hansson et al. | Jul 1997 | S |
| 5642727 | Datta et al. | Jul 1997 | A |
| 5642728 | Andersson et al. | Jul 1997 | A |
| 5643957 | Leone-Bay et al. | Jul 1997 | A |
| 5645051 | Schultz | Jul 1997 | A |
| 5651359 | Bougamont et al. | Jul 1997 | A |
| 5653961 | McNally et al. | Aug 1997 | A |
| 5655516 | Goodman et al. | Aug 1997 | A |
| 5655523 | Hodson et al. | Aug 1997 | A |
| 5657748 | Braithwaite | Aug 1997 | A |
| 5658878 | Backstrom et al. | Aug 1997 | A |
| 5660169 | Kallstrand et al. | Aug 1997 | A |
| 5672581 | Rubsamen et al. | Sep 1997 | A |
| 5673686 | Villax et al. | Oct 1997 | A |
| 5679377 | Bernstein et al. | Oct 1997 | A |
| 5687710 | Ambrosio et al. | Nov 1997 | A |
| 5690910 | Ahmed et al. | Nov 1997 | A |
| 5693338 | Milstein | Dec 1997 | A |
| 5699789 | Hendricks | Dec 1997 | A |
| D389238 | Kirk, III et al. | Jan 1998 | S |
| D389570 | Savolainen | Jan 1998 | S |
| 5705483 | Galloway et al. | Jan 1998 | A |
| D390651 | Smith et al. | Feb 1998 | S |
| D390653 | Blasdell et al. | Feb 1998 | S |
| 5714007 | Pletcher et al. | Feb 1998 | A |
| 5714167 | Milstein et al. | Feb 1998 | A |
| 5715811 | Ohki et al. | Feb 1998 | A |
| 5727333 | Folan | Mar 1998 | A |
| 5727546 | Clarke et al. | Mar 1998 | A |
| 5740793 | Hodson et al. | Apr 1998 | A |
| 5740794 | Smith et al. | Apr 1998 | A |
| 5746197 | Williams | May 1998 | A |
| 5746227 | Rose et al. | May 1998 | A |
| 5747445 | Backstrom et al. | May 1998 | A |
| 5752505 | Ohki et al. | May 1998 | A |
| 5755218 | Johansson et al. | May 1998 | A |
| D395147 | Vidgren et al. | Jun 1998 | S |
| D395499 | Eisele et al. | Jun 1998 | S |
| 5758638 | Kreamer | Jun 1998 | A |
| 5763396 | Weiner et al. | Jun 1998 | A |
| 5766620 | Heiber et al. | Jun 1998 | A |
| 5766633 | Milstein et al. | Jun 1998 | A |
| 5769073 | Eason et al. | Jun 1998 | A |
| 5772085 | Bryant et al. | Jun 1998 | A |
| RE35862 | Steiner et al. | Jul 1998 | E |
| 5775320 | Patton et al. | Jul 1998 | A |
| 5785049 | Smith et al. | Jul 1998 | A |
| 5785989 | Stanley et al. | Jul 1998 | A |
| D397435 | Naumann | Aug 1998 | S |
| 5792451 | Sarubbi et al. | Aug 1998 | A |
| 5794613 | Piskorski | Aug 1998 | A |
| 5797391 | Cook et al. | Aug 1998 | A |
| D398992 | Feret | Sep 1998 | S |
| 5799821 | Lambelet, Jr. et al. | Sep 1998 | A |
| 5807315 | Va Antwerp et al. | Sep 1998 | A |
| 5809997 | Wolf | Sep 1998 | A |
| 5811127 | Milstein et al. | Sep 1998 | A |
| 5813397 | Goodman et al. | Sep 1998 | A |
| 5817343 | Burke | Oct 1998 | A |
| 5824345 | Milstein et al. | Oct 1998 | A |
| 5839429 | Marnfeldt et al. | Nov 1998 | A |
| 5840279 | Narodylo et al. | Nov 1998 | A |
| 5840340 | Milstein et al. | Nov 1998 | A |
| 5846447 | Beatty | Dec 1998 | A |
| 5848589 | Welnetz | Dec 1998 | A |
| 5849322 | Ebert et al. | Dec 1998 | A |
| 5857457 | Hyppola | Jan 1999 | A |
| 5858099 | Sun et al. | Jan 1999 | A |
| 5865012 | Hansson et al. | Feb 1999 | A |
| 5868774 | Reil | Feb 1999 | A |
| 5874064 | Edwards et al. | Feb 1999 | A |
| 5875776 | Vaghefi | Mar 1999 | A |
| 5877174 | Ono et al. | Mar 1999 | A |
| 5881719 | Gottenauer et al. | Mar 1999 | A |
| 5881721 | Bunce et al. | Mar 1999 | A |
| 5884620 | Gonda et al. | Mar 1999 | A |
| 5888477 | Gonda et al. | Mar 1999 | A |
| 5896855 | Hobbs et al. | Apr 1999 | A |
| 5901703 | Ohki et al. | May 1999 | A |
| 5904139 | Hauser | May 1999 | A |
| D410541 | Moulin | Jun 1999 | S |
| D411005 | Coe | Jun 1999 | S |
| 5908639 | Simpkin et al. | Jun 1999 | A |
| 5912011 | Makino et al. | Jun 1999 | A |
| 5918594 | Asking et al. | Jul 1999 | A |
| 5919897 | Dooley et al. | Jul 1999 | A |
| 5921237 | Eisele et al. | Jul 1999 | A |
| 5922253 | Herbert et al. | Jul 1999 | A |
| 5924419 | Kotliar | Jul 1999 | A |
| 5929027 | Takama et al. | Jul 1999 | A |
| D412572 | Gray | Aug 1999 | S |
| D412744 | Braithwaite | Aug 1999 | S |
| D412978 | Cameron | Aug 1999 | S |
| D412979 | Weinstein et al. | Aug 1999 | S |
| 5934273 | Andersson et al. | Aug 1999 | A |
| 5942242 | Mizushima et al. | Aug 1999 | A |
| 5948749 | Igarashi et al. | Sep 1999 | A |
| 5952008 | Backstrom et al. | Sep 1999 | A |
| 5954047 | Armer et al. | Sep 1999 | A |
| 5965701 | Junien | Oct 1999 | A |
| 5971951 | Ruskewicz | Oct 1999 | A |
| D416085 | Forssell et al. | Nov 1999 | S |
| D416621 | Forssell et al. | Nov 1999 | S |
| D416998 | Hodson et al. | Nov 1999 | S |
| D417271 | Denyer et al. | Nov 1999 | S |
| 5975347 | Lambelet, Jr. et al. | Nov 1999 | A |
| 5976569 | Milstein | Nov 1999 | A |
| 5976574 | Gordon | Nov 1999 | A |
| 5977071 | Galloway et al. | Nov 1999 | A |
| 5980865 | Ahmed et al. | Nov 1999 | A |
| 5981488 | Hoffman | Nov 1999 | A |
| 5983893 | Wetterlin | Nov 1999 | A |
| 5985248 | Gordon et al. | Nov 1999 | A |
| 5985309 | Edwards et al. | Nov 1999 | A |
| 5990077 | Drucker | Nov 1999 | A |
| D417732 | Dagsland et al. | Dec 1999 | S |
| D417912 | Dagsland et al. | Dec 1999 | S |
| 5996577 | Ohki et al. | Dec 1999 | A |
| 5997848 | Patton | Dec 1999 | A |
| 6001336 | Gordon | Dec 1999 | A |
| 6006747 | Eisele et al. | Dec 1999 | A |
| 6006753 | Efendic | Dec 1999 | A |
| D418600 | Haerle | Jan 2000 | S |
| D420736 | Moulin | Feb 2000 | S |
| 6026809 | Abrams et al. | Feb 2000 | A |
| 6029663 | Eisele et al. | Feb 2000 | A |
| D421800 | Doat | Mar 2000 | S |
| 6039208 | Lambelet et al. | Mar 2000 | A |
| 6043214 | Jensen et al. | Mar 2000 | A |
| 6045828 | Bystrom et al. | Apr 2000 | A |
| 6051256 | Platz et al. | Apr 2000 | A |
| 6051551 | Hughes et al. | Apr 2000 | A |
| 6055980 | Mecikalski et al. | May 2000 | A |
| 6056169 | Bruna et al. | May 2000 | A |
| 6060069 | Hill et al. | May 2000 | A |
| 6063910 | Debenedetti et al. | May 2000 | A |
| 6071497 | Steiner et al. | Jun 2000 | A |
| 6073629 | Hardy et al. | Jun 2000 | A |
| 6076521 | Lindahl et al. | Jun 2000 | A |
| 6077543 | Gordon et al. | Jun 2000 | A |
| 6080762 | Allen et al. | Jun 2000 | A |
| D428486 | Schuckmann | Jul 2000 | S |
| 6085745 | Levander et al. | Jul 2000 | A |
| 6087334 | Beeley et al. | Jul 2000 | A |
| 6087351 | Nye | Jul 2000 | A |
| 6089228 | Smith et al. | Jul 2000 | A |
| 6095136 | Virtanen | Aug 2000 | A |
| 6098618 | Jennings et al. | Aug 2000 | A |
| 6098619 | Britto et al. | Aug 2000 | A |
| 6099517 | Daugherty | Aug 2000 | A |
| 6102035 | Asking et al. | Aug 2000 | A |
| 6105571 | Coffee | Aug 2000 | A |
| 6105574 | Jahnsson | Aug 2000 | A |
| 6109261 | Clarke et al. | Aug 2000 | A |
| 6109481 | Alexander et al. | Aug 2000 | A |
| 6116237 | Schultz | Sep 2000 | A |
| 6116238 | Jackson et al. | Sep 2000 | A |
| 6116239 | Volgyesi | Sep 2000 | A |
| 6119684 | Nohl et al. | Sep 2000 | A |
| 6119688 | Whaley et al. | Sep 2000 | A |
| 6131567 | Gonda et al. | Oct 2000 | A |
| 6132766 | Sankaram et al. | Oct 2000 | A |
| 6133235 | Galloway et al. | Oct 2000 | A |
| 6142145 | Dagsland | Nov 2000 | A |
| 6152130 | Abrams | Nov 2000 | A |
| 6153613 | Ono et al. | Nov 2000 | A |
| 6155423 | Katzne et al. | Dec 2000 | A |
| 6156114 | Bell et al. | Dec 2000 | A |
| 6158431 | Poole | Dec 2000 | A |
| 6159360 | Gerteis et al. | Dec 2000 | A |
| RE37053 | Hanes et al. | Feb 2001 | E |
| 6182655 | Keller et al. | Feb 2001 | B1 |
| 6187291 | Weinstein et al. | Feb 2001 | B1 |
| 6191102 | DiMarchi et al. | Feb 2001 | B1 |
| 6192876 | Denyer et al. | Feb 2001 | B1 |
| 6193844 | McLaughlin et al. | Feb 2001 | B1 |
| 6193957 | Ahmed | Feb 2001 | B1 |
| D438612 | Suh | Mar 2001 | S |
| D439325 | Frost | Mar 2001 | S |
| D439656 | Andersson et al. | Mar 2001 | S |
| 6198847 | Washizawa | Mar 2001 | B1 |
| D441446 | Dagsland et al. | May 2001 | S |
| D441859 | Pera | May 2001 | S |
| D442685 | Sladek | May 2001 | S |
| 6235725 | Ahmed | May 2001 | B1 |
| D444226 | Geert-Jensen et al. | Jun 2001 | S |
| 6250300 | Andersson et al. | Jun 2001 | B1 |
| 6254854 | Edwards et al. | Jul 2001 | B1 |
| 6257232 | Andersson et al. | Jul 2001 | B1 |
| 6258816 | Singh et al. | Jul 2001 | B1 |
| 6263871 | Brown et al. | Jul 2001 | B1 |
| 6269952 | Watt et al. | Aug 2001 | B1 |
| 6273084 | Frid | Aug 2001 | B1 |
| 6273085 | Eisele et al. | Aug 2001 | B1 |
| 6273086 | Ohki et al. | Aug 2001 | B1 |
| 6277819 | Efendic | Aug 2001 | B1 |
| 6279511 | Loughnane | Aug 2001 | B1 |
| D448076 | von Schuckmann | Sep 2001 | S |
| 6286506 | MacAndrew et al. | Sep 2001 | B1 |
| 6286507 | Jahnsson | Sep 2001 | B1 |
| 6294204 | Rossling et al. | Sep 2001 | B1 |
| D449684 | Christrup et al. | Oct 2001 | S |
| 6298846 | Ohki et al. | Oct 2001 | B1 |
| 6298847 | Datta et al. | Oct 2001 | B1 |
| D450117 | Braithwaite et al. | Nov 2001 | S |
| D451597 | Suh | Dec 2001 | S |
| 6328034 | Eisele et al. | Dec 2001 | B1 |
| 6331318 | Milstein | Dec 2001 | B1 |
| D452910 | Braithwaite et al. | Jan 2002 | S |
| 6335316 | Hughes et al. | Jan 2002 | B1 |
| D453264 | Acevedo, Jr. | Feb 2002 | S |
| 6347629 | Braithwaite | Feb 2002 | B1 |
| 6348447 | Hellstrom et al. | Feb 2002 | B1 |
| 6357442 | Casper et al. | Mar 2002 | B1 |
| 6358058 | Strupat et al. | Mar 2002 | B1 |
| 6358924 | Hoffman | Mar 2002 | B1 |
| 6360743 | Andersson et al. | Mar 2002 | B1 |
| 6360929 | McCarthy | Mar 2002 | B1 |
| D455208 | Bacon et al. | Apr 2002 | S |
| 6363932 | Forchione et al. | Apr 2002 | B1 |
| 6365190 | Gordon et al. | Apr 2002 | B1 |
| 6372258 | Platz et al. | Apr 2002 | B1 |
| 6375975 | Modi | Apr 2002 | B1 |
| 6380357 | Hermeling et al. | Apr 2002 | B2 |
| 6386195 | Coffee | May 2002 | B1 |
| 6388053 | Galloway et al. | May 2002 | B1 |
| 6394085 | Hardy et al. | May 2002 | B1 |
| 6395300 | Straub et al. | May 2002 | B1 |
| 6395774 | Milstein | May 2002 | B1 |
| 6410513 | Galloway et al. | Jun 2002 | B1 |
| D460173 | Harrison et al. | Jul 2002 | S |
| 6415784 | Christrup et al. | Jul 2002 | B1 |
| 6418926 | Chawla | Jul 2002 | B1 |
| 6423344 | Platz et al. | Jul 2002 | B1 |
| D461239 | Cassidy | Aug 2002 | S |
| 6427688 | Ligotke et al. | Aug 2002 | B1 |
| 6428771 | Steiner et al. | Aug 2002 | B1 |
| 6428805 | Dohi et al. | Aug 2002 | B1 |
| 6432383 | Modi | Aug 2002 | B1 |
| 6436443 | Edwards et al. | Aug 2002 | B2 |
| 6439227 | Myrman et al. | Aug 2002 | B1 |
| 6440463 | Feldstein et al. | Aug 2002 | B1 |
| 6441172 | Nefzi et al. | Aug 2002 | B1 |
| D463544 | Engelbreth et al. | Sep 2002 | S |
| 6443143 | Ishida et al. | Sep 2002 | B1 |
| 6444226 | Steiner et al. | Sep 2002 | B1 |
| 6446626 | Virtanen | Sep 2002 | B1 |
| 6446627 | Bowman et al. | Sep 2002 | B1 |
| 6447750 | Cutie et al. | Sep 2002 | B1 |
| 6447751 | Weinstein et al. | Sep 2002 | B1 |
| 6447753 | Edwards et al. | Sep 2002 | B2 |
| 6451337 | Smith et al. | Sep 2002 | B1 |
| 6457470 | Coffee | Oct 2002 | B1 |
| 6468507 | Cutie et al. | Oct 2002 | B1 |
| 6470884 | Horlin | Oct 2002 | B2 |
| 6479049 | Platz et al. | Nov 2002 | B1 |
| 6484715 | Ritsche et al. | Nov 2002 | B1 |
| 6484717 | Dagsland et al. | Nov 2002 | B1 |
| D469527 | Keller et al. | Jan 2003 | S |
| 6503480 | Edwards et al. | Jan 2003 | B1 |
| 6509006 | Platz et al. | Jan 2003 | B1 |
| 6509313 | Smith | Jan 2003 | B1 |
| D469866 | Albulet et al. | Feb 2003 | S |
| 6514482 | Bartus et al. | Feb 2003 | B1 |
| 6518239 | Kuo et al. | Feb 2003 | B1 |
| 6523536 | Fugelsang et al. | Feb 2003 | B2 |
| D471273 | Albulet et al. | Mar 2003 | S |
| 6528096 | Musa et al. | Mar 2003 | B1 |
| 6532437 | Clardy et al. | Mar 2003 | B1 |
| 6536427 | Davies et al. | Mar 2003 | B2 |
| D473298 | Bowman et al. | Apr 2003 | S |
| D473640 | Cuffaro et al. | Apr 2003 | S |
| 6540672 | Simonsen et al. | Apr 2003 | B1 |
| 6540982 | Adjei et al. | Apr 2003 | B1 |
| 6540983 | Adjei et al. | Apr 2003 | B1 |
| 6543448 | Smith et al. | Apr 2003 | B1 |
| 6546929 | Burr et al. | Apr 2003 | B2 |
| 6555127 | Steiner | Apr 2003 | B2 |
| 6555521 | Hermeling et al. | Apr 2003 | B2 |
| D474536 | Albulet et al. | May 2003 | S |
| D475133 | McLuckie | May 2003 | S |
| 6557549 | Schmidt et al. | May 2003 | B2 |
| 6561186 | Casper et al. | May 2003 | B2 |
| 6567686 | Sexton | May 2003 | B2 |
| 6568390 | Nichols et al. | May 2003 | B2 |
| 6569406 | Stevenson et al. | May 2003 | B2 |
| 6571793 | Nilsson et al. | Jun 2003 | B1 |
| 6572893 | Gordon et al. | Jun 2003 | B2 |
| 6575160 | Volgyesi | Jun 2003 | B1 |
| 6575162 | Rand | Jun 2003 | B1 |
| 6578571 | Watt | Jun 2003 | B1 |
| 6582728 | Platz et al. | Jun 2003 | B1 |
| 6583111 | DiMarchi et al. | Jun 2003 | B1 |
| D477665 | Myrman et al. | Jul 2003 | S |
| 6589560 | Foster et al. | Jul 2003 | B2 |
| 6591832 | DeJonge | Jul 2003 | B1 |
| 6592904 | Platz et al. | Jul 2003 | B2 |
| 6595205 | Andersson et al. | Jul 2003 | B2 |
| 6595208 | Coffee et al. | Jul 2003 | B1 |
| D478983 | Whitehall et al. | Aug 2003 | S |
| 6606992 | Smith et al. | Aug 2003 | B1 |
| D479745 | Albulet et al. | Sep 2003 | S |
| 6613308 | Bartus et al. | Sep 2003 | B2 |
| 6615987 | Greenhill et al. | Sep 2003 | B1 |
| 6620910 | Calas et al. | Sep 2003 | B1 |
| 6626173 | Genova et al. | Sep 2003 | B2 |
| D480806 | Engelbreth et al. | Oct 2003 | S |
| 6630169 | Bot et al. | Oct 2003 | B1 |
| 6632258 | Wheelock et al. | Oct 2003 | B1 |
| 6632456 | Backstrom et al. | Oct 2003 | B1 |
| 6635283 | Edwards et al. | Oct 2003 | B2 |
| 6637431 | Ekelius et al. | Oct 2003 | B2 |
| 6640050 | Nichols et al. | Oct 2003 | B2 |
| 6644309 | Casper et al. | Nov 2003 | B2 |
| 6645468 | Cutie et al. | Nov 2003 | B2 |
| 6645504 | Weiner et al. | Nov 2003 | B1 |
| 6652838 | Weinstein et al. | Nov 2003 | B2 |
| 6652885 | Steiner et al. | Nov 2003 | B2 |
| D483860 | Knoch | Dec 2003 | S |
| 6655379 | Clark et al. | Dec 2003 | B2 |
| 6655380 | Andersson et al. | Dec 2003 | B1 |
| 6655381 | Keane et al. | Dec 2003 | B2 |
| 6660716 | Yakubu-Madus et al. | Dec 2003 | B1 |
| 6663898 | Milstein | Dec 2003 | B2 |
| 6668826 | Myrman et al. | Dec 2003 | B1 |
| 6672304 | Casper et al. | Jan 2004 | B1 |
| 6676931 | Dugger, III | Jan 2004 | B2 |
| 6679255 | Pera | Jan 2004 | B2 |
| 6681767 | Patton et al. | Jan 2004 | B1 |
| 6681768 | Haaije de Boer et al. | Jan 2004 | B2 |
| 6685967 | Patton et al. | Feb 2004 | B1 |
| 6696090 | Nilsson et al. | Feb 2004 | B1 |
| 6698421 | Attolini | Mar 2004 | B2 |
| 6698422 | Fugelsang et al. | Mar 2004 | B2 |
| 6698425 | Widerstorm | Mar 2004 | B1 |
| 6701917 | O'Leary | Mar 2004 | B2 |
| 6703361 | Weiner et al. | Mar 2004 | B2 |
| 6703365 | Galloway et al. | Mar 2004 | B2 |
| 6703381 | Ekwuribe et al. | Mar 2004 | B1 |
| 6705313 | Niccolai | Mar 2004 | B2 |
| 6715486 | Gieschen et al. | Apr 2004 | B2 |
| 6715487 | Nichols et al. | Apr 2004 | B2 |
| 6718972 | O'Leary | Apr 2004 | B2 |
| 6720407 | Hughes et al. | Apr 2004 | B1 |
| 6722363 | von Schuckmann | Apr 2004 | B1 |
| D489448 | Shayan | May 2004 | S |
| 6729324 | Casper et al. | May 2004 | B2 |
| 6729328 | Goldemann | May 2004 | B2 |
| 6737045 | Patton | May 2004 | B2 |
| 6745761 | Christrup et al. | Jun 2004 | B2 |
| 6747006 | Efendic | Jun 2004 | B2 |
| 6748946 | Rand et al. | Jun 2004 | B1 |
| 6748947 | Keane et al. | Jun 2004 | B2 |
| 6752145 | Bonney et al. | Jun 2004 | B1 |
| 6755190 | Rasmussen | Jun 2004 | B2 |
| D492769 | Hatanaka | Jul 2004 | S |
| D493220 | Burge et al. | Jul 2004 | S |
| D493519 | Jonsson et al. | Jul 2004 | S |
| 6774112 | Gougoutas | Aug 2004 | B2 |
| 6787152 | Kirby et al. | Sep 2004 | B2 |
| 6790496 | Levander et al. | Sep 2004 | B1 |
| 6792945 | Davies et al. | Sep 2004 | B2 |
| 6797258 | Platz et al. | Sep 2004 | B2 |
| 6799572 | Nichols et al. | Oct 2004 | B2 |
| 6800643 | Cuenoud et al. | Oct 2004 | B2 |
| 6803044 | Catania et al. | Oct 2004 | B1 |
| 6821949 | Bridon et al. | Nov 2004 | B2 |
| 6823863 | Huxham et al. | Nov 2004 | B2 |
| D499802 | Pinon et al. | Dec 2004 | S |
| 6830046 | Blakley et al. | Dec 2004 | B2 |
| 6838075 | Stevenson et al. | Jan 2005 | B2 |
| 6838076 | Platton et al. | Jan 2005 | B2 |
| 6847595 | Tanaka | Jan 2005 | B2 |
| 6848443 | Schmidt et al. | Feb 2005 | B2 |
| 6849708 | Habener | Feb 2005 | B1 |
| 6852690 | Nauck et al. | Feb 2005 | B1 |
| 6858199 | Edwards et al. | Feb 2005 | B1 |
| 6860262 | Christrup et al. | Mar 2005 | B2 |
| 6866037 | Aslin et al. | Mar 2005 | B1 |
| 6871646 | Keane et al. | Mar 2005 | B2 |
| 6871647 | Allan et al. | Mar 2005 | B2 |
| 6880554 | Coffee | Apr 2005 | B1 |
| 6881423 | Dohi et al. | Apr 2005 | B2 |
| 6884435 | O'Hagan et al. | Apr 2005 | B1 |
| 6887459 | Haeberlin | May 2005 | B1 |
| 6887849 | Bridon et al. | May 2005 | B2 |
| 6889687 | Olsson | May 2005 | B1 |
| 6892728 | Helgesson et al. | May 2005 | B2 |
| 6896906 | Hastedt et al. | May 2005 | B2 |
| D506680 | Saelzer | Jun 2005 | S |
| 6904907 | Speldrich et al. | Jun 2005 | B2 |
| 6906030 | Milstein | Jun 2005 | B2 |
| 6916354 | Elliott | Jul 2005 | B2 |
| 6918991 | Chickering, III et al. | Jul 2005 | B2 |
| 6921458 | Chickering, III et al. | Jul 2005 | B2 |
| 6921528 | Edwards et al. | Jul 2005 | B2 |
| 6923175 | Poole | Aug 2005 | B2 |
| D509296 | Minshull et al. | Sep 2005 | S |
| D509898 | Bunce et al. | Sep 2005 | S |
| 6948496 | Eason et al. | Sep 2005 | B2 |
| 6949258 | Zhang | Sep 2005 | B2 |
| 6951215 | Hoffman | Oct 2005 | B1 |
| 6953812 | Joregenson et al. | Oct 2005 | B2 |
| D511208 | Pardonge et al. | Nov 2005 | S |
| D511977 | Saelzer | Nov 2005 | S |
| 6962006 | Chickering, III et al. | Nov 2005 | B2 |
| D512777 | Beisner et al. | Dec 2005 | S |
| 6979437 | Bartus et al. | Dec 2005 | B2 |
| D514222 | Anderson et al. | Jan 2006 | S |
| 6981499 | Andersson et al. | Jan 2006 | B2 |
| 6989155 | Ganderton et al. | Jan 2006 | B1 |
| 6991779 | Steiner et al. | Jan 2006 | B2 |
| D515696 | Lucking et al. | Feb 2006 | S |
| D515924 | Grant | Feb 2006 | S |
| D516211 | Minshull et al. | Feb 2006 | S |
| 6998387 | Goke et al. | Feb 2006 | B1 |
| D518170 | Clarke et al. | Mar 2006 | S |
| D518171 | Anderson et al. | Mar 2006 | S |
| 7022674 | DeFelippis et al. | Apr 2006 | B2 |
| 7025056 | Eason et al. | Apr 2006 | B2 |
| 7028686 | Gonda et al. | Apr 2006 | B2 |
| 7030084 | Ekwuribe et al. | Apr 2006 | B2 |
| 7032593 | Johnston et al. | Apr 2006 | B2 |
| 7035294 | Dove et al. | Apr 2006 | B2 |
| 7047967 | Knudsen | May 2006 | B2 |
| 7048908 | Basu et al. | May 2006 | B2 |
| 7060274 | Blumberg et al. | Jun 2006 | B2 |
| 7067129 | Blumberg et al. | Jun 2006 | B2 |
| 7077130 | Nichols et al. | Jul 2006 | B2 |
| 7080642 | Hodson et al. | Jul 2006 | B2 |
| 7084243 | Glaesner et al. | Aug 2006 | B2 |
| 7093594 | Harrison et al. | Aug 2006 | B2 |
| 7093595 | Nesbitt | Aug 2006 | B2 |
| D527817 | Ziegler et al. | Sep 2006 | S |
| 7101843 | Glaesner et al. | Sep 2006 | B2 |
| 7101866 | Biggadike et al. | Sep 2006 | B2 |
| 7105489 | Hathaway | Sep 2006 | B2 |
| 7107988 | Pinon et al. | Sep 2006 | B2 |
| 7109161 | Gayed | Sep 2006 | B1 |
| D529604 | Young et al. | Oct 2006 | S |
| 7125566 | Etter | Oct 2006 | B2 |
| 7128067 | Byron et al. | Oct 2006 | B2 |
| 7131441 | Keller et al. | Nov 2006 | B1 |
| 7132115 | Musa et al. | Nov 2006 | B2 |
| 7140365 | Poole et al. | Nov 2006 | B2 |
| D533268 | Olfati | Dec 2006 | S |
| 7143764 | Dagsland et al. | Dec 2006 | B1 |
| 7143765 | Asking et al. | Dec 2006 | B2 |
| 7144863 | DeFelippis et al. | Dec 2006 | B2 |
| 7146978 | Edwards et al. | Dec 2006 | B2 |
| 7151456 | Godfrey | Dec 2006 | B2 |
| 7163014 | Nichols et al. | Jan 2007 | B2 |
| D537522 | Cox et al. | Feb 2007 | S |
| 7171965 | Young et al. | Feb 2007 | B2 |
| 7172768 | Hastedt et al. | Feb 2007 | B2 |
| 7179788 | DeFelippis et al. | Feb 2007 | B2 |
| D537936 | Cox et al. | Mar 2007 | S |
| D538423 | Berube et al. | Mar 2007 | S |
| 7185650 | Huber et al. | Mar 2007 | B2 |
| D540671 | Born | Apr 2007 | S |
| D541151 | Born | Apr 2007 | S |
| 7198806 | Berndt | Apr 2007 | B2 |
| 7211557 | DiMarchi et al. | May 2007 | B2 |
| 7219664 | Ruckdeschel et al. | May 2007 | B2 |
| 7223728 | Yakubu-Madus et al. | May 2007 | B2 |
| D544093 | Eriksen | Jun 2007 | S |
| 7231919 | Giroux | Jun 2007 | B2 |
| 7232897 | Hotamisligil et al. | Jun 2007 | B2 |
| 7234459 | Del Bon | Jun 2007 | B2 |
| 7234460 | Greenleaf et al. | Jun 2007 | B2 |
| 7234464 | Goede et al. | Jun 2007 | B2 |
| 7238663 | DeFelippis et al. | Jul 2007 | B2 |
| 7246617 | Hammer et al. | Jul 2007 | B1 |
| D548330 | Cox et al. | Aug 2007 | S |
| D548618 | Ferguson et al. | Aug 2007 | S |
| D548619 | Ferguson et al. | Aug 2007 | S |
| D548833 | Young et al. | Aug 2007 | S |
| D549111 | Ferguson et al. | Aug 2007 | S |
| 7258118 | Goede et al. | Aug 2007 | B2 |
| 7259233 | Dodd et al. | Aug 2007 | B2 |
| D550835 | Tanaka et al. | Sep 2007 | S |
| 7265087 | Goke et al. | Sep 2007 | B1 |
| 7270124 | Rasmussen | Sep 2007 | B2 |
| D552729 | Cox et al. | Oct 2007 | S |
| 7276534 | Milstein | Oct 2007 | B2 |
| 7278419 | Gonda | Oct 2007 | B2 |
| 7278426 | Myrman et al. | Oct 2007 | B2 |
| 7278843 | Feldstein et al. | Oct 2007 | B2 |
| 7279457 | Pohl et al. | Oct 2007 | B2 |
| 7284553 | Hochrainer | Oct 2007 | B2 |
| D557799 | Greenhalgh et al. | Dec 2007 | S |
| 7305986 | Steiner et al. | Dec 2007 | B1 |
| 7306787 | Tarara et al. | Dec 2007 | B2 |
| D560793 | Pearl et al. | Jan 2008 | S |
| 7314859 | Green et al. | Jan 2008 | B2 |
| 7316748 | Li et al. | Jan 2008 | B2 |
| 7331340 | Barney | Feb 2008 | B2 |
| 7334577 | Gumaste et al. | Feb 2008 | B2 |
| 7344734 | Heijerman et al. | Mar 2008 | B2 |
| D566549 | Russell et al. | Apr 2008 | S |
| 7368102 | Tarara et al. | May 2008 | B2 |
| 7373938 | Nichols et al. | May 2008 | B2 |
| 7377277 | Hickey et al. | May 2008 | B2 |
| 7387122 | Nishibayashi et al. | Jun 2008 | B2 |
| 7399528 | Caponetti et al. | Jul 2008 | B2 |
| 7401712 | Kaye et al. | Jul 2008 | B2 |
| 7401713 | Ede et al. | Jul 2008 | B2 |
| 7402564 | Schteingart et al. | Jul 2008 | B1 |
| 7414720 | Wachtel et al. | Aug 2008 | B2 |
| D577815 | Gokhale et al. | Sep 2008 | S |
| 7422013 | Burr et al. | Sep 2008 | B2 |
| D579549 | Birath et al. | Oct 2008 | S |
| 7448375 | Gonda et al. | Nov 2008 | B2 |
| 7448379 | Yamashita et al. | Nov 2008 | B2 |
| 7451761 | Hickey et al. | Nov 2008 | B2 |
| 7453556 | Hochrainer et al. | Nov 2008 | B2 |
| D583463 | Wood et al. | Dec 2008 | S |
| 7461653 | Oliva | Dec 2008 | B2 |
| 7462367 | Schmidt et al. | Dec 2008 | B2 |
| 7464706 | Steiner et al. | Dec 2008 | B2 |
| 7469696 | Yang et al. | Dec 2008 | B2 |
| 7500479 | Nichols et al. | Mar 2009 | B2 |
| 7503324 | Barney et al. | Mar 2009 | B2 |
| 7504538 | Chang et al. | Mar 2009 | B2 |
| 7517874 | Beckett et al. | Apr 2009 | B2 |
| 7520278 | Crowder et al. | Apr 2009 | B2 |
| 7521069 | Patton et al. | Apr 2009 | B2 |
| 7533668 | Widerstrom | May 2009 | B1 |
| D594753 | Eadicicco et al. | Jun 2009 | S |
| 7556798 | Edwards et al. | Jul 2009 | B2 |
| 7559322 | Foley et al. | Jul 2009 | B2 |
| D597418 | Stojek | Aug 2009 | S |
| D597657 | Kinsey et al. | Aug 2009 | S |
| D598785 | Stojek | Aug 2009 | S |
| 7584846 | Senter | Sep 2009 | B2 |
| 7598222 | Prouty, Jr. et al. | Oct 2009 | B2 |
| D604832 | Smutney et al. | Nov 2009 | S |
| D604833 | Polidoro | Nov 2009 | S |
| D605752 | Polidoro | Dec 2009 | S |
| D605753 | Smutney | Dec 2009 | S |
| 7625865 | Colombo | Dec 2009 | B2 |
| 7648960 | Steiner et al. | Jan 2010 | B2 |
| D613849 | Smutney | Apr 2010 | S |
| D614045 | Gaudenzi et al. | Apr 2010 | S |
| D614760 | Smutney et al. | Apr 2010 | S |
| 7694676 | Wachtel | Apr 2010 | B2 |
| 7709639 | Stevenson | May 2010 | B2 |
| 7713937 | Schteingart et al. | May 2010 | B2 |
| 7727963 | Schteingart et al. | Jun 2010 | B2 |
| D620812 | Gaudenzi et al. | Aug 2010 | S |
| 7794754 | Feldstein et al. | Sep 2010 | B2 |
| 7799344 | Oberg | Sep 2010 | B2 |
| 7803404 | Hokenson | Sep 2010 | B2 |
| 7820676 | Leone-Bay et al. | Oct 2010 | B2 |
| D626836 | Lien | Nov 2010 | S |
| D628090 | Stuiber et al. | Nov 2010 | S |
| 7833549 | Steiner et al. | Nov 2010 | B2 |
| 7833550 | Steiner et al. | Nov 2010 | B2 |
| 7842662 | Schteingart et al. | Nov 2010 | B2 |
| D629505 | Adamo | Dec 2010 | S |
| D629506 | Adamo | Dec 2010 | S |
| D629886 | Adamo | Dec 2010 | S |
| D629887 | Adamo | Dec 2010 | S |
| D629888 | Adamo | Dec 2010 | S |
| D635241 | McLean | Mar 2011 | S |
| D635242 | Adamo | Mar 2011 | S |
| D635243 | Kinsey | Mar 2011 | S |
| 7913688 | Cross | Mar 2011 | B2 |
| D636867 | Polidoro et al. | Apr 2011 | S |
| D636868 | Kinsey et al. | Apr 2011 | S |
| D636869 | Laurenzi et al. | Apr 2011 | S |
| 7919119 | Straub et al. | Apr 2011 | B2 |
| 7943178 | Steiner et al. | May 2011 | B2 |
| 7943572 | Cheatham et al. | May 2011 | B2 |
| 7954491 | Hrkach | Jun 2011 | B2 |
| 7959609 | Gaydos et al. | Jun 2011 | B2 |
| D641076 | Grunstad et al. | Jul 2011 | S |
| D643308 | Bergey | Aug 2011 | S |
| D645954 | Hately | Sep 2011 | S |
| D647195 | Clarke et al. | Oct 2011 | S |
| D647196 | Clarke et al. | Oct 2011 | S |
| 8037880 | Zhu et al. | Oct 2011 | B2 |
| 8037881 | Pentafragas | Oct 2011 | B2 |
| 8039431 | Wilson et al. | Oct 2011 | B2 |
| 8047203 | Young et al. | Nov 2011 | B2 |
| D652322 | Stuiber et al. | Jan 2012 | S |
| 8109267 | Villax et al. | Feb 2012 | B2 |
| 8119593 | Richardson | Feb 2012 | B2 |
| D655622 | Sadler et al. | Mar 2012 | S |
| 8133514 | Milstein | Mar 2012 | B2 |
| 8146588 | Steiner et al. | Apr 2012 | B2 |
| 8156936 | Steiner et al. | Apr 2012 | B2 |
| D659020 | Kemner | May 2012 | S |
| D659022 | Kemner | May 2012 | S |
| D660956 | Zuyderhoudt | May 2012 | S |
| 8166970 | Poole et al. | May 2012 | B2 |
| 8172817 | Michaels et al. | May 2012 | B2 |
| 8196576 | Kriksunov | Jun 2012 | B2 |
| 8201555 | Chawla | Jun 2012 | B2 |
| 8202992 | Stevenson | Jun 2012 | B2 |
| D663830 | Sears | Jul 2012 | S |
| D664640 | Smutney et al. | Jul 2012 | S |
| 8217007 | Schteingart | Jul 2012 | B1 |
| 8227409 | Kraft | Jul 2012 | B2 |
| 8236766 | Schteingart | Aug 2012 | B2 |
| 8252916 | Simard et al. | Aug 2012 | B2 |
| 8258095 | Boss et al. | Sep 2012 | B2 |
| 8278308 | Leone-Bay et al. | Oct 2012 | B2 |
| 8293869 | Bossard | Oct 2012 | B2 |
| 8314106 | Kraft | Nov 2012 | B2 |
| D671842 | Bergey | Dec 2012 | S |
| D674893 | Kinsey et al. | Jan 2013 | S |
| 8372804 | Richardson | Feb 2013 | B2 |
| 8389470 | Steiner | Mar 2013 | B2 |
| 8394414 | Steiner et al. | Mar 2013 | B2 |
| 8408200 | Clark et al. | Apr 2013 | B2 |
| 8420604 | Hokenson | Apr 2013 | B2 |
| 8424518 | Smutney | Apr 2013 | B2 |
| 8485180 | Smutney | Jul 2013 | B2 |
| 8486894 | Schteingart et al. | Jul 2013 | B2 |
| 8499757 | Smutney | Aug 2013 | B2 |
| 8512932 | Wilson et al. | Aug 2013 | B2 |
| 8522775 | Malhotra et al. | Sep 2013 | B2 |
| 8536131 | Schteingart et al. | Sep 2013 | B2 |
| 8538707 | Adamo et al. | Sep 2013 | B2 |
| 8539946 | Esteve et al. | Sep 2013 | B2 |
| 8551528 | Grant et al. | Oct 2013 | B2 |
| 8563101 | Spallek | Oct 2013 | B2 |
| 8636001 | Smutney | Jan 2014 | B2 |
| 8642548 | Richardson et al. | Feb 2014 | B2 |
| 8671937 | Steiner et al. | Mar 2014 | B2 |
| 8677992 | Villax | Mar 2014 | B2 |
| 8763606 | Mosier et al. | Jul 2014 | B2 |
| 8778403 | Grant et al. | Jul 2014 | B2 |
| 8783249 | Trent et al. | Jul 2014 | B2 |
| D711740 | Lien | Aug 2014 | S |
| 8808786 | Jinks et al. | Aug 2014 | B2 |
| 8820324 | Smith et al. | Sep 2014 | B2 |
| 8909487 | Adamo et al. | Dec 2014 | B2 |
| 8925726 | Bergey | Jan 2015 | B2 |
| 9041925 | Adamo et al. | May 2015 | B2 |
| 9138407 | Caponetti et al. | Sep 2015 | B2 |
| 9283337 | Lastow | Mar 2016 | B2 |
| D771237 | Smutney et al. | Nov 2016 | S |
| 20010020147 | Staniforth et al. | Sep 2001 | A1 |
| 20010039442 | Gorge et al. | Nov 2001 | A1 |
| 20020000225 | Schuler et al. | Jan 2002 | A1 |
| 20020015737 | Shih et al. | Feb 2002 | A1 |
| 20020033177 | Ohki et al. | Mar 2002 | A1 |
| 20020052381 | Bar-Or et al. | May 2002 | A1 |
| 20020053344 | Davies et al. | May 2002 | A1 |
| 20020053347 | Ziaee | May 2002 | A1 |
| 20020065239 | Caplan et al. | May 2002 | A1 |
| 20020088462 | Genova et al. | Jul 2002 | A1 |
| 20020101590 | Shimaoka | Aug 2002 | A1 |
| 20020144680 | Nilsson et al. | Oct 2002 | A1 |
| 20020161001 | Kanstrup et al. | Oct 2002 | A1 |
| 20030000524 | Andersson et al. | Jan 2003 | A1 |
| 20030010794 | Herdtle et al. | Jan 2003 | A1 |
| 20030013641 | Steiner et al. | Jan 2003 | A1 |
| 20030017211 | Steiner | Jan 2003 | A1 |
| 20030053960 | Heijerman et al. | Mar 2003 | A1 |
| 20030064097 | Patel et al. | Apr 2003 | A1 |
| 20030068378 | Chen et al. | Apr 2003 | A1 |
| 20030099636 | Epshtein et al. | May 2003 | A1 |
| 20030136405 | Goede et al. | Jul 2003 | A1 |
| 20030168370 | Merboth et al. | Sep 2003 | A1 |
| 20030194420 | Holl et al. | Oct 2003 | A1 |
| 20030235538 | Zierenberg | Dec 2003 | A1 |
| 20040022861 | Williams et al. | Feb 2004 | A1 |
| 20040024180 | Drauz | Feb 2004 | A1 |
| 20040025875 | Reber et al. | Feb 2004 | A1 |
| 20040034014 | Kanstrup et al. | Feb 2004 | A1 |
| 20040038865 | Gelber et al. | Feb 2004 | A1 |
| 20040053819 | Dodd et al. | Mar 2004 | A1 |
| 20040062722 | Gonda et al. | Apr 2004 | A1 |
| 20040076588 | Batycky et al. | Apr 2004 | A1 |
| 20040077528 | Steiner et al. | Apr 2004 | A1 |
| 20040096403 | Steiner | May 2004 | A1 |
| 20040107963 | Finlay et al. | Jun 2004 | A1 |
| 20040121964 | Madar et al. | Jun 2004 | A1 |
| 20040138099 | Draeger | Jul 2004 | A1 |
| 20040151059 | Roberts, II et al. | Aug 2004 | A1 |
| 20040151774 | Pauletti et al. | Aug 2004 | A1 |
| 20040157928 | Kim et al. | Aug 2004 | A1 |
| 20040163648 | Burton | Aug 2004 | A1 |
| 20040182387 | Steiner et al. | Sep 2004 | A1 |
| 20040187869 | Bjorndal et al. | Sep 2004 | A1 |
| 20040204439 | Staniforth et al. | Oct 2004 | A1 |
| 20040204440 | Staniforth et al. | Oct 2004 | A1 |
| 20040211419 | Eason et al. | Oct 2004 | A1 |
| 20040211420 | Minshull | Oct 2004 | A1 |
| 20040234615 | Sabetsky | Nov 2004 | A1 |
| 20040234616 | Sabetsky | Nov 2004 | A1 |
| 20040235956 | Quay | Nov 2004 | A1 |
| 20040241232 | Brown et al. | Dec 2004 | A1 |
| 20040247628 | Lintz et al. | Dec 2004 | A1 |
| 20040250812 | Davies et al. | Dec 2004 | A1 |
| 20050000518 | Dunkley et al. | Jan 2005 | A1 |
| 20050039743 | Taylor | Feb 2005 | A1 |
| 20050043228 | DeFelippis et al. | Feb 2005 | A1 |
| 20050043247 | Trunk et al. | Feb 2005 | A1 |
| 20050056281 | Snow | Mar 2005 | A1 |
| 20050070469 | Bloom | Mar 2005 | A1 |
| 20050080000 | Thurow et al. | Apr 2005 | A1 |
| 20050119604 | Bonney et al. | Jun 2005 | A1 |
| 20050124644 | Nilsson et al. | Jun 2005 | A1 |
| 20050147581 | Zamiri et al. | Jul 2005 | A1 |
| 20050153874 | Cheatham et al. | Jul 2005 | A1 |
| 20050155601 | Steiner et al. | Jul 2005 | A1 |
| 20050183723 | Pinon et al. | Aug 2005 | A1 |
| 20050187749 | Singley | Aug 2005 | A1 |
| 20050203002 | Tzannis et al. | Sep 2005 | A1 |
| 20050214251 | Pohl et al. | Sep 2005 | A1 |
| 20050252508 | Koerner | Nov 2005 | A1 |
| 20050265927 | Lee | Dec 2005 | A1 |
| 20050274378 | Bonney et al. | Dec 2005 | A1 |
| 20060000469 | Tseng | Jan 2006 | A1 |
| 20060003316 | Simard et al. | Jan 2006 | A1 |
| 20060040953 | Leone-Bay et al. | Feb 2006 | A1 |
| 20060041133 | Stevenson et al. | Feb 2006 | A1 |
| 20060060194 | Oliva | Mar 2006 | A1 |
| 20060062740 | Rand | Mar 2006 | A1 |
| 20060073105 | Yamashita et al. | Apr 2006 | A1 |
| 20060099269 | Cheatham et al. | May 2006 | A1 |
| 20060102511 | Pasbrig et al. | May 2006 | A1 |
| 20060120969 | Nilsson et al. | Jun 2006 | A1 |
| 20060153778 | Gelber | Jul 2006 | A1 |
| 20060160722 | Green et al. | Jul 2006 | A1 |
| 20060165756 | Catani et al. | Jul 2006 | A1 |
| 20060169280 | Yamashita et al. | Aug 2006 | A1 |
| 20060219242 | Zierenberg | Oct 2006 | A1 |
| 20060239933 | Nilsson et al. | Oct 2006 | A1 |
| 20060239934 | Cheatham | Oct 2006 | A1 |
| 20060243275 | Ruckdeschel et al. | Nov 2006 | A1 |
| 20060249419 | Taylor et al. | Nov 2006 | A1 |
| 20060260777 | Rashba-Step et al. | Nov 2006 | A1 |
| 20060283758 | Pasbrig et al. | Dec 2006 | A1 |
| 20070006876 | Finlay et al. | Jan 2007 | A1 |
| 20070017506 | Bell et al. | Jan 2007 | A1 |
| 20070020191 | Boss et al. | Jan 2007 | A1 |
| 20070027063 | Boss et al. | Feb 2007 | A1 |
| 20070044793 | Kleinstreuer et al. | Mar 2007 | A1 |
| 20070049576 | Barlow et al. | Mar 2007 | A1 |
| 20070059373 | Oberg | Mar 2007 | A1 |
| 20070059374 | Hokenson et al. | Mar 2007 | A1 |
| 20070074989 | Merboth et al. | Apr 2007 | A1 |
| 20070077219 | Fahl et al. | Apr 2007 | A1 |
| 20070086952 | Steiner | Apr 2007 | A1 |
| 20070099454 | Gordon | May 2007 | A1 |
| 20070125375 | Finlay et al. | Jun 2007 | A1 |
| 20070128193 | O'Neil et al. | Jun 2007 | A1 |
| 20070151562 | Jones | Jul 2007 | A1 |
| 20070160789 | Merical et al. | Jul 2007 | A1 |
| 20070175314 | Wanne | Aug 2007 | A1 |
| 20070190163 | Malakhov et al. | Aug 2007 | A1 |
| 20070191462 | Hettiarachchi | Aug 2007 | A1 |
| 20070196503 | Wilson | Aug 2007 | A1 |
| 20070207958 | Bridon et al. | Sep 2007 | A1 |
| 20070225587 | Burnell et al. | Sep 2007 | A1 |
| 20070235029 | Zhu et al. | Oct 2007 | A1 |
| 20070240708 | Schuckmann | Oct 2007 | A1 |
| 20070272763 | Dunne et al. | Nov 2007 | A1 |
| 20070277820 | Crowder et al. | Dec 2007 | A1 |
| 20070277821 | Oliva et al. | Dec 2007 | A1 |
| 20070295332 | Ziegler | Dec 2007 | A1 |
| 20070299074 | Netz et al. | Dec 2007 | A1 |
| 20080008764 | Milstein | Jan 2008 | A1 |
| 20080015457 | Silva | Jan 2008 | A1 |
| 20080039368 | Steiner et al. | Feb 2008 | A1 |
| 20080039402 | Mossalayi et al. | Feb 2008 | A1 |
| 20080047550 | Steiner et al. | Feb 2008 | A2 |
| 20080066739 | LeMahieu et al. | Mar 2008 | A1 |
| 20080108554 | Jackson et al. | May 2008 | A1 |
| 20080108574 | Barlow et al. | May 2008 | A1 |
| 20080115785 | Eason et al. | May 2008 | A1 |
| 20080127970 | Steiner et al. | Jun 2008 | A1 |
| 20080127971 | King et al. | Jun 2008 | A1 |
| 20080127974 | Lastow | Jun 2008 | A1 |
| 20080168987 | Denny et al. | Jul 2008 | A1 |
| 20080190424 | Lucking et al. | Aug 2008 | A1 |
| 20080190425 | Steiner et al. | Aug 2008 | A1 |
| 20080197044 | Hickey et al. | Aug 2008 | A1 |
| 20080216824 | Ooida | Sep 2008 | A1 |
| 20080217199 | Burress et al. | Sep 2008 | A1 |
| 20080255468 | Derchak et al. | Oct 2008 | A1 |
| 20080260838 | Hokenson et al. | Oct 2008 | A1 |
| 20080260840 | Alessi | Oct 2008 | A1 |
| 20080295833 | Rohrschneider et al. | Dec 2008 | A1 |
| 20080312155 | Kitada et al. | Dec 2008 | A1 |
| 20080314384 | Harris et al. | Dec 2008 | A1 |
| 20080319333 | Gavish et al. | Dec 2008 | A1 |
| 20090025720 | Chen | Jan 2009 | A1 |
| 20090068274 | Edwards et al. | Mar 2009 | A1 |
| 20090084379 | Goeckner et al. | Apr 2009 | A1 |
| 20090084380 | Gieschen et al. | Apr 2009 | A1 |
| 20090110647 | Richardson | Apr 2009 | A1 |
| 20090134051 | Rapp et al. | May 2009 | A1 |
| 20090149727 | Truitt et al. | Jun 2009 | A1 |
| 20090151720 | Inoue et al. | Jun 2009 | A1 |
| 20090178676 | Villax et al. | Jul 2009 | A1 |
| 20090205657 | Barney et al. | Aug 2009 | A1 |
| 20090209502 | Haeberlin et al. | Aug 2009 | A1 |
| 20090232891 | Gelber et al. | Sep 2009 | A1 |
| 20090241949 | Smutney | Oct 2009 | A1 |
| 20090250058 | Lastow | Oct 2009 | A1 |
| 20090258818 | Surolia et al. | Oct 2009 | A1 |
| 20090308390 | Smutney | Dec 2009 | A1 |
| 20090308391 | Smutney | Dec 2009 | A1 |
| 20090314291 | Anderson et al. | Dec 2009 | A1 |
| 20090314292 | Overfield | Dec 2009 | A1 |
| 20090320837 | Smith et al. | Dec 2009 | A1 |
| 20100012120 | Herder | Jan 2010 | A1 |
| 20100051027 | Remmelgas et al. | Mar 2010 | A1 |
| 20100065048 | Mueller-Walz et al. | Mar 2010 | A1 |
| 20100086609 | Steiner et al. | Apr 2010 | A1 |
| 20100113363 | Holst et al. | May 2010 | A1 |
| 20100163042 | Bhowmick et al. | Jul 2010 | A1 |
| 20100180894 | Jones et al. | Jul 2010 | A1 |
| 20100181225 | Spallek et al. | Jul 2010 | A1 |
| 20100190701 | Day et al. | Jul 2010 | A1 |
| 20100193380 | Sullivan et al. | Aug 2010 | A1 |
| 20100197565 | Smutney et al. | Aug 2010 | A1 |
| 20100212667 | Smith et al. | Aug 2010 | A1 |
| 20100235116 | Adamo et al. | Sep 2010 | A1 |
| 20100238457 | Adamo et al. | Sep 2010 | A1 |
| 20100278924 | Oberg | Nov 2010 | A1 |
| 20100288276 | Ganderton et al. | Nov 2010 | A1 |
| 20100326438 | Dunne | Dec 2010 | A1 |
| 20110000482 | Gumaste et al. | Jan 2011 | A1 |
| 20110003004 | Hokenson | Jan 2011 | A1 |
| 20110011394 | Edwards et al. | Jan 2011 | A1 |
| 20110023876 | Vehring et al. | Feb 2011 | A1 |
| 20110083667 | Briant | Apr 2011 | A1 |
| 20110155129 | Stedman et al. | Jun 2011 | A1 |
| 20110158935 | Kraft | Jun 2011 | A1 |
| 20110183901 | Cheatham | Jul 2011 | A1 |
| 20120014999 | Grant et al. | Jan 2012 | A1 |
| 20120040899 | Costello | Feb 2012 | A1 |
| 20120071515 | Lu | Mar 2012 | A1 |
| 20120094905 | Costello | Apr 2012 | A1 |
| 20120115777 | Richardson | May 2012 | A1 |
| 20120122775 | Boss et al. | May 2012 | A1 |
| 20120160241 | Oliva | Jun 2012 | A1 |
| 20120164186 | Grant et al. | Jun 2012 | A1 |
| 20120178935 | Stevenson | Jul 2012 | A1 |
| 20120192865 | Steiner et al. | Aug 2012 | A1 |
| 20120207913 | Smyth | Aug 2012 | A1 |
| 20120240929 | Steiner et al. | Sep 2012 | A1 |
| 20120247235 | Adamo et al. | Oct 2012 | A1 |
| 20120247465 | Wachtel | Oct 2012 | A1 |
| 20120328676 | Leone-Bay et al. | Dec 2012 | A1 |
| 20130012710 | Freeman et al. | Jan 2013 | A1 |
| 20130053309 | Kraft | Feb 2013 | A1 |
| 20130104887 | Smutney | May 2013 | A1 |
| 20130118491 | Richardson et al. | May 2013 | A1 |
| 20130125886 | Richardson et al. | May 2013 | A1 |
| 20130143801 | Steiner et al. | Jun 2013 | A1 |
| 20130189365 | Hokenson | Jul 2013 | A1 |
| 20130199527 | Smutney | Aug 2013 | A1 |
| 20130289278 | Kraft | Oct 2013 | A1 |
| 20130291866 | Smutney | Nov 2013 | A1 |
| 20130291867 | Smutney | Nov 2013 | A1 |
| 20130303445 | Wilson et al. | Nov 2013 | A1 |
| 20130338065 | Smutney | Dec 2013 | A1 |
| 20140007873 | Smutney | Jan 2014 | A1 |
| 20140014106 | Smutney | Jan 2014 | A1 |
| 20140083421 | Smutney | Mar 2014 | A1 |
| 20140096771 | Remmelgas et al. | Apr 2014 | A1 |
| 20140100158 | Richardson et al. | Apr 2014 | A1 |
| 20140187490 | Richardson et al. | Jul 2014 | A1 |
| 20140199398 | Grant et al. | Jul 2014 | A1 |
| 20140227359 | Leone-Bay et al. | Aug 2014 | A1 |
| 20140243530 | Stevenson et al. | Aug 2014 | A1 |
| 20140271888 | Grant et al. | Sep 2014 | A1 |
| 20140290654 | Poole et al. | Oct 2014 | A1 |
| 20140302151 | Leone-Bay et al. | Oct 2014 | A1 |
| 20140308358 | Oberg et al. | Oct 2014 | A1 |
| 20140315953 | Leone-Bay et al. | Oct 2014 | A1 |
| 20150031609 | Steiner et al. | Jan 2015 | A1 |
| 20150045295 | Smutney et al. | Feb 2015 | A1 |
| 20150052977 | Adamo et al. | Feb 2015 | A1 |
| 20150065422 | Kraft | Mar 2015 | A1 |
| 20150080298 | Costello et al. | Mar 2015 | A1 |
| 20150108023 | Bergey | Apr 2015 | A1 |
| 20150122258 | Steiner et al. | May 2015 | A1 |
| 20150150980 | Leone-Bay et al. | Jun 2015 | A1 |
| 20150174210 | Boss et al. | Jun 2015 | A1 |
| 20150196724 | Adamo et al. | Jul 2015 | A1 |
| 20150226656 | Adamo et al. | Aug 2015 | A1 |
| 20150231067 | Mann | Aug 2015 | A1 |
| 20150246188 | Steiner et al. | Sep 2015 | A1 |
| 20150283069 | Smutney et al. | Oct 2015 | A1 |
| 20150283213 | Costello et al. | Oct 2015 | A1 |
| 20150290132 | Gelber et al. | Oct 2015 | A1 |
| 20150359744 | Hokenson et al. | Dec 2015 | A1 |
| 20160008557 | Smutney et al. | Jan 2016 | A1 |
| 20160031833 | Wilson et al. | Feb 2016 | A1 |
| 20160067183 | Kraft | Mar 2016 | A1 |
| 20160095990 | Smutney et al. | Apr 2016 | A1 |
| 20160101049 | Wilson et al. | Apr 2016 | A1 |
| 20160151287 | Oberg et al. | Jun 2016 | A1 |
| 20160158156 | Fabio et al. | Jun 2016 | A1 |
| 20160175079 | Adamo et al. | Jun 2016 | A1 |
| 20160193432 | Harris et al. | Jul 2016 | A1 |
| 20160221967 | Stevenson et al. | Aug 2016 | A1 |
| 20160228659 | Smutney et al. | Aug 2016 | A1 |
| 20160243322 | Smutney et al. | Aug 2016 | A1 |
| 20160250297 | Leone-Bay et al. | Sep 2016 | A1 |
| 20160256640 | Overfield et al. | Sep 2016 | A1 |
| 20160287820 | Smutney et al. | Oct 2016 | A1 |
| 20160346212 | Hokenson et al. | Dec 2016 | A1 |
| 20160346394 | Grant et al. | Dec 2016 | A1 |
| Number | Date | Country |
|---|---|---|
| 2536047 | Mar 2005 | CA |
| 2551182 | Aug 2010 | CA |
| 101290219 | Oct 2008 | CN |
| 101851213 | Oct 2010 | CN |
| 102436238 | May 2012 | CN |
| 2840442 | Feb 1982 | DE |
| 3639836 | Jun 1988 | DE |
| 19519840 | Dec 1996 | DE |
| 0069715 | Jan 1983 | EP |
| 0122036 | Oct 1984 | EP |
| 0143524 | Jun 1985 | EP |
| 0180543 | May 1986 | EP |
| 220958 | May 1987 | EP |
| 0237507 | Aug 1987 | EP |
| 0257915 | Feb 1988 | EP |
| 0308637 | Mar 1989 | EP |
| 0360340 | Mar 1990 | EP |
| 0364235 | Apr 1990 | EP |
| 0387222 | Sep 1990 | EP |
| 0388621 | Sep 1990 | EP |
| 00606486 | Dec 1993 | EP |
| 00581473 | Feb 1994 | EP |
| 0655237 | May 1995 | EP |
| 0666085 | Aug 1995 | EP |
| 0748213 | Dec 1996 | EP |
| 0558879 | May 1997 | EP |
| 0844007 | Dec 1998 | EP |
| 1060741 | Dec 2000 | EP |
| 1114644 | Jul 2001 | EP |
| 0837710 | Nov 2001 | EP |
| 0640354 | Dec 2001 | EP |
| 1348428 | Oct 2003 | EP |
| 1364967 | Nov 2003 | EP |
| 0825885 | Mar 2004 | EP |
| 96911738 | Jun 2004 | EP |
| 1598066 | Nov 2005 | EP |
| 0833652 | Feb 2008 | EP |
| 1923087 | May 2008 | EP |
| 2060268 | May 2009 | EP |
| 2314298 | Apr 2011 | EP |
| 475440 | Nov 1937 | GB |
| 716815 | Oct 1954 | GB |
| 2072536 | Oct 1981 | GB |
| 2148841 | Jun 1985 | GB |
| 2240337 | Jul 1991 | GB |
| 2253200 | Sep 1992 | GB |
| 2262452 | Jun 1993 | GB |
| 2398065 | Aug 2004 | GB |
| S55-156085 | Nov 1980 | JP |
| 63-020301 | Jan 1988 | JP |
| 2115154 | Apr 1990 | JP |
| 2-149545 | Feb 1992 | JP |
| H07-041428 | Feb 1995 | JP |
| 09-208485 | Aug 1997 | JP |
| 10234827 | Sep 1998 | JP |
| 2002322294 | Nov 2002 | JP |
| 2003-503420 | Jan 2003 | JP |
| 2004-121061 | Apr 2004 | JP |
| 2006-280620 | Oct 2006 | JP |
| 2007-061281 | Mar 2007 | JP |
| 200505517 | Feb 2005 | TW |
| 9013285 | Nov 1990 | WO |
| 9104011 | Apr 1991 | WO |
| 9106287 | May 1991 | WO |
| 9116038 | Oct 1991 | WO |
| 9116882 | Nov 1991 | WO |
| 9119524 | Dec 1991 | WO |
| 9204069 | Mar 1992 | WO |
| 9208509 | May 1992 | WO |
| 9302712 | Feb 1993 | WO |
| 9314110 | Jul 1993 | WO |
| 9317728 | Sep 1993 | WO |
| 9318754 | Sep 1993 | WO |
| 9400291 | Jan 1994 | WO |
| 9408552 | Apr 1994 | WO |
| 9408599 | Apr 1994 | WO |
| 9419041 | Sep 1994 | WO |
| 9423702 | Oct 1994 | WO |
| 9425005 | Nov 1994 | WO |
| 9500127 | Jan 1995 | WO |
| 9505208 | Feb 1995 | WO |
| 9511666 | May 1995 | WO |
| 9524183 | Sep 1995 | WO |
| 9531979 | Nov 1995 | WO |
| 9534294 | Dec 1995 | WO |
| 9601105 | Jan 1996 | WO |
| 9605810 | Feb 1996 | WO |
| 9613250 | May 1996 | WO |
| 9622802 | Aug 1996 | WO |
| 9627386 | Sep 1996 | WO |
| 9632149 | Oct 1996 | WO |
| 9636314 | Nov 1996 | WO |
| 9636317 | Nov 1996 | WO |
| 9640206 | Dec 1996 | WO |
| 9701365 | Jan 1997 | WO |
| 9704747 | Feb 1997 | WO |
| 9725086 | Jul 1997 | WO |
| 9730743 | Aug 1997 | WO |
| 9735562 | Oct 1997 | WO |
| 9746206 | Dec 1997 | WO |
| 9749386 | Dec 1997 | WO |
| 9826827 | Jun 1998 | WO |
| 9834661 | Aug 1998 | WO |
| 9839043 | Sep 1998 | WO |
| 9841255 | Sep 1998 | WO |
| 9843615 | Oct 1998 | WO |
| 9914239 | Mar 1999 | WO |
| 9918939 | Apr 1999 | WO |
| 9932510 | Jul 1999 | WO |
| 9933862 | Jul 1999 | WO |
| 9952506 | Oct 1999 | WO |
| 0012116 | Mar 2000 | WO |
| 0033811 | Jun 2000 | WO |
| 0059476 | Oct 2000 | WO |
| 0071154 | Nov 2000 | WO |
| 0100654 | Jan 2001 | WO |
| 0181321 | Jan 2001 | WO |
| 0107107 | Feb 2001 | WO |
| 0149274 | Jul 2001 | WO |
| 0151071 | Jul 2001 | WO |
| 0152813 | Jul 2001 | WO |
| 0166064 | Sep 2001 | WO |
| 0168169 | Sep 2001 | WO |
| 0197886 | Dec 2001 | WO |
| 0211676 | Feb 2002 | WO |
| 0212201 | Feb 2002 | WO |
| 0204769 | Jun 2002 | WO |
| 02058735 | Aug 2002 | WO |
| 02059574 | Aug 2002 | WO |
| 02067995 | Sep 2002 | WO |
| 02085281 | Oct 2002 | WO |
| 02098348 | Dec 2002 | WO |
| 02102444 | Dec 2002 | WO |
| 03000202 | Jan 2003 | WO |
| 03015857 | Feb 2003 | WO |
| 03018059 | Mar 2003 | WO |
| 03022304 | Mar 2003 | WO |
| 03055547 | Jul 2003 | WO |
| 03057170 | Jul 2003 | WO |
| 03061578 | Jul 2003 | WO |
| 03072195 | Sep 2003 | WO |
| 03080149 | Oct 2003 | WO |
| 03084502 | Oct 2003 | WO |
| 03086345 | Oct 2003 | WO |
| 03094951 | Nov 2003 | WO |
| 2004012672 | Feb 2004 | WO |
| 2004012720 | Feb 2004 | WO |
| 2004033010 | Apr 2004 | WO |
| 2004035121 | Apr 2004 | WO |
| 2004041338 | May 2004 | WO |
| 2004050152 | Jun 2004 | WO |
| 2004054647 | Jul 2004 | WO |
| 2004056314 | Jul 2004 | WO |
| 2004060458 | Jul 2004 | WO |
| 2004064862 | Aug 2004 | WO |
| 2004075919 | Sep 2004 | WO |
| 2004080401 | Sep 2004 | WO |
| 2004080482 | Sep 2004 | WO |
| 2004103304 | Dec 2004 | WO |
| 2005002654 | Jan 2005 | WO |
| 2005020964 | Mar 2005 | WO |
| 2005023348 | Mar 2005 | WO |
| 2005028699 | Mar 2005 | WO |
| 2005067964 | Jul 2005 | WO |
| 2005081977 | Sep 2005 | WO |
| 2005089722 | Sep 2005 | WO |
| 2005089843 | Sep 2005 | WO |
| 2005102428 | Nov 2005 | WO |
| 2005102429 | Nov 2005 | WO |
| 2005113042 | Dec 2005 | WO |
| 2005113043 | Dec 2005 | WO |
| 2005120616 | Dec 2005 | WO |
| 2006010248 | Feb 2006 | WO |
| 2006017688 | Feb 2006 | WO |
| 2006023849 | Mar 2006 | WO |
| 2006023943 | Mar 2006 | WO |
| 2006023944 | Mar 2006 | WO |
| 2006037636 | Apr 2006 | WO |
| 2006059939 | Jun 2006 | WO |
| 2006061637 | Jun 2006 | WO |
| 2006086107 | Aug 2006 | WO |
| 2006090149 | Aug 2006 | WO |
| 2006105501 | Oct 2006 | WO |
| 2007007110 | Jan 2007 | WO |
| 2007016600 | Feb 2007 | WO |
| 2007019229 | Feb 2007 | WO |
| 2007024953 | Mar 2007 | WO |
| 2007030706 | Mar 2007 | WO |
| 2007033316 | Mar 2007 | WO |
| 2007033372 | Mar 2007 | WO |
| 2007042822 | Apr 2007 | WO |
| 2007068896 | Jun 2007 | WO |
| 2007075534 | Jul 2007 | WO |
| 2007093310 | Aug 2007 | WO |
| 2007098500 | Aug 2007 | WO |
| 2007100535 | Sep 2007 | WO |
| 2007118342 | Oct 2007 | WO |
| 2007118343 | Oct 2007 | WO |
| 2007121411 | Oct 2007 | WO |
| 2007132217 | Nov 2007 | WO |
| 2007144607 | Dec 2007 | WO |
| 2007144614 | Dec 2007 | WO |
| 2008001744 | Jan 2008 | WO |
| 2008008021 | Jan 2008 | WO |
| 2008014613 | Feb 2008 | WO |
| 2008020217 | Feb 2008 | WO |
| 2008060484 | May 2008 | WO |
| 2008092864 | Aug 2008 | WO |
| 2008110809 | Sep 2008 | WO |
| 2009005546 | Jan 2009 | WO |
| 2009008001 | Jan 2009 | WO |
| 2009009013 | Jan 2009 | WO |
| 2009047281 | Apr 2009 | WO |
| 2009055030 | Apr 2009 | WO |
| 2009055740 | Apr 2009 | WO |
| 2009055742 | Apr 2009 | WO |
| 2009095684 | Aug 2009 | WO |
| 2009121020 | Oct 2009 | WO |
| 2009140587 | Nov 2009 | WO |
| 2009047281 | Dec 2009 | WO |
| 2009152477 | Dec 2009 | WO |
| 2009155581 | Dec 2009 | WO |
| 2010021879 | Feb 2010 | WO |
| 2010078373 | Jul 2010 | WO |
| 2010080964 | Jul 2010 | WO |
| 2010102148 | Sep 2010 | WO |
| 2010105094 | Sep 2010 | WO |
| 2010108046 | Sep 2010 | WO |
| 2010125103 | Nov 2010 | WO |
| 2010144785 | Dec 2010 | WO |
| 2010144789 | Dec 2010 | WO |
| 2011017554 | Feb 2011 | WO |
| 2011056889 | May 2011 | WO |
| 2011082328 | Jul 2011 | WO |
| 2011163272 | Dec 2011 | WO |
| 2012064892 | May 2012 | WO |
| 2012135765 | Oct 2012 | WO |
| 2012174472 | Dec 2012 | WO |
| 2012174556 | Dec 2012 | WO |
| 2013016754 | Feb 2013 | WO |
| 2013063160 | May 2013 | WO |
| 2014012069 | Jan 2014 | WO |
| 2014036323 | Mar 2014 | WO |
| 2014066856 | May 2014 | WO |
| 2014144895 | Sep 2014 | WO |
| 2015010092 | Jan 2015 | WO |
| 2015021064 | Feb 2015 | WO |
| 2015063100 | May 2015 | WO |
| 2015148905 | Oct 2015 | WO |
| Entry |
|---|
| Leahy et al. Beta-cell dysfunction in type II diabetes mellitus. Curr Opin Endocrinol Diabetes 2:300-306, 1995. |
| Leiner et al. “Particles facilitate the absorption of insulin in a primary cell culture model of alveolar epithelium without evidence of cytotoxicity.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 467-P. |
| Leiner et al. “The pharmacokinetic profile of insulin administered by inhalation in the rat.” Diabetes 53 Supplement, Jun. 2004, A111. |
| Lian et al. A self-complementary self-assembling microsphere system: application for intravenous delivery of the antiepileptic andneuroprotectant compound felbanate. J Pharm Sci 89:867-875, 2000. |
| Lindner et al. “Increase in serum insulin levels is correlated with lung distribution after pulmonary delivery of Technosphere/Insulin.” Diabetologia 46:A277, 2003. |
| Mandal “Inhaled insulin for diabetes mellitus.” Am J Health Sys Pharm 62:1359-64, 2005. |
| Mann “Pulmonary insulin—the future of prandial insulin therapy.” Presented at the 5th Annual Meeting of the Diabetes Technology Society, Nov. 2005, abstract A94. |
| Monnier et al. “Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.” JAMA 295:1681-7, 2006. |
| Nathan et al. “Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.” N Engl J Med 353:2643-53, 2005. |
| Nemmar et al., Passage of inhaled particles into the blood circulation in humans. Circulation pp. 411-414 (2002). |
| Newman, Principles of metered-dose inhaler design. Respiratory Care, vol. 50, No. 9, pp. 1177-1190 (2005). |
| Next Generation Inhaler Nears Market, Manufacturing Chemist, Cambridge Consultants, Polygon Media Ltd. (2006). |
| Non-covalent interactions from UCDavis ChemWiki, pp. 1-5. Accessed by Examiner on Jul. 23, 2013 and cited in Office Action issued on Jul. 26, 2013 in U.S. Appl. No. 12/830,557. |
| Oberdorster et al., Correlation between particle size, in vivo particle persistence, and lung injury. Environ Health Perspect 102 Suppl 5, pp. 173-179 (1994). |
| Oberdorster et al.,Pulmonary effects of inhaled ultrafine particles. International Archives of Occupational and Environmental Health, vol. 74, pp. 1-8 (2001). |
| O'Neill, Air pollution and inflammation in type 2 diabetes: a mechanism for susceptibility. Occup Environ Med. vol. 64, pp. 373-379 (2007). |
| Owens et al. “Alternative routes of insulin delivery.” Diabetic Medicine 20:886-898, 2003. |
| Patton et al. “Clinical pharmacokinetics and pharmacodynamics of inhaled insulin.” Clin Pharmacokinet 43:781-801, 2004. |
| Pesic, Inhaler delivers more drug to the deep lung, says Cambridge Consultants. in-Pharma Technologist.com, http://www/in-pharmatechnologist.com/content/view/print/344335, Dec. 1, 2010. |
| Peyrot et al. “Resistance to insulin therapy among patients and providers.” Diabetes Care 28:2673-2679, 2005. |
| Pfeiffer et al. Insulin secretion in diabetes mellitus. Am J Med 70:579-88, 1981. |
| Pfützner A et al. “Lung distribution of radiolabeled Technosphere™/Insulin.” Diabetes 52 Supplement, Jun. 2003, A107. |
| Pfützner A et al. Pilot study with Technosphere/PTH(1-34)—a new approach for effective pulmonary delivery of parathyroid hormone (1-34). Horm Metab Res 35:319-323, 2003. |
| Pfützner A et al. “Variability of insulin absorption after subcutaneous and pulmonary application in patients with type 2 diabetes.” Diabetes 51 Supplement, Jun. 2002, A47-48. |
| Pfützner A. et al. “Influence of small dose i.v., s.c. and pulmonary insulin treatment on prandial glucose control in patients with Type 2 diabetes.” 37th Annual Meeting of the EASD, Sep. 9-13, 2001, abstract 812. |
| Pfutzner et al. “Inhaled Technosphere/Insulin Shows a Low Variability in Metabolic Action in Type 2 Diabetic Patients.” Diabetes 49 Supplement, May 2000, A121. |
| Pfutzner et al. “Pulmonary Insulin Delivery by Means of the Technosphere Drug Carrier Mechanism.” Expert Opin Drug Deliv 2:1097-1106, 2005. |
| Pfutzner, Technosphere/Insulin—A new approach for effective delivery of human insulin via the pulmonary route. Diabetes Technology & Therapeutics, vol. 4, No. 5, pp. 589-594 (2002). |
| Polonsky et al. “Abnormal Patterns of Insulin Secretion in Non-insulin-Dependent Diabetes Mellitus.” N Eng J Med 318:1231-39, 1988. |
| Raskin et al. “Continuous Subcutaneous Insulin Infusion and Multiple Daily Injection Therapy are Equally Effective in Type 2 Diabetes.” Diabetes Care 26:2598-2603, 2003. |
| Rave et al. “Dose Response of Inhaled Dry-Powder Insulin and Dose Equivalence to Subcutaneous Insulin Lispro.” Diabetes Care 28:2400-2405, 2005. |
| Rave et al. “Results of a Dose-Response Study with a New Pulmonary Insulin Formulation and Inhaler.” Diabetes 49, Supplement, May 2000, A75. |
| Raz et al. “Pharmacodynamics and Pharmacokinetics of Dose Ranging Effects of Oralin Versis S.S. Regular Insulin in Type 1 Diabetic Subjects.” Fourth Annual Diabetes Technology Meeting, Philadelphia, 2004. |
| Rhodes et al. “Technosphere: Microspherical Particles from Substituted Diketopiperazines for Use in Oral Drug Delivery.” 208th ACS National Meeting, Aug. 1994. |
| Rosenstock et al. “Inhaled Insulin Improves Glycemic Control when Substituted for or Added to Oral Combination Therapy in Type 2 Diabetes.” Ann Intern Med 143:549-558, 2005. |
| Roumeliotis, New inhaler launched with a bag, in-Pharma Technologist.com, Decision News Media SAS (2006). |
| Rousseau et al. “Drug delivery by fumaryl diketopiperazine particles: evidence for passive transport.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 484-P. |
| Sakagami et al. “Respirable microspheres for inhalation: the potential of manipulating pulmonary disposition for improved therapeutic efficacy.” Clin Pharmacokinet 44:263-77, 2005. |
| Shimada et al. Translocation pathway of the intertracheally instilled ultrafine particles from the lung into the blood circulationin the mouse. Toxicologic Pathology pp. 949-957 (2006). |
| Skyler JS et al. “Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects.” Diabetes Care 28:1630-1635, 2005. |
| Steiner et al. “A novel glucagon delivery system for the management of hyperinsulinemia.” Diabetes 49 Supplement, May 2000, A368. |
| Steiner et al. “Bioavailability and pharmacokinetic properties of inhaled dry powder Technosphere®/Insulin.” Diabetes 49 Supplement, May 2000, A126. |
| Steiner et al. “Technosphere®, a novel drug delivery system for oral administration of calcitonin.” Pharmaceutical Res 11:S299, 1994. |
| Steiner et al. Technosphere(TM)/Insulin—proof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endocrinol Diabetes 110:17-21, 2002. |
| Svartengren et al., Added External Resistance Reduces Oropharyngeal Deposition and Increases Lung Deposition of Aerosol Particles in Asthmatics. Am. J. Respir. Crit. Care Med., vol. 152, pp. 32-27, 1995. |
| Taylor et al. “Aerosols for macromolecule delivery. Design challenges and solutions.” Am J Drug Deliv 2:143-155, 2004. |
| Telko et al., Dry Powder Inhaler Formulation. Respiratory Care, Sep. 2005, vol. 50, No. 9, 1209-1227. |
| Vaczek, Accelerating drug delivery firms exploring new drug-delivery routes and devices intently awaiting the commercial launch of Exubera. Pharmaceutical & Medical Packaging News, vol. 14, No. 6 (2006). |
| Warren et al. “Postprandial versus prandial dosing of biphasic insulin aspart in elderly type 2 diabetes patients.” Diabetes Res Clin Pract 66:23-29, 2004. |
| White JR et al. “Inhaled insulin: an overview.” Clinical Diabetes 19:13-16, 2001. |
| “An inhaled insulin formulation (Technosphere Insulin) effectively improves glycaemic control in patients with type 2 diabetes mellitus.” Inpharma Weekly, vol. 1522, Jan. 28, 2006, p. 8. |
| Baso A et al. “Effects of a change in the pattern of insulin delivery on carbohydrate tolerance in diabetic and nondiabetic humans in the presence of differing degrees of insulin resistance.” J Clin Invest 97:2351-2361, 1996. |
| Bayés M et al. “Gateways to clinical trials” Methods Find Exp Clin Pharmacol 24:431-455, 2002. |
| Belmin J et al. “Novel drug delivery systems for insulin. Clinical potential for use in the elderly.” Drugs Aging 20:303-12, 2003. |
| Boss AH et al. “Inhaled Technosphere®/Insulin: Glucose elimination at the right time?” Poster presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 443-P. |
| Boss AH et al. “Insulin bio-effect is limited by speed of absorption and elimination: similarities between an inhaled insulin formulation that mimics first-phase kinetics and i.v. insulin.” Diabetologia 47:A314, 2004. |
| Boss AH et al. “Mimicry of the early phase insulin response in humans with rapidly available inhaled insulin accelerates post prandial glucose disposal compared to slower bioavailable insulin.” Presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 1373-P. |
| Boss AH et al. “Does kinetics matter? Physiological consequences of the ability of Technosphere®/Insulin inhalation to mimic first phase insulin release.” Presented at the 5th Annual Meeting of the Diabetes Technology Society, Nov. 2005, abstract A14. |
| Boss AH et al. “Markedly reduced post prandial glucose excursions through inhaled Technosphere®/Insulin in comparison to SC injected regular insulin in subjects with type 2 diabetes.” 1st Annual Meeting of the European Association for the Study of Diabetes, Sep. 2005, abstract 816. |
| Boss AH et al. “The variability and time-action profile of inhaled Technosphere®/Insulin compares favorably to that of subcutaneous human regular insulin.” Presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 358-OR. |
| Brownlee M et al. “Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications.” JAMA 295:1707-8, 2006. |
| Caumo et al. “First-phase insulin secretion: does it exist in real life” Considerations on shape and function. Am J Physiol Endocrinol Metab 287:E371-E385, 2004. |
| Cefalu “Concept, strategies and feasibility of noninvasive insulin delivery.” Diabetes Care 27:239-246, 2004. |
| Cefalu “Novel routes of insulin delivery for patients with type 1 or type 2 diabetes.” Ann Med 33:579-586, 2001. |
| Cerasi et al. Decreased sensitivity of the pancreatic beta cells to glucose in prediabetic and diabetic subjects. A glucose dose-response study. Diabetes 21(4):224-34, 1972. |
| Cernea et al. “Dose-response relationship of oral insulin spray in healthy subjects.” Diabetes Care 28:1353-1357, 2005. |
| Cheatham et al. “Desirable dynamics and performance of inhaled insulin compared to subcutaneous insulin given at mealtime in type 2 diabetes: A report from the Technosphere®/Insulin study group.” Diabetes Tech Ther 6:234-235, 2004. |
| Cheatham et al. “A novel pulmonary insulin formulation replicates first phase insulin release and reduces s-proinsulin levels.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 457-P. |
| Cheatham et al. “Prandial Technosphere®/Insulin inhalation provides significantly better control of meal-related glucose excursions than prandial subcutaneous insulin.” Presented at the Diabetes Technology Society meeting, Oct. 2004. |
| CN Office Action cited in application No. 200880122670.3 mailed on Nov. 23, 2011. |
| Coors et al., Polysorbate 80 in medical products and nonimmunologic anaphylactoid reactions. Ann. Allergy Asthma Immunol., 95(6): 593-599 (2005). Abstract only. Accessed by Examiner on Jul. 22, 2013 and cited in Office Action issued on Jul. 26, 2013 in U.S. Appl. No. 12/830,557. |
| Definition of analog from http://cancerweb.ncl.ac.uk/omd/about.html, pp. 1-5. Accessed by Examiner on Jul. 7, 2005 and cited in Office Action issued on Jul. 26, 2013 in U.S. Appl. No. 12/830,557. |
| Del Prato “Unlocking the opportunity of tight glycaemic control. Far from goal.” Diabetes Obesity Metabolism 7:S1-S4, 2005. |
| Drug Delivery, Easing the drug delivery route, Jun. 2006, Pharmaceutical & Medical Packaging News, Canon Communications. |
| Edelman SV Type II diabetes mellitus. Adv Int Med 43:449-500, 1998. |
| Edwards et al., Recent advances in pulmonary drug delivery using large, porous inhaled particles. Journal of Applied Physiology, pp. 379-385 (1998). |
| English tranaslation of Chinese Office Action for Chinese Patent application No. 201080026117.7. |
| Exubera indications, dosage, storage, stability. Http://www.rxlist.com/cgi/generic4/exubera—ids.htm. |
| Exubera package insert, p. 1. |
| Ferrin et al, Pulmonary retention of ultrafine and fine particles in rats. Am. J. Repir. Cell Mol. Biol., pp. 535-542 (1992). |
| File History of Related U.S. Appl. No. 13/921,104, filed Jun. 18, 2013. |
| File History of Related U.S. Appl. No. 13/941,365, filed Jul. 12, 2013. |
| File History of Related U.S. Appl. No. 14/092,810, filed Nov. 27, 2013. |
| Gates BJ “Update on advances in alternative insulin therapy.” Advances in Pharmacy 1:159-168, 2003. |
| Grant et al “Both insulin sensitivity and maximal glucose elimination rate are reduced in type 2 diabetes.” Presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 2202-PO. |
| Grant et al. “The distribution of 14C-labeled particles following intra-tracheal liquid installation in the Sprague-Dawley rat.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 461-P. |
| Gupta et al. Contemporary approaches in aerosolized drug delivery to the lung. J Controlled Resease 17:129-148, 1991. |
| Harsch IA “Inhaled Insulins: Their potential in the treatment of diabetes mellitus.” Treat Endocrinol 4:131-138, 2005. |
| Heinemann, L., et al., “Current status of the development of inhaled insulin” Br. Diabetes Vasc Dis 4:295-301, 2004. |
| Hirsch IB “Insulin analogues.” N Engl J Med 352:174-83, 2005. |
| Insulin inhalation NN 1998, Drugs R & D, 2004, pp. 46-49, Adis Data Information BV. |
| International Search Report for PCT/US2010/038287. |
| Kapitza et al. “Dose-response characteristics for a new pulmonary insulin formulation and inhaler.” Presented at the 35th Annual Meeting of the EASD, Sep. 2000, abstract OP29 184. |
| Katchalski, Ephraim, “Synthesis of Lysine Anhydride”, J. Amer. Chem. Soc., vol. 68, 1946, pp. 879-880. |
| Kaur et al., A delineation of diketopiperazine self-assembly processes: understanding the molecular events involved in NΛe-(Fumaroyl) diketopiperazine of L-Lys (FDKP) Ineractions. Molecular Pharmaceutics, vol. 5, No. 2, pp. 294-315 (2008). |
| Klinger et al., Insulin-micro and nanoparticles for pulmonary delivery. International Journal of Pharmaceutics, vol. 377, pp. 173-179 (2009). |
| Kohler et al. Non-radioactive approach for measuring lung permeability: inhalation of insulin. Atemw Lungenkrkh 13:230-232, 1987. |
| Kopple, Kenneth D., “A Convenient Synthesis of 2.,5-Piperazinediones”, J. Org. Chem., vol. 33, No. 2, 1968, pp. 862-864. |
| Krueger et al. “Toxicological profile of pulmonary drug delivery agent.” Presented at the American Diabetes Association 64th Scientific Sessions, Jun. 2004, abstract 465-P. |
| Laureano et al. “Rapid absorption and elimination of insulin from the lung following pulmonary administration of Technosphere®/Insulin: A pharmacokinetic study in a rat model.” Presented at the American Diabetes Association 65th Scientific Sessions, Jun. 2005, abstract 445-P. |
| Pfuetzner A, Rave K, Heise T, et al. Inhaled Technosphere™/insulin results in low variability in metabolic action in type 2 diabetic patients. Exp Clin Endocrinol Diabetes 2000; 108:S161. |
| Pfuetzner A, Rave K, Heise T, et al. Low variability in metabolic action in type 2 diabetic patients with inhaled Technosphere/insulin. Diabetologia 2000; 43:Abstract 774. |
| Phillips M, Amin N, Boss AH, et al. Pulmonary functions (over 2 years) in diabetic subjects treated with Technosphere® insulin or usual antidiabetic treatment. Diabetologia 2009; 52 (suppl 1). |
| Pohl R, Muggenberg BA, Wilson BR, et al. A dog model as predictor of the temporal properties of pulmonary Technosphere/insulin in humans. Respiratory Drug Delivery 2000; VII: 463-465. |
| Potocka E, Amin N, Cassidy J, et al. Insulin pharmacokinetics following dosing with Technosphere® insulin in subjects with chronic obstructive pulmonary disease. Current Medical Research and Opinion 2010; 26:2347-2353. |
| Potocka E, Baughman R A, Derendorf H. Population pharmacokinetic model of human insulin following different routes of administration. Journal of Clinical Pharmacology 2011;51:1015-1024. |
| Potocka E, Baughman R, Derendorf H. Population Pharmacokinetic Model of Regular Human Insulin Following Different Routes of Administration. AAPS Journal. 2009; 11(S1). Available from: http://www.aapsj.org. Presented at the 2009 AAPS (American Association of Pharmaceutical Scientists) National Biotechnology Conference, Jun. 21-24, Seattle, WA. |
| Potocka E, Baughman RA, Derendorf J. A population PK/PD model of Technosphere® insulin administered to healthy and type 2 diabetics. ADA 2010; Poster 624. |
| Potocka E, Baughman RA, Schwartz SL, et al. Pharmacokinetics of AFRESA® unchanged in patients with chronic obstructive pulmonary function ADA 2009; Poster 437. |
| Potocka E, Cassidy J P, Haworth P, et al. Pharmacokinetic characterization of the novel pulmonary delivery excipient fumaryl diketopiperazine. Journal of diabetes science and technology 2010;4:1164-1173. |
| Potocka E, Cassidy JP, Haworth P, et al. Pharmacokinetic characterization of fumaryl diketopiperazine. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 291. |
| Potocka E, Hovorka R, Baughman R, et al. Characterization of metabolism parameters following Technosphere® insulin and insulin Lispro. ADA 2010; Poster 1561. |
| Potocka E, Hovorka R, Baughman RA, et al. AFRESA™ supresses endogenous glucose production earlier than a rapid-acting analog (Lispro) and inhaled Exubera® ADA 2009; Oral 232. |
| Potocka E, Hovorka R, Baughman RA, et al. Technosphere® insulin suppresses endogenous glucose production earlier than a rapid-acting analog (lispro) and an inhaled insulin (exubera). Diabetologia 2009; 52 (suppl 1). |
| Prabhu et al. “A study of factors controlling dissolution kinetic of zinc complexed protein suspensions in various ionic species”, Int. J. Pharm. 217(1-2):71-8 (2001). |
| Laube et al., The lung as an alternative route for delivery for insulin in controlling postrprandial glucose levels in patients with diabetes. Chest, Preliminary Report 114 (6) : 1734-1739 (1998). |
| Quattrin et al. “Efficacy and Safety of Inhaled Insulin (Exubera) Compared with Subcutaneous Insulin Therapy in Patients with Type 1 Diabetes.” Diabetes Care, vol. 27, No. 11, Nov. 2004, p. 2622-2627. |
| Quddusi et al. “Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans.” Diabetes Care 26:791, 2003. |
| Rachman et al. “Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM.” Diabetes 45:1524, 1996. |
| Raju et al., Naseseazines A and B: a new dimeric diketopiperazine framework from a marine-derived actinomycete, Streptomyces sp. Organic letters, vol. 11, No. 17, pp. 3862-3865 (2009). |
| Raskin P, Heller S, Honka M, et al. Pulmonary function over 2 years in diabetic patients treated with prandial inhaled Technosphere® Insulin or usual antidiabetes treatment: A randomized trial. Diabetes, Obesity and Metabolism 2012;14:163-173. |
| Raskin P, Phillips M, Amin N, et al. Hypoglycemia in patients with type 1 diabetes incorporating prandial inhaled Technosphere® insulin into their usual diabetes treatment regimen vs continuing their usual diabetes management. AACE 2010; Poster 283. |
| Raskin P, Phillips MD, Rossiter A, et al. A1C and hypoglycemia in patients with type 2 diabetes mellitus incorporating prandial inhaled Technosphere® insulin into their usual antihyperglycemic regimen vs continuing their usual antihyperglycemic regimen. ADA 2010; Abstract 359-OR. |
| Raufman et al., Exendin-3, a novel peptdie from Heloderma horridum venom, interacts with vasoactive intestinal peptide receptors and a newly described receptor on dispersed aciin from guinea pig pancreas. J. Biol. Chem. 266(5) : 2897-2902 (1991). |
| Raufman et al., Truncated glucagon-like peptide-1 interacts with exendin receptors on dispersed acini from guina pig pancreas. J. Biol. Chem. 267(30) : 21432-21437 (1992). |
| Raun et al. “Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, where as a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not.” Diabetes 56:8, 2007. |
| Rave et al. “Coverage of Postprandial Blood Glucose Excursions with Inhaled Technosphere Insulin in Comparison to Subcutaneously Injected Regular Human Insulin in Subjects with Type 2 Diabetes.” Diabetes Care, vol. 30, No. 9, pp. 2307-2308, Sep. 2007. |
| Rave et al. “Inhaled Technosphere Insulin in Comparison to Subcutaneous Regular Human Insulin: Time Action Profile and Variability in Subjects with Type 2 Diabetes.” Journal of Diabetes Science and Technology, vol. 2, Issue 2, pp. 205-212, Mar. 2008. |
| Rave et al. “Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin.” Diabetes Care 28:1077, 2005. |
| Rave K, Heise T, Pfuetzner A, et al. Assessment of dose-response characteristics for a new pulmonary insulin formulation and inhaler. Exp Clin Endocrinol Diabetes 2000; 108:S161. |
| Rave K, Potocka E, Boss AH, et al. Pharmacokinetics and linear exposure of AFRESA™ compared with the subcutaneous injection of regular human insulin Diabetes, Obesity and Metabolism 2009; 11:715-720. |
| Razavi et al. “TRPVI+ sensory neurons control beta cell stress and islet inflammation in autoimmune disease.” Cell 127:1123, 2006. |
| Retrieved from website: http://groups.molbiosci.northwestern.edu/holmgren/Glossary/Definitions/Def-P/placebo.html, 1 page, Retrieved on Mar. 12, 2013. |
| Richardson et al. “Technosphere Insulin Technology.” Diabetes Technology & Therapeutics, vol. 9, Supplement 1, pp. S65-S72, 2007. |
| Richardson PC, Potocka E, Baughman RA, et al. Pharmacokinetics of Technosphere® insulin unchanged in patients with chronic obstructive pulmonary disease. Diabetologia 2009; 52 (suppl 1). |
| Richter et al. “Characterization of glucagon-like peptide-1(7-36)amide receptors of rat membranes by covalent cross-linking.” FEBS Letters 280:247, 1991. |
| Richter et al. “Characterization of receptors for glucagon-like peptide-1 (7-36)amide on rat lung membranes.” FEBS Letters 267:78, 1990. |
| Riddle “Combining Sulfonylureas and Other Oral Agents.” Am J Med, 2000, vol. 108(6A), pp. 15S-22S. |
| Riddle et al. “Emerging therapies mimicking the effects of amylin and glucagon-like peptide 1.” Diabetes Care 29:435, 2006. |
| Ritzel et al. “Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 (7-36 amide) after subcutaneous injection in healthy volunteers. Dose-response-relationships.” Diabetologia 38:720, 1995. |
| Rosen et al., Substance P microinjected into the periaqueductal gray matter induces antinociception and is released folloing morphine administration. Brain Research, 1001: 87-94 (2004). |
| Rosenmund et al., Diketopiperazines from Leuchs Anhydrides. Angew Chem Intern. Edit. vol. , No. 2 (1970). |
| Rosenstock “Dual therapy with inhaled human insulin (Exubera(R)) as add-on to metformin (with stopping sulfonurea) is better than triple therapy with rosiglitazone add-on to combination metformin and sulfonurea in poorly controlled Type 2 diabetes.” Diabetes 57:supplement 1:A557, Abstract 2018-PO, 2008. |
| Exubera package insert, p. 1, 2008. |
| Fadl et al., Effects of MDI spray angle on aerosol penetration efficiency through an oral airway cast. Journal of Aerosol Science, vol. 38, No. 8, pp. 853-864 (2007). |
| Falsone et al., The Biginelli dihydropyrimidone synthesis using polyphosphate ester as a mild and efficient cyclocondensation/dehydration reagent. Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University, pp. 122-134 (2001). |
| Farr, S.J. et al., Pulmonary insulin administration using the AERx® system:physiological and physiochemical factors influencing insulin effectiveness in healthy fasting subjects. Diabetes Tech. Ther. 2:185-197, 2000. |
| Fehmann et al. “Cell and molecular biology of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulin releasing polypeptide.” Endocrine Reviews 16:390, 1995. |
| Festa et al., “LDL particle size in relation to insulin, proinsulin, and insulin sensitivity” Diabetes Care, 22 (10):1688-1693 (1999). |
| Forst et al., “Metabolic Effects of Mealtime Insulin Lispro in Comparison to Glibenclamide in Early Type 2 Diabetes”, Exp. Clin. Endocrinol. Diabetes, 2003, 111, 97-103. |
| Fritsche et al. “Glimepiride Combined with Morning Insulin Glargine, Bedtime Neutral Protamine Hagedorm Insulin, or Bedtime Insulin Glargine in Patients with Type 2 Diabetes.” American College of Physicians 2003. |
| Galinsky et al., A synthesis of diketopiperazine's using polyphosphoric acid. Journal of the American Pharmaceutical Association, vol. 46, No. 7, pp. 391-393 (1957). |
| Garber, “Premixed insulin analogues for the treatment of diabetes mellitus”, Drugs, 66(1):31-49 (2006). |
| Garg et al. “Improved glycemic control without an increase in severe hypoglycemic episodes in intensively treated patients with type 1 diabetes receiving morning, evening, or split dose insulin glargine.” Diabetes Research and Clinical Practice 66 (2004) 49-56. |
| Garg SK, Kelly W, Freson B, et al. Treat-to-target Technosphere® insulin in patients with type 1 diabetes. ADA 2011; Abstract 941-P. |
| Garg SK, McGill JB, Rosenstock J, et al. Technosphere® insulin vs insulin lispro in patients with type 1 diabetes using multiple daily injections. ADA, Abstract 917-P (2011). |
| Glucagon for Injection (1999) glucagon for injection (rDNA origin), pp. 1-7. |
| Glucagon-like peptide-1; http://en.wikipedia.org/wiki/Glucagon-like peptide-1 (accessed Apr. 24, 2015). |
| GLUCOPHAGE Product Insert. Jan. 2009. |
| GLUCOTROL Product Insert. Sep. 2006. |
| Gnudi L, Lorber D, Rosenstock J, et al. Basal/bolus with prandial inhaled Technosphere® insulin (TI) plus insulin glargine qd vs biaspart 70/30 insulin bid in type T2 diabetes mellitus inadequately controlled on insulin with/without oral agents. Diabetologia 2009; 52 (suppl 1). |
| Goke et al., Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J. Biol. Chem. 268(26):19650-19655 (1993). |
| Golpon et al. “Vasorelaxant effect of glucagon-like peptide-(7-36) amide and amylin on the pulmonary circulation of the rat.” Regulatory Peptides 102:81, 2001. |
| Gonzalez et al., Actualizacion del tratamiento farmacologico de la diabetes mellitus tipo 2. Del Sistema Nacional de Salud. Volumen 32, No. 1, pp. 3-16 (2008)—full article in Spanish with English abstract. |
| Gotfried M, Cassidy JP, Marino MT, et al. Lung deposition and absorption of insulin from Technosphere® insulin. Diabetologia 2009; 52 (suppl 1). |
| Grant M, Harris E, Leone-Bay A, Rousseau K. Technosphere®/insulin: Method of action. Diabetes Technology Meeting 2006; Poster. |
| Grant ML, Greene S, Stowell GW, et al. Mimicking endogenous peptide secretion by inhalation APS 2009; poster. |
| Greene et al. “Effects of GLP-1 Technosphere(TM) powder: administered by pulmonary insufflation in male obese Zucker diabetic fat (ZDF) rats.” Diabetes Technology Meeting, San Francisco, Oct. 2007. |
| Greene et al., Greene's protective groups in organic synthesis. 4th ed., pp. 781-783 (2007). |
| Gurrieri et al., Thermal condensation of some alpha-aminoacids with phatalic acid. Thermochimica Acta, 7 (1973) 231-239. |
| Gutniak et al. “Antidiabetogenic action of glucagon-like peptide-1 related to administration relative to meal intake in subjects with type 2 diabetes.” J Int Med 250:81, 2001. |
| Gutniak et al. “Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus.” NEJM 326:1316, 1992. |
| Gutniak et al. “GLP-1 tablet in type 2 diabetes in fasting and postprandial conditions.” Diabetes Care 20:1874, 1997. |
| Gutniak et al. “Potential therapeutic levels of glucagon-like peptide I achieved in humans by a buccal tablet.” Diabetes Care 19:843, 1996. |
| Gutniak et al. “Subcutaneious injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM.” Diabetes Care 17:1039, 1994. |
| Guyton et al., “Acute Control of Llocal Blood Flow”, Textbook of Medical Physiology, Chapter 17, 10th Edition, W.B. Saunders Company, pp. 176-177, 2000. |
| Gyore et al., Thermal Analysis, vol. 2—Proceedding Fourth ICTA Budapest 1974; 387-394. |
| Haak “New developments in the treatment of type 1 diabetes mellitus.” Exp Clin Endocrinol Diabetes 107:Suppl 3: S108, 1999. |
| Haffner et al., “Proinsulin and insulin concentrations I relation to carotid wall thickness”, Strock 29:1498-1503 (1998). |
| Hagedorn et al. “Protamine Insulin”, JAMA, 106:177-180 (1936). |
| Haino, Takeharu et al. “On-beads Screening of Solid-Attached Diketopiperzines for Calix[5]Arene-Based Receptor.” Tetrahedron Letters, 40(20), 3889-3892, 2003. |
| Halozyme Press Release. Jun. 6, 2009. |
| Hanley et al., “Cross-sectional and prospective associations between proinsulin and cardovascular disease risk factors in a population experiencing rapid cultural transition” Diabetes Care 24(7): 1240-1247 (2001). |
| Hassan et al. “A Randomized, Controlled Trial Comparing Twice-a-Day Insulin Glargine Mixed with Rapid-Acting Insulin Analogs Versus Standard Neutral Protamine Hagedom (NPH) Therapy in Newly Diagnosed Type 1 Diabetes.” Pediatrics, 121(3), e466-e472, 2008. |
| Hassan et al. “In vivo dynamic distribution of 131I-glucagonOlike peptide-1 (7-36) amide in the rat studied by gamma camera.” Nucl Med Biol 26:413, 1999. |
| Hausmann et al. “Inhaled insulin as adjunctive therapy in subjects with type 2 diabetes failing oral agents: a controlled proof of concept study.” Diabetes Obesity and Metabolism 8:574, 2006. |
| Hayasaka et al. “Proliferation of type II pneumocytes and alteration in their apical surface membrane antigenicity in pulmonary sarcoidosis.” Chest 116:477, 1999. |
| Chelikani et al., Intravenous infusion of glucagon-like peptide-1 potently inhibits food intake, sham feeding, and gastric emptying in rats. Am J Physiol. Regul. Integr. Comp. Physiol., 288(6):R1695-706, 2005. |
| Chemical Abstracts, vol. No. 114(22), Abstract No. 214519x (1990). |
| Chemicaland21.com. Solvents. Dec. 12, 2008. Available from: <http://web.archive.org/web20081212035748/http://www.chemicalland21.com/info/SOLVENTS.htm. |
| Chow et al., Particle Engineering for Pulmonary Drug Delivery. Pharmaceutical Research, vol. 24, No. 3, pp. 411-437 (2007). |
| Glee et al. Nature Genetics 38:688-693, 2006. |
| Cobble “Initiating and Intensifying Insulin Therapy for Type 2 Diabetes: Why, When, and How.” Am J Ther. Jan. 8, 2009. |
| Coffey et al. “Valuing heath-related quality of life in diabetes.” Diabetes Care 25:2238, 2002. |
| Colagiuri et al., Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes associated with improved outcomes? Diabetes Care, vol. 25, pp. 1410-1417 (2002). |
| Combettes and Kargar, C, Newly Approved and Promising Antidiabetic Agents. Therapie, Jul.-Aug. 2007: 62 (4): 293-310. |
| Costello et al., “Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism in prostate epithelial cells”, Journ. Biol. Chem. 272(46):28875-28881 (1997). |
| Cricket TM Single-Use Inhalers [on-line]. MannKind Technologies Website, posted in 2011, [retrieved on Jul. 30, 2012]. Retrieved from the Internet. <URL:mannkindtechnologies,com/DeviceTechnology/CricketSingleUseInhalers.aspx>. |
| Crosby, J. “Dog Normals”, <http://vetmedicine.about.com/od/diseasesconditionsfaqs/tp/TP—dogfacts.htm>, copyright 2013. |
| Cruetzfeldt et al. “Glucagonostatic actions and reduction of fasting hyerglycemia by exogenous glucagon-like peptide i(7-36) amide in type 1 diabetic patients.” Diabetes Care 19:580, 1996. |
| D'Alessio et al., Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J. Clin. Invest., 97:133-38 (1996). |
| Database adisinsight, “Gucagon-like peptide-1 inhalation—MannKind Corporation”, Database accession No. 2009:1048 Abstract. |
| Davis “Postprandial Physiology and the Pathogenesis of Type 2 Diabetes Mellitus.” Insulin, vol. 3, Apr. 1, 2008, pp. 132-140. |
| De Heer et al. “Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide-1.” Diabetes 56:438, 2007. |
| Deacon “Therapeutic strategies based on glucagon-like peptide 1.” Diabetes. Sep;53(9):2181-9, 2004. |
| Deacon et al., “Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig”, Am. J. Physiol. 271 (Endocrino. Metab. 34): E458-E464, 1996. |
| DECODE study group. “Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.” Lancet. Aug. 21, 1999;354(9179):617-21. |
| DedicatedPhase, “Preclinical Trials and Research”, <http://www.dedicatedphase1.com/preclinical-research.html>, copyright 2006-2011, p. 1. |
| Delgado-Aros et al. “Effect of GLP-1 on gastric volume, emptying, maximum volume ingested and postprandial symptoms in humans.” Am J Physiol Gastrointest Liver Physiol 282:G424, 2002. |
| Diabetes: Counting Carbs if You Use Insulin, WedMD, http://diabetes.webmd.com/carbohydrate-counting-for-people-who-use-insulin#m Oct. 1, 2010. |
| Diez et al. “Inhaled insulin—a new therapeutic option in the treatment of diabetes mellitus” Expert Opin. Pharmacother, 2003, 4, 191-200. |
| Dorwald, F.A. Side reactions in organic synthesis. Wiley, (2005). |
| Doyle et al. “Glucagon-like peptide-1.” Recent Prog Horm Res. 2001;56:377-99. |
| Dreamboat TM Reusable Inhalers [on-line]. MannKind Technologies Website, posted in 2011, Retrieved from the Internet: <URL: mannkindtechnologies.com/Device Technology/Dream Boat Reuseable Inhalers.aspx>. |
| Drucker “Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes.” Curr Pharma Design 7:1399, 2001. |
| Drucker et al., “The incretin system:glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes”, www.thelancet.com, vol. 368, pp. 1696-1705, Nov. 11, 2006. |
| Dungan et al., Glucagon-like peptide 1-based therapies for type 2 diabetes: a focus on exntadtide. Clinical Diabetes, 23: 56-62 (2005). |
| Dunn, “Zinc-ligand interactions modulate assembly and stability of the insulin hexamer”, Biometals, 18(4):295-303 (2005). |
| Edited by Fukushima, Masanori, “Arterial Sclerosis,” Merck Manual 17th, Japanese Edition, NIKKEI BP Corp., p. 1659-1663, 1999. |
| Edwards CMB et al. “Cardiovascular and pancreatic endocrine response to glucagon-like peptide-1(7-36) amide in the conscious calf.” Exp Physiol 82:709, 1997. |
| Edwards CMB et al. “Subcutaneous glucagon-like peptide-1(7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects.” Clinical Science 96:719, 1998. |
| Eggers et al., Molecular confinement influences protein structure and enhances thermal protein stability. Protein Sci., 10:250-261 (2001). |
| Ehlers et al. “Recombinant glucagon-like peptide-1 (7-36 amide) lowers fasting serum glucose in a broad spectrum of patients with type 2 diabetes.” Horm Metab Res 35:611, 2003. |
| Eissele et al., Rat gastric somatostatin and gastrin relase: interactions of exendin-4 and truncated glucagon-like peptide-1 (GLP-1) amide. Life Sci., 55(8):629-634 (1994). |
| Elliot et al., Parenteral absorption of insulin from the lung in diabetic children. Austr. Paediatr. J. 23: 293-297 (1987). |
| Elrick et al. “Plasma insulin response to oral and intravenous glucose administration.” J Clin Endocr 24:1076, 1964. |
| Engelgau MM “Screening for type 2 diabetes.” Diabetes Care 23:1563-1580, 2000. |
| Engwerda et al., Improved pharmackinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology. Diabetes Care, vol. 34, Aug. 2011, pp. 1804-1808. |
| Erlanger et al., Phosphorous pentoxide as a reagent in peptide synthesis. College of Physicians and Surgeons—Columbia Univeristy, vol. 26, pp. 2534-2536 (1960). |
| Exubera indications, dosage, storage, stability. Http://www.rxlist.com/cgi/generic4/exubera—ids.htm, 2008. |
| Bilheimer DW, Ren H, Boss AH. Analysis of cardiovascular adverse events in patients with type 1 or type 2 diabetes enrolled in selected therapeutic trials in the phase 2/3 Technosphere® insulin development program. ADA 2011. Poster 922-P. |
| Billings CC, Smutney CC, Howard CP, et al. Handleability and characterization of inhalation profiles using the Gen2 delivery system in a pediatric population. Diabetes Technology Meeting 2010; poster. |
| Biodel's Intellecutal Property position strengthened for ultra-rapid-acting insulin programs by notice of intent to grant from European Patent Office. Newswire Feed, published May 2, 2012. |
| Blazquez E et al. “Glucagon-like peptide-1 (7-36) amide as a novel neuropeptide.” Mol Neurobio 18:157, 1998. |
| Bloomgarden “Gut-derived incretin hormones and new therapeutic approaches.” Diabetes Care 27:2554, 2004. |
| Boer et al., Design and application of a new modular adapter for laser diffraction characterization of inhalation aerosols. International Jornal of Pharmaceutics 249, pp. 233-245 (2002). |
| Boer et al., Inhalation characteristics and their effects on in vitro drug delivery from dry powder inhalers. Part 1. Inhalation characteristics, work of breathing and volunteers' preference in dependence of the inhaler resistance. Int. J. Pharm. 130 (1996) 231-244. |
| Bojanowska “Physiology and pathophysiology of glucagon-like peptide-1 (GLP-1): the role of GLP-1 in the pathogenesis of diabetes mellitus, obesity and stress.” Med Sci Monit 11:RA271, 2005. |
| Bonner-Weir S et al. “New sources of pancreatic beta-cells.” Nat Biotechnol 23:857-61, 2005. |
| Boss et al. “Prandial Insulin: Is Inhaled Enough?” Drug Development Research 69(3):138-142 (2008). |
| Boss A H, Petrucci R, Lorber D. Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin. Journal of diabetes science and technology 2012;6:773-779. |
| Boss AH, Baughman RA, Evans SH, et al. A 3 month comparison in type 1 diabetes of inhaled Technosphere®/Insulin (TI) to Sc administered rapid-acting insulin analogue (RAA) as prandial insulin in a basal/prandial regimen. Diabetes 2006; 55:A97. |
| Boss AH, Evans SH, Firsov I, et al. Technosphere® insulin as effective as sc rapid acting insulin analogue in providing glycemic control in a 6-month study of patients with type 2 diabetes. Diabetes Technology Meeting 2006; poster. |
| Boss AH, Evans, SH, Ren, H, et al. Superior post prandial glucose control in patients with type 1 diabetes when using prandial technosphere insulin compared to NovoLog. Diabetologia 2006; Abstract 181. |
| Boss AH, Marino MT, Cassidy JP, et al. C-peptide correction method to determine exogenous insulin levels in pharmacokinetic studies using Technosphere® insulin. Diabetologia 2009; 52 (suppl 1). |
| Boss AH, Raskin P, Philips M, et al. Glycosylated hemoglobin and hypoglycaemia in patients with Type 2 diabetes mellitus: Technosphere® insulin and usual antihyperglycaemic regimen vs usual antihyperglycaemic regimen. Diabetologia 2010;53(suppl 1). |
| Brandt D, Boss AH. The next generation insulin therapy. OndrugDelivery 2006 (published online). |
| Brange et al., “Insulin Structure and Stability”, Pharm Biotechnol, 5:315-50 (1993). |
| Bray “Exanatide” Am J Health—Sys Pharm 63:411, 2006. |
| Bruce, D.G., et al. “Physiological importance of deficiency of early prandial insulin secretion in non-insulin-dependent diabetes.” Diabetes 37:736-44, 1988. |
| Bullock BP et al. “Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor” Endocrinology 137:2968, 1996. |
| Burcelin et al. “Encapsulated, genetically engineered cells, secreting glucagon-like peptide-1 for the treatment of non-insulin-dependent diabetes mellitus.” Ann N Y Acad Sci. Jun. 18, 1999;875:277-85. |
| Calles-Escandon, J. and Robbins, D.C. “Loss of early phase insulin release in humans impairs glucose tolerance and blunts thermic effect of glucose.” Diabetes 36:1167-72, 1987. |
| Camilleri, Clinical Practice: Diabetic Gastroparesis. The New England Journal of Medicine, 356: 820-829 (2007). |
| Campos et al. “Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon0like peptide-1 in the mouse.” Endocrinology 134:2156, 1994. |
| Cassidy J P, Amin N, Marino M, et al. Insulin lung deposition and clearance following Technosphere® insulin inhalation powder administration. Pharmaceutical Research 2011; 28:2157-2164. |
| Cassidy J, Amin N, Baughman R, et al. Insulin kinetics following Technosphere® insulin inhalation powder administration unchanged in albuterol-treated asthmatics. ADA 2010; Poster 522. |
| Cassidy J, Baughman RA, Tonelli G, et al. Use of rapid acting insulin analog as the baseline infusion during glucose clamping improves pharmacokinetic evaluation. ADA 2007; 56: Abstract 602-P. |
| Cassidy JP, Baughman RA, Schwartz SL, et al. AFRESA® (Technosphere® insulin) dosage strengths are interchangeable ADA 2009; Poster 433. |
| Cassidy JP, Marino MT, Amin N, et al. Lung deposition and absorption of insulin from AFRESA® (Technosphere® insulin) ADA 2009; Poster 425. |
| Cassidy JP, Potocka E, Baughman RA, et al. Pharmacokinetic characterization of the Technosphere® inhalation platform Diabetes Technology Meeting 2009. poster. |
| Cefalu et al., Inhaled human insulin treatment in patients with type 2 diabetes mellitus. Ann. Int. Med., 2001, 134(3): 203-207. |
| Ceglia et al. “Meta-analysis: efficacy and safety of inhaled insulin therapy in adults with diabetes mellitus.” Ann Intern Med 145:665, 2006. |
| Cernea et al. “Noninjectable Methods of Insulin Administration.” Drugs of Today 2006, 42 (6): 405-424. |
| Chan et al., “Pharmacological Management of Type 2 Diabetes Mellitus: Rationale for Rational Use of Insulin”, Mayo Clin Proc, 2003, 78, 459-467. |
| Chase et al., “Redefining the clinical remission period in children with type 1 diabetes”, Pediatric Diabetes, 2004, 5, 16-19. |
| Fabio et al., Heat-stable dry powder oxytocin formulations or delivery by oral inhalation. AAPS PharmSciTech, (2015). |
| ACTOS Product Insert. Aug. 2008. |
| Adjusting Mealtime Insulin Doses. BD Diabetes. http://www.bd.com/diabetes/page.aspx?cat=7001&id=7280 (2014). |
| Ahren “GLP-1 and extra-islet effects.” Horm. Med Res 36:842, 2004. |
| Ahren B et al. “Characterization of GLP-1 effects on b-cell function after meal ingestion in humans.” Diabetes Care 26:2860, 2003. |
| Ahren B., Glucagon-like peptide-1 (GLP-1): a gut hormone of potential interest in the treatment of diabetes. BioEssays, V. 20, pp. 642-651 (1998). |
| Akerlund et al., Diketopiperazine-based polymers from common acids. Journal of Applied Polymer Science (2000), 78(12), 2213-2218. |
| Alabraba et al. Diabetes Technology & Therapeutics. Jul. 2009, 11(7): 427-430. |
| Alcohols limited. Alcohol speciality solvents—Go green! Jul. 24, 2010. Available from: <http://webarchive.org/web/20100724193725/http://www.alcohols.co.uk/speciality—solvents.php>. |
| Aljada et al. “Insulin inhibits the pro-inflammatroy transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations.” The Journal of Clinical Endocrinology and Metabolism, vol. 87, No. 3, p. 1419-1422, 2002. |
| Al-Showair et al., Can all patients with COPD use the correct inhalation flow with all inhalers and does training help? Respiratory Medicine, vol. 101, No. 11, p. 2395-2401 (2007). |
| American Diabetes Association, “Standards of medical care in diabetes—2009”, Diabetes Care, Jan. 2009, 32 Suppl 1: S13-61. |
| Amin N, Boss AH, Petrucci R, et al. Pulmonary functions (over 2 years) in diabetic subjects treated with AFRESA® or usual antidiabetic treatment ADA 2009; Poster 570. |
| Amin N, et al. Long-term sustained safety and efficacy of continued use of Technosphere insulin in subjects with type 2 diabetes. Abstract—Oral Presentation 215, 48th EASD Annual Meeting, Sep. 29-Oct. 2, 2009, Vienna Austria. |
| Amin N, Marino MT, Cassidy JP, et al. Acute pulmonary effects of Technosphere® insulin inhalation powder administered using a Gen2B inhaler compared to MedTone® C inhaler. Diabetes Technology Meeting 2010; poster. |
| Amin N, Phillips M, Boss AH, et al. Pulmonary functions (over 2 years) in diabetic patients treated with Technosphere® insulin (TI) or usual antidiabetic treatment. Third International Conference on Advanced Technologies and Treatments for Diabetes. 2010; Poster 290. |
| Angelo et al., Technosphere Insulin: Defining the Role of Technosphere Particles at the Celluar Level. J. Diabetes Sci. Technol., vol. 3, Issue 3, pp. 545-554 (2009). |
| Angelo et al. Technosphere® insulin inhalation powder: Defining the mechanism of action. ADA 2008; 57: Poster 428-P. |
| Antosiewiez et al., Prediction of pH-dependent properties of proteins. J Mol. Biol., 238:415-436 (1994). |
| Arakawa et al., Preferential interactions determine protein solubility in three-component solutions: the MgCl2 system. Biochemistry, 29:1914-1923 (1990). |
| Ashwell et al. “Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.” 2006 Diabetes UK, Diabetic Medicine, 23, 879-886. |
| Ashwell et al., “Optimal timing of injection of once-daily insulin gargine in people with Type 1 diabetes using insulin ispro at meal-times” 2005 Diabetes UK, Diabetic Medicine, 23, 46-52. |
| Atherton, F. et al. “Synthesis of 2(R)-A3(S)-Acylamino-2-OXO-1-Azetidinyloxy U-Acetic Acids.” Tetrahedron, vol. 40, No. 6, Jan. 1, 1984, pp. 1039-1046. |
| AVANDIA Product Insert, Oct. 2008. |
| Baggio et al. “A recombinant human glucagon-like peptide (GLP)-1-albumin protein (Albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostatsis.” Diabetes 53:2492, 2004. |
| Baggio et al. “Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, regulates fasting glycemia and noneneteral glucose clearance in mice.” Endocrinology 141:3703, 2000. |
| Baggio et al. “Harnessing the therapeutic potential of glucagon-like peptide-t” Treat Endocrinol 1:117, 2002. |
| Drucker et al., Minireview: The glucagon-like peptides. Endocrinology, vol. 142, No. 2, pp. 521-527 (2001). |
| Balkan B et al. “Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms.” Am J. Physiol Regulatory Integrative Comp Physiol 279:R1449, 2000. |
| Barnett AH et al. “An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with glibenclamide as adjunctive therapy in patients with Type 2 diabetes poorly controlled on metformin.” Diabetes Care 29(8):1818-1825, 2006. |
| Barnett et al., An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with metformin as adjunctive therapy in patients with type 2 diabetes poorly controlled on a sulfonylurea. Diabetes Care, 29(6): 1282-1287 (2006). |
| Barragan et al. “Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide in rats.” Am J. Physiol 266 (Endocrinol Metab 29):E459, 1994. |
| Bauer et al., “Assessment o beta-adrenergic receptor blockade after isamoitane, a 5-HT1-receptor active compound, in healthy volunteer”, Clin. Pharmacol Ther 53:76-83 (1993). |
| Bauer et al., “Pharmacodynamic effects of inhaled dry powder formulations of fenterol and colforsin in asthma”, Clin Pharmacol Ther 53:76-83, 1993. |
| Baughman R, Cassidy J, Amin N, et al. A phase I, open-label study of the effect of albuterol or fluticasone on the pharmacokinetics of inhaled Technosphere® insulin inhalation powder in healthy subjects. ADA 2010; Poster 528. |
| Baughman R, Cassidy J, Levy B, et al. Technosphere® insulin inhalation powder pharmacokinetics unchanged in subjects who smoke. Diabetes 2008; 57: A128. |
| Baughman R, Haworth P, Litwin J, et al. No cardiac effects found with therapeutic and suprtherapeutic doses of Technosphere® inhalation powder: results from a thorough QTc clinical study. ADA 2011. Poster 933-P. |
| Baughman, RA, Evans, SH, Boss, AH, et al. Technosphere insulin does not affect pulmonary function in a 6 month study of patients with type 2 diabetes. Diabetologia 2006;49:177-118. |
| Beers et al., Section 2—Chapter 13—Diabetes Mellitus, The Merck Manual of Diagnosis and Therapy, Merck Research Laboratories, pp. 165-177 (1999). |
| Behme et al. “Glucagon-like peptide-1 improved glycemic control in type 1 diabetes.” BMC Endocrine Disorders 3:3, 2003. |
| Bellary et al. “Inhaled insulin:new technology, new possibilities.” Int J Clin Pract 60:728, 2006. |
| Benita, Charaterization of Drug-Loaded Poly(d,I-lactide) Microspheres. J. Pharm. Sci., 73: 1721-1724 (1984). |
| Benito E et al. “Glucagon-like peptide-1-(7-36) amide increases pulmonary surfactant secretion through a cyclic adenosine 3′,5′-monophosphate-dependent protein kinase mechanism in rat type II pneumocytes.” Endocrinology 139:2363, 1998. |
| Bensch et al., Absorption of intact protein molecules across the pulmonary air-tissue barrier, Science 156: 1204-1206 (1967). |
| Berge et al., “Pharmaceutical Salts”, J. Pharmaceutical Sciences, Review Article, 66(1):1-19 (1977). |
| Bergenstal R, Kapsner P, Rendell M, et al., Comparative efficacy and safety of AFRESA® and a rapid-acting analog both given with glargine in subjects with T1 DM in a 52-week study ADA 2009; Poster 479. |
| Bergeron et al. “Macromolecular Self-Assembly of Diketopiperazine Tetrapeptides.” J. Am. Chem. Soc. 116, 8479-8484, 1994. |
| Lee et al., Intrapulmonary potential of polyethylene glycol-modified glucagon-like peptide-1s as a type 2 anti-diabetic agent. Regulatory Peptides, 152:101-107 (2009). |
| Selam, Jean-Louis. Inhaled Insulin: Promises and Concerns. Journal of Diabetes Science and Technology, vol. 2, Issue 2, pp. 311-315 (2008). |
| Shields, Irritable bowel syndrome, archived Jun. 21, 2009, available at: https://web.archive.org/web/200906211 00502/http://www.gastroenterologistpaloalto.com/conditions-diseases-irritable-bowelsyndrome-palo-alto-ca. html; Aug. 26, 2015 is U.S. Appl. No. 14/139,714. |
| Smith et al., Evaluation of novel aerosol formulations designed for mucosal vaccination against infleunza virus. Vacine, vol. 21, pp. 2805-2812 (2003). |
| U.S. Appl. No. 14/873,041, filed Oct. 1, 2015. |
| Design U.S. Appl. No. 29/504,212, filed Oct. 2, 2014. |
| U.S. Appl. No. 15/017,153, filed Feb. 5, 2016. |
| Young et al., Encapsulation of lysozyme in a biodegradable polymer by preparation with a vapor-over-liquid antisolvent. Journal of Pharmaceutical Sciences, 88:640-650 (1999). |
| Hazard Prevention and Control in the Work Environment: Airborne Dust WHO/SDE/OEH/99. 14 Chapter 1—Dust: Definitions and Concepts [retrieved from internet by Examiner in European case on Sep. 22, 2015]. <URL: http://www.who.int/occupational—health/publications/airdust/en/> published on Oct. 29, 2004 as per Wayback Machine. |
| Owens et al., Blood glucose self-monitoring in type 1 and type 2 diabetes: reaching a multidisciplinary consensus. Diabetes and Primary Care, vol. 6, No. 1, pp. 8-16 (2004). |
| U.S. Appl. No. 14/905,236, filed Jan. 14, 2016. |
| U.S. Appl. No. 14/991,777, filed Jan. 8, 2016. |
| U.S. Appl. No. 14/971,785, filed Dec. 16, 2015. |
| U.S. Appl. No. 14/910,235, filed Feb. 4, 2016. |
| Amodeo et al., Pain peptides. Solution structure of orphanin FQ2. FEBS Letters, vol. 473, Issue 2, pp. 157-160 (2000). |
| Vanderah et al., FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2): A peripheral efficacious k opioid agonist with unprecedented selectivity. The Journal of Pharmacology and Experimental Therapeutics, vol. 310, No. 1, pp. 326-333 (2004). |
| Krondahl et al., Regional differences in bioavailability of an opioid tetrapeptide in vivo rats after administration to the respiratory tract. Peptides, vol. 23, No. 3, pp. 479-488 (2002). |
| Design U.S. Appl. No. 29/553,303, filed Jan. 29, 2016. |
| Design U.S. Appl. No. 29/553,302, filed Jan. 29, 2016. |
| Design U.S. Appl. No. 29/553,305, filed Jan. 29, 2016. |
| Design U.S. Appl. No. 29/553,300, filed Jan. 29, 2016. |
| Nathan DM et al. “Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.” Diabetes Care 29:1963-1972, 2006. |
| Nathan DM et al. “Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.” Diabetes Care 31:173-175, 2008. |
| Nathan DM et al. “Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.” Diabetes Care 32:193-203, 2009. |
| Nathan, “Initial Management of Glycemia in Type 2 Diabetes Melllitus” N. Eng. J. Med., 2002, 347, 1342-9. |
| Nauck “Is glucagon-like peptide 1 an incretin hormone?” Diabetologia 42:373-379, 1999. |
| Nauck et al. “Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans.” Am J Physiol 273 (Endocrinol Metabl 36):E981, 1997. |
| Nauck et al. “Reduced incretin effect in type 2 (non-insulin-dependent) diabetes.” Diabetologia 29:46-52, 1986. |
| Nauck et al., Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab., 87:1239-1246, 2002. |
| Nauck et al., Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. Diabetologia, 39:1546-1553, 1996. |
| Nauck et al., Normalization of fasting hyperglycemia by exogenous GLP-1 (7-36 amide) in type 2 diabetic patients. Diabetologia, 36:741-744, 1993. |
| NHS Clinical Guidelines, “Type 1 diabetes diagnosis and mangement of type 1 diabetes in children and young people”, National Collaborating Centre for Women's and Children's Health Commissioned by the National Institute for Clinical Excellence, Sep. 2004, p. 1-217. |
| Nystrom et al. “Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetic patients with stable coronary artery disease.” Am J Physiol Endocrinol Metabl 287:E1209, 2004. |
| Okumura et al., Intratracheal delivery of insulin: absorption from solution and aerosol by rat lung. Int. J. Pharmaceuticals 88: 63-73 (1992). |
| Orgsoltab et al., Division of Organic Chemistry. Ohio Northern University. Nov. 24, 2009. Available from: <http://www.2.onu.edu/˜b-meyers/organic—solvents.html>. |
| Oshima et al. “Comparison of half-disappearance times, distribution volumes and metabolic clearance rates of exogenous glucagon-like peptide 1 and glucagon in rats.” Regulatory Peptides 21:85, 1988. |
| Ostrovsky, Gene. Mannkind Inhalation Insulin Going to FDA to Seek Approval [on-line]. MedGadget.com, posted on Mar. 17, 2009, Retrieved from the Internet: <URL:http://medgadget.com/2009/03mannkind—inhalation—insulin—going—to—fda—to—seek—approval.html>. |
| Owens et al. “Inhaled human insulin.” Nature Reviews, Drug Discovery, vol. 5, No. 5, pp. 371-372, May 2006. |
| Ozyazgan et al. “Effect of glucagon-like peptide-1)7-36) and exendin-4 on the vascular reactivity in streptozotocin/nicotinamide-induced diabetic rats.” Pharmacology 74:119, 2005. |
| Pacini P, Marino MT. Evaluation of endogenous and exogenous components to peripheral insulin concentration during administration of inhaled insulin. ADA 2010; Abstract 2094-PO. |
| Patton “Mechanisms of macromolecule absorption by the lungs.” Advanced Drug Delivery Reviews 19:3, 1996. |
| Patton “Unlocking the opportunity of tight glycaemic control. Innovative delivery of insulin via the lung.” Diabetes Obesity and Metabolism 7:S5, 2005. |
| Patton & Platz, Routes of Delivery: Case Studies: pulmonary delivery of peptides and proteins for systemic action. Adv. Drug. Del. Rev. 8: 179-196 (1992). |
| Patton et al. “The lungs as a portal of entry for systemic drug delivery.” Proc Am Thorac Soc 1:338, 2004. |
| Patton et al., “Inhaled Insulin”, Advanced Drug Delivery Reviews, 35, Feb. 1999, p. 235-247. |
| Onoue et al., Dry powder inhalation systems for pulmonary delivery of therapeutic peptides and proteins. Expert Opin. Ther. Patents 18(4):429-442 (2008). |
| Pearson et al., Systematically Initiating Insulin, supplemental to vol. 32, No. 1, 19S-28S, 2006. |
| Perera et al. “Absorption and Metabolic Effect of Inhaled Insulin.” Diabetes Care, vol. 25, No. 12, Dec. 2002, p. 2276-2281. |
| Petkowicz et al., “Hypoglycemic effect of liposome-entrapped insulin adminstered by various routes into normal rats”, Pol. J. Pharmacol. Pharm. 41:299-304 (1989). |
| Petrucci R, Amin N, Lovertin P. et al. Pulmonary function tests remain similar in patients who received Technosphere® insulin and in patients currently receiving standard antidiabetic therapy. Diabetologia 2009; 52 (suppl 1). |
| Peyrot M, Rubin RR, Otterbach K. Effect of Technosphere® inhaled insulin on treatment satisfaction, glycemic control and quality of life. Diabetes 2006; 55:Abstract 423-P. |
| Pezron et al., Insulin aggregation and asymmetric transport across human bronchial epithelial cell monolayers (Calu-3). J. Pharmaceutical Sci. 91: 1135-1146 (2002). |
| Li et al. “GLP-1; a novel zinc finger protein required in somatic cells of the gonad for germ cell development.” Dev Biol 301:106, 2007. |
| Li, Jun. Chapter 15: Drug Therapy of Metabolic Diseases. Clinical Pharmacotherapy, People's Medical Publishing House, 1st Edition, pp. 333-335 (2007). |
| Lim, “Microencapsulation of Living Cells and Tissues”, J. Pharm. Sci., 70: 351-354 (1981). |
| Liu et al., “Pulmonary delivery of free and liposomal insulin”, Pharmaceuticals Res. 10:228-232, 1993. |
| Lorber D, Howard CP, Ren H, et al. Reduced incidence and frequency of hypoglycemia in an integrated analysis of pooled data from clinical trials of subjects with type 2 diabetes using prandial inhaled Technosphere® insulin. AACE 2010; Poster 270. |
| Luque et al. “Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes.” J. Endocrinol 173:465, 2002. |
| Luzi, L. and DeFronzo, R.A. “Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans” Am. J. Physiol. 257 (Endocrinol. Metab. 20):E241-E246, 1989. |
| Luzio, S.D., et al. “Intravenous insulin simulates early insulin peak and reduces post-prandial hyperglycaemia/hyperinsulinaemia in type 2 (non-insulin-dependent) diabetes mellitus.” Diabetes Res. 16:63-67, 1991. |
| Malhotra et al., Exendin-4, a new peptide from Heloderma suspectum venom, potentiates cholecystokinin-induced amylase release from rat pancreatic acini. Regulatory Peptides, 41:149-56, 1992. |
| MannKind Corporation “Postprandial hyperglycemia: clinical significance, pathogenesis and treatment.” MannKind Corporation Monograph. 2009. |
| MannKind Corporation, Pulmonary Delivery: Innovative Technologies Breathing New Life into Inhalable Therapeutics, www.ondrugdelivery.com, 2006. |
| Burcelin et al., Long-lasting antidiabetic effect of a dipeptidyl peptidase IV-resistant analong of glucagon-like peptide-1. Metabolism, vol. 48, No. 2, pp. 252-258 (1999). |
| Marino MT, Cassidy JP, Smutney CC, et al. Bioequivalence and dose proportionality of Afrezza® inhalation powder administered using a Gen2 inhaler compared to the MedTone® inhaler. Diabetes Technology Meeting 2010; poster. |
| Marino MT, Cassidy JP, Smutney CC, et al. Improvement in bioavailability of FDKP with the NexGen2A device: Implications for delivery of pulmonary insulin. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 108. |
| Marino MT, Cassidy JP, Smutney CC, et al. Improvement in bioavailability of FDKP and insulin with the NGDSB device. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 107. |
| Marino MT. A pharmacokinetic/pharmacodynamic model of inhaled insulin with application to clinical trial simulation. ADA 2010; Abstract 2105-PO. |
| Marino MT. Cassidy JP, Baughman RA, et al. C-peptide correction method to determine exogenous insulin levels in pk studies using AFRESA® (Technosphere® insulin [TI]) ADA 2009; Poster 1451. |
| Marshall “Preventing and detecting complications of diabetes.” BMJ 333:455, 2006. |
| Mastrandrea “A breath of life for inhaled insulin: severe subcutaneous insulin resistance as an indication.” Pediatric Diabetes 2010: 11: 377-379. |
| Mathiowitz, Morphology of Polyanhydride Microsphere Delivery Systems, Scanning Microscopy, 4: 329-340 (1990). |
| Mathiowitz, Novel microcapsules for delivery systems. Reactive Polymers, 6: 275-283 (1987). |
| Mathiowitz, Polyanhydride microspheres as drug carriers I, hot-melt microencapsulation. J. Controlled Medicine, 5: 13-22 (1987). |
| Mathiowitz, Polyanhydride microspheres as drug carriers II, microencapsulation by solvent removal. J. Appl. Polymer Sci., 35: 755-774 (1988). |
| Mathiowitz, Polyanhydride microspheres IV, morphology and characterization systems made by spray drying. J. App. Polymer Sci., 45: 125-134 (1992). |
| Matsui et al. “Hyperplasia of type II pheumocytes in pulmonary lymphangioleiomyomatosis. Immunohistochemical and electron microscope study.” Arch Pathol Lab Med 124:1642, 2000. |
| Matthews DR et al. “Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.” Diabetologia. Jul. 1985;28(7):412-9. |
| McElduff A et al. “Influence of acute upper respiratory tract infection on the absorption of inhaled insulin using the AERx(R) insulin diabetes management system.” Br J Clin Pharmacol 59:546, 2005. |
| McMahon et al., “Effects of basal insulin supplementation on disposition of mixed meal in obese patients with NIDDM”, Diabetes, vol. 38, pp. 291-303 (1989). |
| Meier et al. “Absence of a memory effect for the insulinotropic action of glucagon-like peptide-1 (GLP-1) in healthy volunteers.” Horm Metab Res 35:551, 2003. |
| Meier et al. “Secretion, degradation, and elimination of glucagon-like peptide-1 and gastric inhibitor polypeptide in patients with chronic renal insufficiency and healthy control subjects.” Diabetes 53:654, 2004. |
| Meier et al. “The glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans.” Am J Physiol Endocrinol Metab 290:E1118, 2006. |
| Mendes et al., A non-dimensional functional relationship for the fine particle fraction produced by dry powder inhalers, Aerosol Science 38, pp. 612-624 (2007). |
| Mentlein et al., Dipeptidyl peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1 (7-36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem., 214:829-835, 1993. |
| Merck Manual 17th, Japanese Edition, NIKKEI BP Corp., 1999, p. 167-179. |
| Mitchell et al. “Intranasal Insulin: PK Profile Designed Specifically for Prandial Treatment of Type 2 Diabetes.” Drug Development Research 69(3):143-152 (2008). |
| Montrose-Rafizadeh et al., Diabetes, 45(Suppl. 2):152A, 1996. |
| Moren, Aerosols in Medicine (2nd Ed.), Elsevier, pp. 321-350 (1993). |
| Mudaliar et al., Insulin Therapy in Type 2 Diabetes. Endocrinology and Metabolism Clinics, vol. 30, No. 4, pp. 1-32 (2001). |
| Nagai et al., “Powder Dosage Form of Insulin for Nasal Administration”, J. Control Ref., 1:15-22 (1984). |
| Narayan et al. “Impact of recent increase in incidence on future diabetes burden.” Diabetes Care 29:2114, 2006. |
| Naslund E et al. “GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans.” Am J Physiol (Regulatory Integrative Comp Physiol 46):R910, 1999. |
| Naslund E et al. “Prandial subcutaneous injections of glucagon-like petide-1 cause weight loss in obese human subjects.” Br J Nutrition 91:439, 2004. |
| International Search Report mailed on Nov. 21, 2013 for International Application No. PCT/US2013/057397 filed on Aug. 29, 2013. |
| Eavarone et al., A voxel-based monte carlo model of drug release from bulk eroding nanoparticles. Journal of Nanoscience and Nanotechnology, vol. 10, pp. 5903-5907 (2010). |
| Marino MT, Cassidy JP, Smutney CC, et al. Improvement in bioavailability of FDKP with the NexGen2A device: Implications for delivery of pulmonary insulin. Diabetes Technology Meeting 2009; poster. |
| Heine “Unlocking the opportunity of tight glycaemic control. Promise ahead: the role of inhaled insulin in clinical practice.” Diabetes, Obesity and Metabolism 7:S19, 2005. |
| Heinemann “Variability of Insulin Absorption and Insulin Action.” Diabetes Technology & Therapeutics, vol. 4, No. 5, pp. 673-682. 2002. |
| Heinemann L et al. “Time-action profile of inhaled insulin.” Diabetic Med 14:63-72, 1997. |
| Heinemann, L. “Intra-individual Variability of the Metabolic Effect of Inhales Insulin Together with an Absorption Enhancer”, Diabetes Care, vol. 23, No. 9, Sep. 2000, p. 1343-1347. |
| Heise et al. “The effect of insulin antibodies on the metabolic action of inhaled and subcutaneous insulin.” Diabetes Care 28:2161, 2005. |
| Herbst et al., Insulin Strategies for Primary Care Providers. Clinical Diabetes, vol. 20, No. 1, pp. 11-17 (2002). |
| Heubner et al. “On inhalation of insulin” Klinische Wochenschrift 16:2342, 1924. (Original and English translation provided in one document). |
| Heyder “Particle Transport onto Human Airway Surfaces”, Eur. J. Respir. Dis, Suppl. 119, 29-50 (1982). |
| Heyder, “Alveolar deposition of inhaled particles in humans”, Am. Ind. Hyg. Assoc. J. 43(11): 864-866 (1982). |
| Hirsch, “Type 1 Diabetes Mellitus and the Use of Flexible Insulin Regimens” American Family Phyician, Nov. 15, 1999, p. 1-16. |
| Hirshberg B et al. “Islet transplantation: where do we stand now?” Diabetes Metab Res Rev 19:175-8, 2003. |
| Hite et al. “Exhuberance over Exubera.” Clin Diabetes 24(3):110-114, 2006. |
| Hoet et al., Review: Nanoparticles—known and unknown health risks. Journal of Nanobiotechnology, vol. 2, No. 12, (15 pages) (2004). |
| Hollander et al. “Efficacy and Safety of Inhaled Insulin (Exubera) Compared with Subcutaneous Insulin Therapy in Patients with Type 2 Diabetes.” Diabetes Care, vol. 27, No. 10, Oct. 2004, p. 2356-2362. |
| Holst “Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1.” Diabetes Metab Res Rev 18:430, 2002. |
| Holst et al. “On the effects of glucagon-like peptide-1 on blood glucose regulation in normal and diabetic subjects.” Ann N Y Acad Sci. Dec. 26, 1996;805:729-36. |
| Howard C, Ren H, Rossiter A, et al. Reduced incidence and frequency of hypoglycemia in an integrated analysis of pooled data from clinical trials of subjects with type 1 diabetes using prandial inhaled Technosphere® insulin. Diabetologia 2009; 52 (suppl 1). |
| Howard CP, Gnudi L, Loiter D, et al. Prandial inhaled Technosphere® insulin plus insulin glargine vs. biaspart 70/30 insulin in type 2 diabetes inadequately controlled with/without oral agents. Third International Conference on Advanced Technologies and Treatments for Diabetes. 2010; Poster 300. |
| Howard CP, Loiter D, Ren H, et al. Reduced incidence and frequency of hypoglycemia in pooled data from trials of type 2 diabetics using prandial inhaled Technosphere® insulin. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 304. |
| Howard CP, Petrucci R,Amin N, et al. Pulmonary function test remain similar in patients who received Technosphere® insulin and in patients currently receiving standard antidiabetic therapy. AACE 2010; Poster 267. |
| Howard CP, Ren H, Rossiter A, Boss AH. Reduced incidence and frequency of hypoglycemia in pooled data from trials of type 1 diabetics using prandial inhaled Technosphere® insulin. Third International Conference on Advanced Technologies and Treatments for Diabetes. 2010; Poster 302. |
| Howard CP, Ren H, Rossiter A, et al. Reduced incidence and frequency of hypoglycemia in an integrated analysis of pooled data from clinical trials of subjects with type 1 diabetes using prandial inhaled Technosphere® insulin. AACE 2010; Poster 269. |
| Howard CP, Rubin RR, Peyrot. M. Patient reported outcomes in adults with type 2 diabetes using mealtime AFRESA® (inhaled Technosphere® insulin) and basal insulin versus premixed insulin ADA 2009; Poster 551. |
| http://www.bilcaresolutions.com/en/products/pharma-packaging-innovations-pvc-aclar-films <URL:http://web.archive.org/web/20110127102552/http://www.bilcaresolutions.com/en/products/pharma-packaging-innovations-pvc-aclar-films> published on Jan. 27, 2011 as per “Wayback Engine”. |
| http://www.pmpnews.com/article/blister-packaging-materials (May 26, 2009). |
| Huda et al. “Gut peptides and the regulation of appetite.” Obesity Reviews 7:163, 2006. |
| Hui et al., The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects. European Journal of Endocrinology, 146: 863-869 (2002). |
| Hussain et al. “State of insulin self-association does not affects its absorption from the pulmonary route.” Eur. J. Pharm. Sciences 25:289-298, 2005. |
| Ikeda, Kuniki et al. “Peptide Antibiotics. XXVI. Syntheses of Cyclodipeptides Containing N. delta.-p-aminobenzenesulfonyl Ornithine Residue.” Chemical & Pharmaceutical Bulletin, 20(9), 1849-55, 1972. |
| Imeryuz et al. “Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms.” Am J Physiol 273 (Gastrointest Liver Physiol 36):G920, 1997. |
| Insulin is a natural product from http://www.levemir.com/startingoninsulin/whatisinulin.aspx, pp. 1-3. Accessed by Examiner on Apr. 30, 2014 and in Non-Final Offfice Action dated May 22, 2014 for U.S. Appl. No. 13/797,657 and in Non-Final Office Action dated May 22, 2014 for U.S. Appl. No. 12/883,369. |
| International Search Report for PCT International Application No. PCT/US2010/055323 filed on Nov. 3, 2010. |
| Written Opinion mailed on Jul. 1, 2013 for International Application No. PCT/US2013/032162 filed on Mar. 15, 2013. |
| International Search Report mailed on Jun. 21, 2010 for International Application No. PCT/US2010/027038 filed on Mar. 11, 2010. |
| Written Opinion for International Application No. PCT/US2011/060057 filed on Nov. 9, 2011. |
| International Search Report mailed Mar. 18, 2013 for International Application No. PCT/US2012/061749 filed on Oct. 24, 2012. |
| International Search Report mailed on Jun. 20, 2012 for International Applicaion No. PCT/US2012/031695 filed on Mar. 30, 2012. |
| International Search Report mailed on Nov. 19, 2014 for International Application No. PCT/US2014/049817 filed on Aug. 5, 2014. |
| International Search Report for International Application No. PCT/US2010/020448 filed on Jan. 8, 2010. |
| International Search Report mailed on Mar. 11, 2010 for International Application No. PCT/US2009/069745 filed on Dec. 29, 2009. |
| International Search Report mailed on Oct. 17, 2011 for International Application No. PCT/US2010/026271 filed on Mar. 4, 2010. |
| International Search Report for International Application No. PCT/US2010/038287 filed on Jun. 11, 2010. |
| Ishibashi, Norio et al. “Studies on Flavord Peptides. Part V. A Mechanism for Bitter Taste Sensibility in Peptides.” Agricultural and Biological Chemistry, 52(3), 819-27, 1988. |
| Iwanij et al., Characterization of the Glucagon Receptor and its Functional Domains Using Monoclonal Antibodies. The Journal of Biological Chemistry, vol. 265, No. 34, pp. 21302-21308, 1990. |
| Jain et al. “Insulin Therapy in Type 2 Diabetic Subjects Suppresses Plasminogen Activator Inhibitor (PAI-1) Activity and Proinsulin-like Molecules Independently of Glycaemic Control.” Diabetic Medicine, vol. 10, No. 1, p. 27-32, 1993. |
| Johnson et al., Peptide turn mimetics. Biotechnology and Pharmacy, p. 366-378 (1993). |
| International Search Report for International Application No. PCT/US2013/050392 filed on Jul. 12, 2013. |
| Rosenstock et al. “Efficacy and Safety of Technosphere Inhaled Insulin Compared With Technosphere Powder Placebo in Insulin-Naive Type 2 Diabetes Suboptimally Controlled with Oral Agents.” Diabetes Care, vol. 31, No. 11, pp. 2177-2182, 2008. |
| Rosenstock et al., “Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes”, Diabetes Care, 28(4):950-5 (2005). |
| Rosenstock J, Baughman RA, Ribera-Schaub T, et Al. A randomized, double-blind, placebo controlled study of the efficacy and safety of inhaled Technosphere® insulin in patients with type 2 diabetes (T2DM). Diabetes 2005;54: 4bstract 357-OR. |
| Rosenstock J, Lorber D, Petrucci R, et al. Basal/bolus with prandial inhaled Technosphere® insulin (TI) plus insulin glargine qd vs biaspart 70/30 insulin bid in T2 DM inadequately controlled on insulin with/without oral agents ADA 2009; Poster 466. |
| Rosenstock J, Lorger DL. Gnudi L, et al.Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. Lancet 2010;375:2244-2253. |
| Rossiter A, Amin N, Harris R, et al. Pulmonary safety of inhaled Technosphere® insulin therapy in adults with diabetes using high-resolution computerized tomography of the chest. Diabetologia 2009; 52 (suppl 1). |
| Rossiter A, Howard C, Amin N, et al. Technosphere® insulin: Safety in type 2 diabetes mellitus. ADA 2010; Poster 523. |
| Rubin RR, Peyrot M. Psychometric properties of an instrument for assessing the experience of patients treated with inhaled insulin: The inhaled insulin treatment questionnaire (INTQ) Health & Quality of Life Outcomes 2010.8:32. |
| Rubin RR, Peyrot M; Patient reported outcomes in adults with type 1 diabetes using mealtime AFRESA® (inhaled Technosphere® insulin) or rapid acting insulin with basal insulin ADA 2009; Poster 1881. |
| Ryan EA et al. “Successful islet transplantation. Continued insulin reserve provides long-term glycemic control.” Diabetes 51:2148-2157, 2002. |
| Sajeesh et al., Cyclodextrin-insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery. International Journal of Pharmaceuticals, 2006, 325, pp. 147-154. |
| Sakr, A new approach for insulin delivery via the pulmonary route: design and pharmacokinetics in non-diabetic rabbits. International Journal of Pharmaceutics, 86: 1-7 (1992). |
| Salib, Utilization of sodium alginate in drug microencapsulation. Pharazeutische Industrie, 40(11a): 1230-1234 (1978). |
| Saraceni C et al. “Effects of glucagon-like peptide-1 and long-acting analogues on cardiovascular and metabolic function.” Drugs R D 8:145, 2007. |
| Sarrach et al., “Binding and entrapment of insulin by liposomes made of lecithin-phosphotidix acid in acid solution” Pharmazie 40:642-645, 1985 (German and English Abstract). |
| Savage et al., “Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying healthy volunteers”, Gut, vol. 28, pp. 166-170, 1987. |
| Sawhney et al., Bioerodible hydrogels based on photopolymerized poly(ethylene glycol)-co-poly(a-hydroxy acid) diacrylate macromere. Macromolecules, 26: 581-587 (1993). |
| Schaffer et al. “Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks.” PNAS 100:4435-4439, 2003. |
| Schepp et al., Eur. J. Pharmacol., 269:183-91, 1994. |
| Scherbaum “Unlocking the opportunity of tight glycaemic control. Inhaled insulin: clinical efficacy.” Diabetes Obesity and Metabolism 7:S9-S13, 2005. |
| Schirra et al. “Gastric emptying and release of incretin hormones after glucose ingestion in humans.” J Clin Invest 97:92-103, 1996. |
| Schluter et al., “Pulmonary Administration of Human Insulin in volunteers and Type I Diabetics”, Diabetes, 33, (Suppl) 298 (1984). |
| Schneider et al., “Stimulation by proinsulin of expression of plasminogen activator inhibitor type 1 in endothelial cells”, Diabetes 41(7):890-895 (1992). |
| Schon, Istvan et al. “Formation of Aminosuccinyl Peptides During Acidolytic Deprotection Followed by their Tranformation to Piperazine-2, 5-dione Derivatives in Neutral Media.” International Journal of Peptide & Protein Research, 14(5), 485-494, 1979. |
| Schroder, “Crystallized carbohydrate spheres as a slow release matrix for biologically active substances”, Biomaterials 5:100-104, 1984. |
| Scrocchi et al. “Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene.” Nature Medicine 2:1254-1258, 1996. |
| Seshiah & Balaji, “Early Insulin Therapy in Type 2 Diabetics”, Int. J. Diabetes in Developing Countries, 2003, 23, 90-93. |
| Seville, P.C. et al., Preparation of dry powder dispersions for non-viral gene delivery by freeze-drying and spray dying. J. Gene Medicine 2002; 4:428-437. |
| Shah et al. “Lack of suprression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus.” J Clin Indocrinol Metab 85:4053, 2000. |
| Shelly et al. “Polysorbate 80 hypersensitivity.” The Lancet 345:1312, 1995. |
| Shojania et al. “Effect of quality improvement strategies for type 2 diabetes on glycemic control.” JAMA 296:427, 2006. |
| Silverstein et al., “Care of Children and Adolescens with Type 1 Diabetes, A Statement of the American Diabetes Association”, Diabetes Care, Jan. 2005, vol. 28, p. 186-212. |
| Singh et al., Use of 125I-[Y39]exendin-4 to characterize exendin receptors on dispersed pancreatic acini and gastric chief cells from guinea pig. Regul. Pept. 53 : 47-59 (1994). |
| Simms JR, Carballo I, Auge CR, et al. Assessment of immunotoxic effects on humoral and cellular immune parameters following repeated inhalation of Technosphere insulin in the rat. Diabetes 2005;54:Abstract 2078-PO. |
| Skyler, Pulmonary insulin: current status. Diabetes Voice, vol. 51, Issue I, p. 23-25, 2006. |
| Skyler “Pulmonary Insulin Delivery—State of the Art 2007.” Diabetes Tecnology & Therapeutics, vol. 9, Supplement 1, pp. S1-S3. 2007. |
| Smith et al. “New-onset diabetes and risk of all-cause and cardiovascular mortality.” Diabetes Care 29:2012, 2006. |
| Smutney CC, Friedman EM, Amin N. Inspiratory efforts achieved in use of the Technosphere® insulin inhalation system. Diabetes Technology Meeting 2008; Poster SMUT8052. |
| Smutney CC, Friedman EM, Amin N. Inspiratory efforts achieved in use of the Technosphere® insulin inhalation system. Journal of Diabetes Science and Technology 2009 3(5):1175-1189. |
| Smutney CC, Polidoro JM, Adamo B, et al. In-vitro performance improvement realized in a next generation dry powder delivery system. Diabetes Technology Meeting 2009; poster. |
| Smutney CC, Polidoro JM, Adamo B, Shah S. In vitro performance improvement realized in a next generation dry powder delivery system. Third International Conference on Advanced Technologies and Treatments for Diabetes 2010; Poster 122. |
| Smutney CC, Polidoro JM. Easy-to-use next-generation pulmonary insulin delivery system. ADA 2010; Abstract 2093. |
| Smutney CC, Polidoro JM. Improvements realized in a next-generation pulmonary insulin delivery system. ADA 2010; Abstract 2097. |
| Sodium chloride is a natural product from http://www.wqpmag.com/potassium-chloride-vs-sodium-chloride, pp. 1-3. Accessed by Examiner on May 16, 2014 and in Non-Final Ofthce Action dated May 22, 2014 for U.S. Appl. No. 13/797,657 and in Non-Final Office Action dated May 22, 2014 for U.S. Appl. No. 12/883,369. |
| Standl et al. “Good Glycemic Control With Flexibility in Timing of Basal Insulin Supply.” Diabetes Care, vol. 28, No. 2, Feb. 2005. |
| Stanley et al. “Gastrointestinal satiety signals III. Glucagon-like peptide 1, oxyntomodulin, peptide YY and pacretic peptide.” Am J Physiol Gastrointest Liver Physiol 286:G693, 2004. |
| Steinberg et al. “A new approach to the safety assessment of pharmaceutical excipients.” Reg Toxicol Pharmacol 24:149, 1996. |
| Steiner, K et al. “The relative importance of first- and second-phase insulin secretion in countering the action of glucagon on glucose turnover in the conscious dog.” Diabetes 31:964-972, 1982. |
| Steiner S, Rave K, Heise T, et al. Pharmacokinetic properties and bioavailablility of inhaled drug powder Technosphere™/insulin. Exp Clin Endocrinol Diabetes 2000; 108:S161. |
| Steiner S, Rave K, Heise T, et al. Technosphere™/insulin: Bioavailability and pharmacokinetic properties in healthy volunteers. Diabetologia 2000;43:Abstract 511-P. |
| Steiner SS, Burrell BB, Feldstein R, et Al Pulmonary delivery of Technosphere™/insulin: Increased bioefficacy and bioavailability in clinical trials using the PDC Medtone™ inhaler. Proceed Int'l Symp Control Rel Bioact Mater 2000; 27: 1000-1001. |
| Stowell et al. “Development of GLP-1 Technosphere(TM) powder: an inhaled GLP-1 product.” Diabetes Technology Meeting, San Francisco, Oct. 2007. |
| Strack “Inhaled Human Insulin.” Drugs of Today 2006, 42 (4): 207-221. |
| Sturis et al., GLP-1 deriative liraglutide in rats with beta-cell deficiences: influence of metabolic state on beta-cell mass dynamics. British Journal of Pharmacology, 140: 123-132 (2003). |
| Sympatecs. Dry Dispersion for Laser Diffraction and Image Analysis, 2011. XP-002586530. |
| Leone-Bay et al., Innovation in drug delivery by inhalation. Ondrugdelivery, No. 7, pp. 4-8 (2010). |
| Tack CJ, Boss AH, Baughman RA, et al. A randomized, double blind, placebo controlled study of the forced titration of prandial Technosphere®/Insulin in patients with type 2 diabetes mellitus. Diabetes 2006;55:Abstract 428-P. |
| Tack CJ, Christov V, deGalan BE, et al. Randomized forced titration to different doses of Technosphere® insulin demonstrates reduction in postprandial glucose excursions and hemoglobin A1c in patients with type 2 diabetes. J Diabetes Sci Technol 2008; 2(1) :47-57. |
| Tang-Christensen et al. “Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats.” Am J Physiol 271 (Regulatory Integrative Comp Physiol 40):R848, 1996. |
| Teeter et al. “Dissociation of lung function changes with humoral immunity during inhaled human insulin therapy.” Am J Resp Crit Care Med 173:1194, 2006. |
| The American Diabetes Association “Insulin Administration” Diabetes Care, vol. 27, Supplement 1, S106-S109 (2004). |
| Gerber et al., Treatment satisfaction with inhaled insulin in patients with type 1 diabetes. Diabetes Care 24:1556-1559 (2001). |
| The Lancet. 1989, vol. 333, p. 1235-1236. |
| Thorens “Expression cloning of the pancreatic b-cell receptor for the gluco-incretin hormone glucagon-like peptide-1.” PNAS 89:8641, 1992. |
| Thorens B et al. “Cloning and function expression of the human islet GLP-1 receptor: demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.” Diabetes 42:1678, 1993. |
| Todd et al. “Glucagon-like peptide-1 (GLP-1: a trial of treatment in non-insulin-dependent diabetes mellitus.” Eur J Clin Invest 27:533, 1997. |
| Todd et al. Subcutaneous glucagon-like peptide-1 improves postprandial glucaemic control over a 3-week period in patients with early type 2 diabetes. Clinical Science 95:325, 1998. |
| Toft-Nielson et al. “Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes.” J Clin Endocrinol Metab 86:3853, 2001. |
| Toft-Nielson et al. “Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglcaemia.” Diabetologia 41:1180, 1998. |
| Toft-Nielson et al. “The effect of glucagon-like peptide-1 (GLP-1) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones” Diabetes 45:552, 1996. |
| Tornusciolo D.R. et al., Biotechniques 19(5):800-805, 1995. Simultaneous detection of TDT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells and multiple immunohistochemical markers in single tissue sections. |
| Triantafyllidis et al., Structural, compositional and acidic characteristics of nanosized amorphous or partially crystalline ZSM-5 zeolite based materials. Microporous and Mesoporous Materials, 75:89-100 (2004). |
| Tu N, Kramer DA, Baughman RA. Inhaled Technosphere® Insulin improves glycemic control without weight gain. Diabetes 2007;56:Abstract 471-P. |
| Tuley et al., Experimental observations of dry powder inhaler dose fluidisation. International Journal of Pharmaceutics, 358, pp. 238-247 (2007). |
| Utah Valley University. Saponification. © 2009. Available from: <http://science.uvu.edu/ochem/index.php/alphabetical/s-t/saponification/printpage/>. |
| Vahl et al. “Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1-(9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans.” J Clin Endocrinol Metabol 88:1772, 2003. |
| Van Alfen-Van Der Velden et al. “Successful treatment of severe subcutaneou insulin resistance with inhaled insulin therapy”, Pediatric Diabetes 2010: 11:380-382. |
| Vara E et al. “Glucagon-like peptide-1 (7-36) amide stimulates surfactant secretion in human type II pneumocytes.” Am J Resp Crit Care Med 163:840-846, 2001. |
| Vella A et al. “Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes.” Diabetes 49:611, 2000. |
| Vella A et al. “The gastrointestinal tract and glucose tolerance.” Curr Opin Clin Nutr Metab Care 7:479, 2004. |
| Vendrame et al. “Prediabetes: prediction and prevention trials.” Endocrinol Metab Clin N Am, 2004, vol. 33, pp. 75-92. |
| Verdich C, et al., A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab., 86:4382-4389, 2001. |
| Vilsboll et al. “Reduced postprandial concentrations of intact biologically active glucagon-like peptide-1 in type 2 diabetic patients.” Diabetes 50:609, 2001. |
| Vilsboll et al. “Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects.” J Clin Endocrinol Metab 88:220, 2003. |
| Vilsboll et al., “Evaluation of β-Cell Secretary Capacity Using Glucagon-Like Peptide 1”, Diabetes Care, vol. 23, No. 6, pp. 807-812, Jun. 2000. |
| Vilsboll et al., “Incretin secretion in Relation to Meal Size and Body Weight in Healthy Subjects and People with Type 1 and Type 2 diabetes Mellitus”, The Journal of Clinical Endrocronology & Metabolism, vol. 88, No. 6, pp. 2706-2713, 2003. |
| Amorij et al., Development of stable infleunza vaccine powder formulations challenges and possibilities. Pharmaceutical Research, vol. 25, No. 6, pp. 1256-1273 (2008). |
| Audouy et al., Development of a dried influenza whole inactivated virus vaccine for pulmonary immunization. Vaccine, vol. 29, pp. 4345-4352 (2011). |
| Volund “Conversion of insulin units to SI units.” American Journal of Clinical Nutrition, Nov. 1993, 58(5), pp. 714-715. |
| Wachters-Hagedoorn et al. “The rate of intestinal glucose absorption is correlated with plasma glucose-dependent insulinotropic polypeptide concentrations in healthy men.” J Nutr 136:1511, 2006. |
| Wang et al., Glucagon-like peptide-1 is a physiological incretin in rat. J. Clin. Invest., 95 : 417-421 (1995). |
| Wang et al., Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells. Diabetologia, 47:478-487, 2004. |
| Wareham et al., “Fasting Proinsulin Concentrations Predict the Development of Type 2 Diabetes”, Diabetes Care, 1999, 22, 262-70. |
| Waterhouse et al., “Comparatie assessment of a new breath-actuated inhaler in patients with reversible airways obstruction”, Respiration 59:155-158 (1992). |
| WebMD (retrieved from http://www.webmd.com/pain-management/tc/pain-management-side-effects-of-pain-medicines in 2012, 4 pages). |
| Wei et al. “Tissue-specific expression of the human receptor for glucagon-like peptide-1: brain and pancreatic forms have the same deduced amino acid sequence.” FEBS Letters 358:219, 1995. |
| Neir et al. “Glucagonlike peptide 1 (7-37) actions on endocrine pancreas.” Diabetes 38:338, 1989. |
| Weiss, SR et al. “Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents.” Arch Intern Med 163:2277-2282, 2003. |
| Weissberger, “Mannkind: Overlooked Biotech with Excellent Prospects (Part V),” http://www.investorvillage.com/smbd.asp?mb=2885&mn=45817&pt=msg&mid=5021385 (posted on Jun. 19, 2008, accessed on Oct. 18, 2012). |
| West, Solid State Chemistry and its Applications, Chp 10, Solid Solutions. Wiley, New York, 358 (1998). |
| Wettergren A et al. “Truncated GLP-1 (proglucagon 78-107-Amide) inhibits gastric and pancreatic functions in man.” Digestive Diseases and Sciences 38:665, 1993. |
| Wigley et al., Insulin across respiratory mucosae by aerosol delivery. Diabetes 20(8): 552-556 (1971). |
| Willms B et al. “Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients.” J. Clin Endocrinol Metab 81:327, 1996. |
| Wilson BR et al. “Technospheres(TM) for pulmonary and nasal applications.” Respiratory Drug Delivery VIII, 2002,p. 545. |
| Wilson et al., Spray-drying, a viable technosphere formulation process option to lyophilization, http://www.aapsj.org/abstracts/AM—2004/AAPS2004-002724.PDF, 1 page, 2004. |
| Witchert, Low molecular weight PLA: A suitable polymer for pulmonary administered microparticles. J. Microencapsulation, 10(2): 195-207 (1993). |
| Wright et al., Inhaled Insulin: Breathing new life into diabetes therapy. Nursing, vol. 37, No. 1, p. 46-48 (2007). |
| Wong et al. “From cradle to grave: pancreatic b-cell mass and glucagon-like peptide-1.” Minerva Endocrinologica 31:107, 2006. |
| Wuts et al. “The Role of Protective Groups in Organic Synthesis,” John Wiley, New York, 2nd Ed. 1991. |
| Yan et al., Analgesic action of microinjection of neurokinin A into the lateral reticular nucleus and nucleus raphe magnus in rats. Acta Physiologica Sinica, vol. 48, No. 5, pp. 493-496 (1996)—abstract. |
| Yang et al., Division and differentiation of natural antibody-producing cells in mouse spleen. PNAS, 104(11): 1542-4546 (2007). |
| Yoshida et al., Absorption of insulin delivered to rabbit trachea using aerosol dosage form. J. Pharm. Sci. 68(5): 670-671 (1979). |
| Yoshioka et al., “Serum proinsulin levels at fasting and after oral glucose load in patients with Type 2 (non-insulin dependent) diabetes mellitus”, Diabetogia, 1988, 31, 355-60. |
| Yu W, Marino MT, Cassidy JP, et al. Insulin antibodies associated with Technosphere® insulin. ADA 2010; Abstract 216-OR. |
| Yusta B et al. “GLP-1 receptor activation improves b-cell function and survival following induction of endoplasmic reticulum stress.” Cell Metabolism 4:391, 2006. |
| Zander et al., Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet, 359:824-830, 2002. |
| Zethellius et al., “Proinsulin is an Independent Predictor of Coronary Heart Disease”, Circulation 105:2153-2158 (2002). |
| Zimmerman, K., “Respiratory System: Fats, Function, and Diseases”, <www.livescience.com/22616-respiratory-system.html>, copyright 2013, p. 1. |
| Zisser et al. “In Patients Using Technospere Insulin. Variation in PPG Stayed Within ADA-recommended Targets Despite Large Variations in Glucose Load.” Mannkind Corporation (2010), ADA 2010; Poster 554. |
| Zisser H, Jovanovic L, Markova K, et al. Technosphere® insulin effectively controls postprandial glycemia in patients with type 2 diabetes mellitus. Diabetes Technology and Therapeutics 2012;14:997-1001. |
| Wasada, Glucagon-like peptide-1 (GLP-1). Nihon Rinsho, vol. 62, No. 6, pp. 1175-1180 (2004) (full Japanese article with English abstract). |
| Bosquillon et al., Pulmonary delivery of growth hormone using dry powders and visualization of its local fate in rates. Journal of Controlled Release 96: 233-244 (2004). |
| Cho et al., Targeting the glucagon receptor family for diabetes and obesity therapy. Pharmacology & Therapeutics 135: 247-278 (2012). |
| Definition of medicament from http://medical-dictionary.thefreedictionary.com/medicament, retrieved by the Examiner on Mar. 20, 2015 and cited in Office Action issued on Mar. 26, 2015 in U.S. Appl. No. 13/942,482. |
| Definition of matrix from http://medical-dictionary.thefreedictionary.com/matrix, retrieved by the Examiner on Mar. 5, 2015 and cited in Office Action issued on Mar. 26, 2015 in U.S. Appl. No. 12/471,260. |
| Diabetes Frontier, vol. 10, No. 5, p. 647-657 (1999) (full Japanese article with translated English portion provided in separate attachment, portion translated in English is the bottom of p. 655 and the left column of p. 656). |
| Ely et al., Effervescent dry powder for respiratory drug delivery. European Journal of Pharmaceutics and Biopharmaceutics 65: 346-353 (2007). |
| European Search report for European Application 14192154.4 mailed on Mar. 19, 2015. |
| Extended European Search report for European Application 14187552.6 mailed on Mar. 2, 2015. |
| Gillespie et al., Using carbohydrate counting in diabetes clinical practice. Journal of the American Diabetic Association, vol. 98, No. 8, p. 897-905 (1998). |
| Yamamoto et al., Engineering of Poly (DL-lactic-co-glycolic acid) Nano-composite particle for dry powder inhalation dosage forms of insulin with spray fludized bed granulating system. J. Soc. Powder Technol., Japan, 41: 514-521 (2004). |
| Johnson et al., “Turbuhaler a new device for dry powder terbutaline inhalation”, Allergy 43(5):392-395 (1988). |
| Johnson et al: RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. J Biol Chem., 279 (23):24794-802, 2004. |
| Johnson, Keith A., Preparation of peptide and protein powders for inhalation. Advanced Drug Delivery Reviews 1997; 26:3-15. |
| Jones et al., An investigation of the pulmonary absorption of insulin in the rat. Third European Congress of Biopharmaceutics and Pharmacokinetics, (1987). |
| Joseph et al. “Oral delivery of glucagon-like peptide-1 in a modified polymer preparation normalizes basal glycaemia in diabetic db/db mice.” Diabetologia 43:1319-1328, 2000. |
| Joy et al. “Incretin mimetics as emerging treatments for type 2 diabetes.” Annal Pharmacother 39:110, 2005. |
| Juntti-Berggren et al. “The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dyslipoproteinemia in NIDDM patients.” Diabetes Care 19:1200-1206, 1996. |
| Kanse et al. “Identification and characterization of glucagon-like peptide-1 7-36 amide-binding sites in the rat brain and lung.” FEBS Letters 241:209, 1988. |
| Kapitza C et al. “Impact of particle size and aerosolization time on the metabolic effect of an inhaled insulin aerosol.” Diabetes Tech Ther 6:119, 2004. |
| Kapsner P, Bergenstal RM, Rendell M, et al. Comparative efficacy and safety of Technosphere® insulin and a rapid-acting analog both given with glargine in subjects with type 1 diabetes in a 52-week study. Diabetologia 2009; 52 (suppl 1). |
| Katz et al. “Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.” J. Clin. Endocrinol. Metab. 85:5402-2410, 2000. |
| Kawai et al. “Evidence that glucagon stimulates insulin secretion through its own receptor in rats.” Diabetologia 38:274, 1995. |
| Kawamori et al. “Does hyperinsulinemia accelerate atherosclerosis?” Department of Medicine, Juntendo University School, vol. 13, No. 12, p. 954-960, 1994. |
| Kelley, D. et al. “Impaired postprandial glucose utilization in non-insulin dependent diabetes mellitus.” Metabolism 43:1549-1557, 1994. |
| Kenny AJ et al. “Dipeptidyl peptidase IV, a kidney brush-border serin peptidase.” Biochem J. 155:169, 1976. |
| Kim et al. “Development and characterization of a glucagon-like peptide 1-albumin conjugate. The ability to activate the glucagon-like peptide 1 receptor in vivo.” Diabetes 52:751, 2003. |
| Kinzig et al. “The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness.” J Neurosci 22:10470, 2002. |
| Kirk et al. “Disparities in HbA1c levels between African-American and non-hispanic white adults with diabetes.” Diabetes Care 29:2130, 2006. |
| Kitabchi, Proinsulin and C-peptide:a review. May 26, 1977 (5):547-87, http://www/ncbi.nlm.nih.gov/pubmed/403392. |
| Knop et al. “No hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis.” Diabetes Care 26:2581, 2003. |
| Knop et al. “Reduced incretin effect in type 2 diabetes. Cause or consequence of the diabetic state?” Diabetes 56:1951, 2007. |
| Kohler, “Aerosols for Systemic Treatment”, Lung (Suppl.) 677-684 (1990). |
| Komada et al., Intratracheal delivery of peptide and protein agents: absorption from solution and dry powder by rat lung. J. Pharm. Sci. 83(6): 863-867 (1994). |
| Komatsu et al. “Glucagonostatic and insulinotropic action of glucagon-like peptide-1 (7-36)-amide.” Diabetes 38:902, 1989. |
| Koning et al., Relationship between inspiratory flow through simulated dry powder inhalers and peak maximal inspiratory pressure. Flow Through a Simulated DPI, Chapter 3, pp. 43-56 (2001). |
| Labiris et al., Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. British Journal of Clinical Pharmocology 56: 588-599 (2003). |
| Kontny et al., Issues Surrounding MDI Formulation Development with Non-CFC Propellants), J. Aerosol Med 4(3), 181-187 (1991). |
| Kraft KS, Grant M. Preparation of macromolecule-containing drug powders for pulmonary delivery Methods in Molecular Biology 2009;480:165-174. |
| Kreymann B et al. “Glucagon-like peptide-1 7-36: a physiological incretin in man.” The Lancet, Dec. 5, 1987, p. 1300. |
| Krssak, M. et al. “Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes.” Diabetes 53:3048-3056, 2004. |
| Kwon et al. “Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets.” Diabetes 53:S225, 2004. |
| Lankat-Buttgereit B et al. “Molecular cloning of a cDNA encoding for the GLP-1 receptor expressed in rat lung.” Exp Clin Endocrinol 102:241, 1994. |
| Lebovitz “Therapeutic options in development for management of diabetes: pharmacologic agents and new technologies.” Endocr Pract 12:142, 2006. |
| Lee et al. “Synthesis, characterization and pharmacokinetic studies of PEGylated glucagon-like peptide-1.” Bioconjugate Chem 16:377, 2005. |
| Lee et al., “Development of an Aerosol Dosage Form Containing Insulin”, J. Pharm. Sci. 65(4), 567-572 (1976). |
| Leone-Bay et al. “Evaluation of novel particles as an inhalation system for GLP-1.” Diabetes, Obesity and Metabolism. 11:1050-1059, 2009. |
| Leone-Bay A, Grant M. Technosphere® Technology: A Platform for inhaled protein therapeutics. OndrugDelivery 2006 (published online). |
| Leone-Bay A, Grant M. Technosphere®/insulin: mimicking endogenous insulin release. In: Rathbone M, Hadgraft J, Roberts M, et al, eds. Modified Release Drug Delivery, 2e. New York, NY: Informa Healthcare USA, Inc; 2008. |
| Kieffer et al. “The glucagon-like peptides.” Endocrine Reviews 20:876, 1999. |
| Kim et al., Dose-response relationships of inhaled insulin delivered via the aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes. Diabetes Care, 26:2842-2847 (2003). |
| Klonoff, David C. M.D., Afrezza inahled insulin: the fastest-acting FDA-approved insulin on the market has favorable properties. Journal of Diabetes Science and Technology, vol. 8(6): 10-71-1073 (2014). |
| U.S. Appl. No. 15/377,641, filed Dec. 13, 2016. |
| U.S. Appl. No. 15/418,388, filed Jan. 27, 2017. |
| U.S. Appl. No. 15/421,743, filed Feb. 1, 2017. |
| Chan et al., Physical stability of salmon calcitonin spray-dried powders for inhalation. Journal of Pharmaceutical Sciences, vol. 93, No. 3, pp. 792-804 (2004). |
| Mumenthaler et al., Feasibility study on spray-drying protein pharmaceuticals: recombinant human growth hormone and tissue-type plasminogen activator. Pharm Res., 11(1):12-20 (1994). |
| Sarala et al., Technosphere: New drug delivery system for inhaled insulin. Future Prescriber, vol. 13, No. 1, pp. 14-16 (2012). |
| U.S. Appl. No. 15/233,794, filed Aug. 10, 2016. |
| U.S. Appl. No. 15/300,239, filed Sep. 28, 2016. |
| Uwaifo et al., Novel pharmacologic agents for type 2 diabetes. Endocrinology and Metabolism Clinics of North America, vol. 34, No. 1, pp. 155-197 (2005). |
| Xi-de Tu, et al. Pharmaceutics. Oct. 2002, 3rd edition, second printing, p. 905. |
| Lane et al., Influence of post-emulsification drying processes on the microencapsulation of Human Serum Albumin. International Journal of Pharmaceutics, 307: 16-22 (2006). |
| U.S. Appl. No. 15/152,355, filed May 11, 2016. |
| U.S. Appl. No. 15/182,503, filed Jun. 14, 2016. |
| Number | Date | Country | |
|---|---|---|---|
| 20140014106 A1 | Jan 2014 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61671041 | Jul 2012 | US |
