Patent Grant
11383048
The present invention generally pertains to a system for delivering a predetermined amount of a substance to a natural orifice of the body.
Many devices of the prior art focus on a mechanism to allow better aerosol formation and better dispersion in the nasal cavity. Other mechanisms for better delivery focus on special formulations that include materials and structures to allow better absorption in the target tissue.
Each of these strategies has its advantages and disadvantages. For example, improvements to the delivery device can improve bringing the material to the desired area, but will neglect the need to enhance the absorption of the compound into and through the mucosal layer. On the other hand, improvements to the composition, the formulation or both can improve absorption into and through the mucosal layer, but may well neglect the difficulty of delivering a sufficient amount of the material to the desired tissue.
It is therefore a long felt need to provide a system which can be optimized for efficient delivery of a substance to a target site, said optimization neglecting neither the need to bring sufficient material to the target site, nor the need to ensure adequate absorption into and through the mucosal layer.
It is an object of the present invention to provide a device with capabilities of improving the transfer of medicament to the predetermined desired location. Furthermore, the present invention provides a device which improves the delivery of medicament through the tissue.
It is another object of the present invention to disclose a system for delivering a predetermined amount of a substance or combination of substances into a natural orifice of the body for absorption in a target. Furthermore, the combination of the delivery device and the composition can have either an additive or a synergistic effect, where the additive or synergistic effect of the combination can improve the efficacy of the delivered substance, can improve the safety of the delivered substance, can alter a delay between dispensing and activation, can alter the duration of activation, can improve user compliance and any combination thereof.
It is further an object of the present invention to disclose the system, wherein the active agent is selected from a group consisting of a peptide, a protein, an antibody, nucleic acid, a small molecule, a cell, a stem cell, a nanoscale particle, a microscale particle, a purified natural biologic, a synthetic biologic; and any combination thereof.
It is further an object of the present invention to disclose the system, wherein at least one said substance comprises a member of a group consisting of a medicament, a carrier, a bulking agent, an inert material, a flavoring material, an odorizing material, an excipient and any combination thereof.
It is further an object of the present invention to disclose the system, wherein said substance is selected from a group consisting of a gas, a liquid, a powder, an aerosol, a slurry, a gel, a suspension and any combination thereof.
It is further an object of the present invention to disclose the system, wherein the substance comprises a penetration enhancer selected from a group consisting of a micro-emulsion, a nano-emulsion of the following: a surfactant, a part of a surfactant, an oil, a co-surfactant, an aqueous phase and any combination thereof; the penetration enhancer allowing: better absorption in the mucosal tissue, better permeation and absorption in the target cells, better stability of an encapsulated drug, better stability of an active ingredient and any combination thereof.
It is further an object of the present invention to disclose the system, wherein the substance comprises a mucoadhesive agent such as, but not limited to, bioadhesive proteins, carbohydrates and mucoadhesive polymers
It is another object of the present invention to disclose a device for delivering a predetermined amount of at least one substance to a body orifice of a subject, the device comprising: (a) a container (also refers to as capsule) for containing at least one substance; (b) a delivery end for placement in proximity to the orifice, the delivery end being in fluid communication with the container; (c) a valve mechanically connectable to the container, characterized by at least two configurations: (i) an ACTIVE CONFIGURATION in which the valve enables delivery of a predetermined amount of the substance from the container to the body orifice via the delivery end; and, (ii) an INACTIVE CONFIGURATION, in which the valve prevents delivery of the predetermined amount of the substance from the container to the body orifice (d) a trigger mechanism adapted to reconfigure the valve from the ACTIVE CONFIGURATION to the INACTIVE CONFIGURATION, and vice versa; wherein the trigger mechanism is adapted to reconfigure the valve from the INACTIVE CONFIGURATION to the ACTIVE CONFIGURATION for a predetermined period of time in response to activation of the trigger mechanism; and (e) a fluid tight chamber adapted to contain predetermined amount of pressurized gas at a predetermined pressure; wherein the pressurized gas, once the valve is reconfigured from the INACTIVE CONFIGURATION to the ACTIVE CONFIGURATION, is adapted to entrain the substance and deliver the same to the body orifice.
It is another object of the present invention to disclose a syringe like device for delivering a predetermined amount of at least one substance to a body orifice of a subject, the device characterized by a main longitudinal axis; the device comprising: (a) a delivery end for placement in proximity to the orifice; (b) a container for containing at least one substance; the container being in fluid communication with the delivery end; (c) a valve mechanically connectable to the container, characterized by at least two configurations: (i) an ACTIVE CONFIGURATION in which the valve enables delivery of predetermined amount of the substance from the container to the body orifice via the delivery end; and, (ii) an INACTIVE CONFIGURATION, in which the valve prevents delivery of the predetermined amount of substance from the container to the body orifice; (d) a trigger mechanism adapted to reconfigure the valve from the ACTIVE CONFIGURATION to the INACTIVE CONFIGURATION, and vice versa; wherein the trigger mechanism is adapted to reconfigure the valve from the INACTIVE CONFIGURATION to the ACTIVE CONFIGURATION for a predetermined period of time in response to activation of the trigger mechanism; (e) a fluid tight chamber adapted to contain predetermined amount of pressurized gas at a predetermined pressure, the fluid-tight chamber in fluid communication with the valve; and (f) a charging mechanism adapted to provide the predetermined amount of pressurized gas, the charging mechanism comprising a lever mechanism adapted to reversibly move a piston by a predetermined amount, a pump and any combination thereof; wherein the pressurized gas, once the valve is reconfigured from the INACTIVE CONFIGURATION to the ACTIVE CONFIGURATION, is adapted to entrain the substance and deliver the same to the body orifice.
It is another object of the present invention to disclose the system or the syringe-like device, comprising a nozzle or delivery end.
It is another object of the present invention to disclose the system or the syringe-like device, wherein the nozzle or delivery end comprises at least one said extension.
It is another object of the present invention to disclose the system or the syringe-like device, wherein at least one said extension is adapted to ensure proper positioning of the delivery end in said nasal passage, said proper positioning selected from a group consisting of: delivery end centralized in a nasal passage, delivery end touching a predetermined portion of a nasal passage, delivery end close to a predetermined portion of a nasal passage, said extension seals an opening of a nasal passage so that material can not escape therefrom, said extension seals a nasal passage so that substance does not contact undesired portions thereof, said extension seals a nasal passage so that substance remains in a predetermined portion thereof, said extension reduces the discomfort of contact between said delivery end and a nasal passage.
It is another object of the present invention to disclose a capsule for containing at least one flowable substance, said capsule having a main longitudinal axis, said capsule comprising at least one compartment, said compartment adapted to contain said at least one flowable substance; wherein, during dispensing of said at least one flowable substance, a carrier gas passing through said capsule entrains said at least one flowable substance contained within said at least one compartment such that said at least one flowable substance has a predetermined distribution within said dispensed mixture.
It is another object of the present invention to disclose a method for dispensing a flowable substance, comprising steps of:
thereby dispensing said flowable substance by entraining said at least one flowable substance in said carrier gas such that said at least one flowable substance has a predetermined distribution within said dispensed mixture.
In order to better understand the invention and its implementation in practice, a plurality of embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, wherein
The following description is provided, alongside all chapters of the present invention, so as to enable any person skilled in the art to make use of said invention and sets forth the best modes contemplated by the inventor of carrying out this invention. Various modifications, however, will remain apparent to those skilled in the art, since the generic principles of the present invention have been defined specifically to provide a means delivering a predetermined amount of a substance to a natural orifice of the body.
The term ‘capsule’ or ‘container’ hereinafter refers to a container adapted to contain a flowable substance. The term flowable refers hereinafter to any liquid, gas, aerosol, powder and any combination thereof.
The term ‘plurality’ hereinafter refers to an integer greater than or equal to one.
The term ‘olfactory epithelium’ hereinafter refers to a specialized epithelial tissue inside the nasal cavity. The olfactory epithelium lies in the upper top portion of the nasal cavity.
The term ‘substance’ hereinafter refers to any substance capable of flowing. Such a substance can be a granular material, including a powder; a liquid; a gel; a slurry; a suspension; and any combination thereof.
The term ‘gas’ refers to any fluid that can be readily compressed. Gases as used herein include, but are not limited to, air, nitrogen, oxygen, carbon dioxide, helium, neon and xenon. Devices charged by hand will normally use air as the carrier gas.
The term ‘channel’ hereinafter refers to a passageway allowing passage of a fluid through at least a portion of a mixing mechanism. The channel can be disposed within a portion of the mixing mechanism, forming a closed bore; it can be on an exterior of a portion of the mixing mechanism, forming a groove on the portion of the mixing mechanism, and any combination thereof.
The term ‘about’ refers hereinafter to a range of 25% below or above the referred value.
The term ‘biologic’ or ‘biologic response modifier’ hereinafter refers to material manufactured in or extracted from biological sources such as a genetically engineered protein derived from human genes, or a biologically effective combination of such proteins.
In all of the embodiments of the device shown hereinbelow, identical numbers refer to identical functions.
All figures shown herein are illustrative and none is to scale.
The present invention teaches a device for delivering a predetermined amount of a substance, preferably comprising a medication or combination of medications, into a body orifice of a subject, the orifice comprising any of the body's natural orifices, including a nostril, the mouth, the ear, the throat, the urethra, the vagina, the rectum and any combination thereof.
In preferred embodiments of the device, the device comprises a delivery mechanism and a medicament capsule, as described hereinbelow. The device can apply a broad range of drugs and materials to the nasal cavity for local effect, deliver a broad range of drugs and materials through the nasal cavity to the systemic circulation, deliver a broad range of drugs and materials through the nasal cavity to the central nerve system (CNS) the brain, spinal cord and associated nerves, and any combination thereof.
The drugs to be applied could be, but are not limited to, pharmaceuticals, natural compounds, biologics, hormones, peptides, proteins, viruses, cells, stem cells and any combination thereof.
However, it should be emphasized that the device can be provided alone as well as in combination with a capsule.
In some cases the capsule would be provided with a known medicament within the same and in another cases the capsule would be ‘filled’ with the medicament just before use.
In some embodiments of the present invention, the device operating characteristics and the substance characteristics can be jointly optimized to maximize uptake of the substance at the desired site. In preferred variants of such embodiments, uptake is further optimized by exploiting synergies between delivery characteristics generated by the device and by the formulation or composition of the delivered material
In some embodiments, the substance comprises one or more agents to optimize delivery through the mucosal membrane by means of mucoadhesive agent and/or a permeability enhancer agent and/or a particulate formulation in the nano-particle or macro-particle range, and any combination thereof. In such embodiments, the combination of the device and substance enhance the delivery of the active agent to the target tissue (nasal epithelium and more specifically olfactory epithelium).
A non-limiting example is a composition comprising a drug to be delivered and at least one chemical permeation enhancer (CPE). In a preferred embodiment, the composition contains two or more CPEs which, by using a nasal delivery device, affect in an additive manner or behave synergistically to increase the permeability of the epithelium, while providing an acceptably low level of cytotoxicity to the cells. The concentration of the one or more CPEs is selected to provide the greatest amount of overall potential (OP). Additionally, the CPEs are selected based on the treatment. CPEs that behave primarily by transcellular transport are preferred for delivering drugs into epithelial cells. CPEs that behave primarily by paracellular transport are preferred for delivering drugs through epithelial cells. Also provided herein are mucoadhesive agents that enable the extension of the exposure period of the target tissue/mucus membrane to the active agent, for the enhancement of delivery of the active agent to and through the mucus membrane.
In contrast to prior-art nasal delivery devices and technologies, the devices of the present invention can produce a fine aerosol in the nasal cavity or other desired body orifice at the target area and at the location of the target tissue instead of within the device or immediately after exit from the device. Utilizing the pressure as a driving force and the air as a carrier allows the material to be released from the nozzle in a pre-aerosolized state. The properties of the resultant aerosol are typically dependent on the properties of the device and of the medium into which the device is discharged. The properties of the device which affect the aerosol characteristics are the delivery pressure, the volume of the delivery gas, and the characteristics of its orifice.
In some embodiments, the aerosol properties are fairly independent of the delivered substance, in other embodiments, the pressure, volume, orifice characteristics, and delivered substance properties can be co-optimized.
In prior-art devices the aerosol is produced at the immediate exit from the device. Typically, the aerosol comprises a wide “fan” of aerosol and a low driving force. Therefore, large droplets typically deposit very close to the exit from the device, while smaller droplets tend to quickly contact the walls of the passage, so that deposition is typically predominantly close to the delivery end of the device, with little of the substance reaching desired sites deeper in the orifice, such as the turbinates of the nose.
In contrast, in the present device, the pre-aerosolized mixture of gas and substance exits the device with a significant driving force as a mixture of aerosol and preaerolized material (fluid or powder). When the preaerosolized material hits the walls of the nasal passages, it “explodes” into a fine aerosol that is capable of being driven by the pressure deep into the nasal passages to deposit in the desired region.
In these typical prior art devices, if more than one substance is to be delivered, the substances will mix in the capsule or vial during storage and prior to delivery. Reactions can occur between the various components, limiting storage time and possibly requiring inconvenient storage conditions, such as keeping the capsules in a refrigerator before use.
The pressure to deliver the substance is the pressure of inhalation, which is quite variable, both between patients and between different inhalations by the same patient.
The embodiment of
In this embodiment, the chamber wall also comprises an indicator window (1300), so that the user has a visual indication that the device is properly charged before triggering and that the device is properly discharged after triggering.
An indicator can provide an indication to the user of at least one of the following (a) that the substance is entrained within the enclosed air; (b) transport of the substance from the container to the nasal passages has been successful; (c) the predetermined amount of pressurized gas is at the predetermined pressure, and any combination thereof.
The indication can be a visual indication such as a change of color, an audible predetermined sound pattern and any combination thereof.
In the embodiment of
The device comprises at least one valve. The valve allows entry of air into the chamber (1400) at all times, but air cannot exit the chamber (1400) until the valve is triggered.
To charge the device, the handle (1600) is rotated outward and downward from the position in
The device is now in the activated configuration.
In the embodiment (1000) of
It should be noted that, in preferred embodiments, the pressurized and predetermined amount of compressed gas is inert and will not react with the substance.
In this embodiment, the device comprises an optional grip handle (1700), which can be seen below the air intake nozzle (1810). It provides the user a better grip on the device.
The embodiments disclosed in
The characteristics of the aerosol depend on the delivery pressure, the volume of air delivered and the characteristics of the orifice, namely its size and shape. The delivery pressure and the volume of air delivered depend on the pressure of the gas in the chamber in the loaded state, on the volume of the chamber in the loaded state, and on the characteristics of the fluid connection between the chamber and the delivery orifice. The less change there is in these characteristics during an activation and between activations, the more reliable and the more reproducible the device will be. Therefore, in controlling the characteristics of the fluid connection, the time taken to open the valve needs to be taken into consideration. In devices of the current invention, the valve opening times are both reproducible and short and are not in any way dependant on the user, so that the delivery comprises a short, reproducible, high pressure pulse of the gas.
The non-activated state and the loaded state appear identical; they differ in that, in the loaded state the chamber contains pressurized gas whereas, in the non-activated state, the chamber does not contain pressurized gas.
In some embodiments, intended for use in emergencies, the device is a single-use device with only two states, a loaded state and an activated state. The device is provided in the loaded state; activation of the trigger mechanism discharges the gas and substance.
In other emergency-use embodiments, the device is provided in the pre-activated state. The user transforms the device into the loaded state, pressurizing the gas, and activates the trigger mechanism to discharge the gas and substance.
In
The cross-section of
In reference to
The levers are connected by means of a ratchet system (1612) to a plunger (1616) which fits snugly, fluid-tightly and slidably within the barrel (1400).
The levers (1610) have at least two positions, a first, parallel position where the levers (1610) are substantially parallel to the sides of the chamber (1400) and a second, perpendicular position where the levers (1610) are substantially perpendicular to the sides of the chamber (1400).
In the parallel position, the plunger (1616) is extended as far as possible away from the delivery (distal) end (1100) of the device (1000). In the perpendicular position, the plunger (1616) is as close as possible to the delivery (distal) end (1100) of the device (1000).
Dispensing a material from a rechargeable embodiment of the device operating in the manner of the embodiment shown in
In some embodiments operating in the manner of the embodiment shown in
In other embodiments, the device is provided without a capsule or with no drug in its capsule and the drug is loaded into the capsule as a preliminary step, as described hereinbelow, before charging and activation of the device.
The charging mechanism shown in
To charge the mechanism, the single side lever (1620) is rotated from the parallel position (
In some embodiments of devices operating in this manner where the handle is substantially parallel to the barrel in the charged position, moving the handle into the charged position, parallel to the barrel, locks the handle and insures that full charging of the device is retained until activation.
It can be seen from the exploded view of the embodiment (
In the embodiment of
In further reference to
In the embodiment of
In some variants of the embodiment of
In some embodiments, a one-way ratchet is used instead of a two-way ratchet (1652). In reusable versions of such embodiments, the plunger (1636) is pulled out (rather than screwed out) to fill the device and screwed down using the key (1654) during charging. In one-use, prefilled devices, a one-way ratchet would be the preferred embodiment, as there is no need to pull out the plunger (1636).
The pump pumps a predetermined amount of gas into the chamber (1400). Determination of the predetermined amount of gas can be by means of a pressure gauge, a mass flow meter, a scale, or any other means known in the art of delivering a predetermined amount of gas into a predetermined volume.
The gas can be air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon and any combination thereof.
The pump can be a motor-driven pump or a manually-driven pump. The motor power can be provided by conventional electrical mains power, by a battery, by gasoline or other liquid fuel, by solid fuel, by solar power, or by any other power source adapted to drive a pump.
In a manually-driven pump, the pump mechanism can comprise a commercial indiflator (
Pump-driven devices can be either pre-filled with air (or a predetermined gas or mixture of gases) or it can be filled by the user utilizing ambient air as compressible gas.
The location of the nozzle or delivery end of the device in the nasal cavity at the time of drug release affects the location of the aerosol in the nasal cavity and the distribution of the drug in the different nasal epithelium layers. These elements affect the drug absorption at the nasal cavity and thus distribution of the drug in the systemic and CNS targets. Therefore, different nozzle shapes and sizes can be used to control the location of introduction of the aerosol into the nasal cavity. Embodiments of nozzle shapes can be seen in the embodiments disclosed herein.
In the embodiment shown, the device is activated by pressing together the two halves of the trigger cover (1822, 1828), thereby rotating the stopcock (1826) from its OFF position (
In preferred variants of embodiments with a stopcock trigger (1820), a return mechanism returns the stopcock (1826) to the closed position. The return mechanism can be a spring (not shown), a deactivation pin (1829), any combination thereof, or any other return mechanism known in the art.
In some embodiments, the stopcock (1826) is used without the trigger cover (1822, 1828). In such embodiments, triggering is by manually rotating the stopcock handle (1824) to the ON position (
The device comprises a hollow upstream portion (1881) fluid-tightly connected to a hollow downstream portion (1889). In this embodiment, the activation mechanism (1880) comprises a cup-shaped insert (1884) fitting snugly and fluid-tightly within the hollow interior of the device. The outer rim of the insert (1884) is preferably fixed to the outer wall of the activation mechanism (1880), with its inner rim (1885) able to slide on an inner wall (1886), preferably tubular, of the activation mechanism (1880). In the activation mechanism's (1880) closed position, a stop (1882) is firmly held by the inner rim (1885) of the insert.
The inner wall of the activation mechanism (1880) comprises a throughgoing bore (1883). In some variants of this embodiment, a flexible tube (1888) is fluid-tightly fixed to the wall (1886) such that there is flexible tubing in at least the portion of the wall abutting the stop (1882). In other variants of this embodiment, the flexible tube (1888) passes through the bore (1883).
In preferred variants of this embodiment of an activation mechanism, in the closed position, the stop (1882) fits into and sits in a hole in the inner wall (1886). In other variants, the stop (1882) fits into and sits in a depression in the inner wall (1886).
When the activation mechanism (1880) is in the closed position, the flexible tube (1888) is pinched between the stop (1882) and the inner side of the throughgoing bore (1883).
When the activation mechanism (1880) is activated, the insert (1884) slides up along the wall, releasing the stop (1882) so that the pinched region in the flexible tube (1888) is released, thereby releasing the pressurized gas and dispensing the substance.
In the embodiment shown in
In some embodiments, flexible filling material such as, but not limited to, flexible tubing, can be placed within the region of the device (not shown) containing the substance to be delivered in order to reduce dead space within the device. Reducing dead space will not affect the characteristics of the aerosol formed after release, but it will decrease pressure loss and increase air speed within the device, thereby substantially reducing residual substance remaining within the device after completion of activation, either within the capsule or adhering to the interior walls of the device, e.g., within the nozzle. It is well known in the art that residual material within a delivery device can be released on subsequent uses of the device and that the amount of such residual material released during a given use of a device is extremely variable. Therefore, minimizing residual substance within the device will increase the accuracy and reproducibility of delivery, thereby increasing increase its repeatability and reliability, both by maximizing the fraction of the substance actually delivered from the current capsule and by minimizing the amount of residual substance on the walls of the device.
It should be noted that the capsules (disclosed hereinbelow) are designed so as to avoid residual volume within the capsule itself, since, even in the case of a single dose or disposable capsule there are safety issues involved in disposing of capsules containing residual amounts of hazardous drugs or other hazardous component in the composition.
Other trigger mechanisms include, but are not limited to, a releasable catch, a pressable button a detactable predetermined sound pattern, a detectable predetermined light pattern, a movable lever, a slider movable from a first position to a second position, a rotatable knob is rotated, a releasable latch adapted and any combination thereof.
The predetermined sound pattern can be: a constant-pitch sound, a varying-pitch sound, a constant volume sound, a varying volume sound and any combination thereof.
The predetermined light pattern can be: a constant-color light, a varying-color light, a constant brightness light, a varying brightness light and any combination thereof.
In some embodiments, the device comprises a unidirectional valve such that gas can flow from the charging mechanism to the delivery end, but is unable to flow in the reverse direction.
In some embodiments, a substance to be dispensed (which can comprise any number of materials) can be stored within a capsule, either as the substance to be dispensed or as a precursor or precursors, with the capsule placeable within the device, as described hereinbelow. In such embodiments, the capsule is ruptured during activation, either all at once or in stages, thereby dispensing the substance.
In other embodiments, a substance, prepared in a conventional matter, is introducible into a holding chamber within the device and, on activation of the device, the substance is dispensed. Embodiments of this kind are primarily intended for use as emergency dispensing devices, since any flowable substance can be introduced into the holding chamber and since the holding chamber, which has no facilities for separating precursors or for providing an inert atmosphere in the chamber, is not intended for long-term storage of substances.
In some embodiments, the capsule chamber in which the capsule can be placed can also function as a holding chamber, so that the substance can be dispensed either from the capsule or directly from the holding chamber.
In other embodiments, an insert can be placed within the capsule chamber, with the interior of the insert being a holding chamber.
An embodiment of the activation mechanism of such an emergency-type dispensing device (1000) is shown in
In this embodiment, the means of loading the substance into the device is a syringe (2000). The syringe (2000) can be placed in the injection port (2100,
In some embodiments, the syringe is left in the injection port. In other embodiments, a cover (2300) is provided for the injection port, so that, after loading the substance into the chamber, the injection port can be sealed by means of the cover. As shown in the embodiment of
In the embodiment shown, a pinch triggering mechanism is used, as shown hereinabove in
In reference to
In order to prevent material from escaping from the nasal passages or entering undesired areas in the nasal cavity, in some embodiments, the nozzle comprises a medial extension, an expandable portion (1120).
In the exemplary embodiments of
The nozzle tip and the tip extension (1110) have a number of holes (1112, 1113) which fluidly connect the bore of the nozzle (1100) to the exterior of the device, allowing material to exit from the interior of the device. In the exemplary embodiments shown, there is a hole (1113) (
In some embodiments, the extension (1110) can be padded, can comprise soft material, can comprise flexible material and any combination thereof.
Extensions, both tip extensions and medial extensions, can have a number of functions. A non-limiting list of such functions is (1) ensuring proper positioning of the nozzle (1100) in the nasal passages, where the proper position can be the nozzle (1100) centralized in the nasal passages, the nozzle (1100) touching a predetermined portion of the nasal passages, or the nozzle (1100) closer to a predetermined portion of the nasal passages, (2) sealing the nasal passages so that material can not escape therefrom, (3) sealing the nasal passage so that substance does not contact undesired portions thereof, (4) sealing the nasal passage so that substance remains in a predetermined region of the nasal passage, (5) reducing the discomfort of contact between the nozzle and the nasal passages, especially in embodiments where the extension is intended to seal against the walls of the nasal passages, by providing a soft and/or flexible contact region and any combination thereof. Proper positioning can be for the purpose of improving delivery of a substance to a predetermined area, preventing clogging of the holes by nasal secretions, preventing clogging of the holes by contact with the nasal passages, mucosa and any combination thereof.
Nozzle extensions, both those that are expanded during the activation procedure and those that have a predetermined shape and do not expand, can either (1) be attached to the nozzle in a way that they are removed from the nasal cavity with the nozzle tip itself, or (2) have the option of being releasable from the nozzle tip so that they stay in the nasal cavity until they are pulled out by the user or by a caregiver, or any combination thereof. In embodiments where at least one nozzle extension remains in a nasal cavity, preferably, the nozzle extension or extensions are removed after a predetermined time, preferably a short time.
In some embodiments, the holes (1112) in the nozzle (1100) do not lie substantially in a plane perpendicular to the main longitudinal axis of the nozzle (1100). In such embodiments, the holes (1112) can lie along a line parallel to the main longitudinal axis of the nozzle (1100), along a line forming a spiral around the nozzle (1100), irregularly in the distal portion of the nozzle (1100), regularly spaced in the distal portion of the nozzle (1100), and any combination thereof.
Therefore, dispersion of the drug can be substantially from a ring perpendicular to the main longitudinal axis of the nozzle (1100) (holes (1112) around the edge of the extension (1110)), from a circle perpendicular to the main longitudinal axis of the nozzle (1100) (holes (1113) in the distal tip of the nozzle (1100)), from a line (holes (1112) parallel to the main longitudinal axis of the nozzle (1100) or in a spiral around the main longitudinal axis of the nozzle (1100)), or from at least part of the surface of a volume extending along the side of the nozzle (1100).
In some embodiments, the size of the tip extension (1110) is selected so that the extension (1110) is in contact with the nasal passages substantially along its entire circumference. In such embodiments, material exiting holes (1113) in the distal tip of the nozzle (1100) or holes (1112) on the distal face of the extension (1110) can not reach regions proximal to the extension (1110) and will reach only regions deeper in the nasal passages than the extension (1110). In such embodiments, the substance will reach the upper parts of the nasal passages and the lungs.
Material exiting from holes (1112) in locations where the extension (1110) is in contact with the nasal passages will deposit directly on the walls of the nasal passages. In such embodiments, deposition is in a very narrow band; the location of the band can be tailored for the material of interest.
Material exiting holes (1112) proximal to the region of the extension (1110) in contact with the walls of the nasal passages will be unable to reach locations distal to the region of the extension (1110) in contact with the walls of the nasal passages and will therefore deposit in the lower parts of the nasal passages.
Returning to
The expandable portion (1120) is preferably inflated after insertion of the device into the nasal passage. Inflation can be before or at the time of activation of the device.
In embodiments where delivery is to a nostril, delivery of the substance can be improved by inducing sniffing in the user.
Sniffing (short, sharp breaths through the nose, for example, when smelling something) is highly correlated with soft palate (Velum) position. Sniffs are rapidly modulated in an odorant-dependent fashion by a dedicated olfactomotor system, and affect the position of the soft palate at the posterior end of the nasal cavity. When sniffing through the nose, the palate is in its upper position to cause separation between the nasal cavity and the oral cavity.
In addition to conscious control, sniffing may be reflexively elicited by chemicals, functioning as either irritants or odors in the nose. Overall sniff duration and pattern can be modulated in real time to optimize olfactory perception. When the olfactory system encounters a concentrated odorant, sniff vigor is reduced and sniff time is reduced; when it encounters a diluted odorant, sniff vigor is increased and duration lengthened. Odorant pleasantness also affects sniffing; sniff vigor and duration increase when smelling a pleasant odor and decrease when smelling an unpleasant odor.
In preferred embodiments, the device disclosed herein can release odorant into the nasal cavity of the user in order to reflexively elicit sniffing. The odorant can be a single odorant or a mixture of odorants and can comprise compounds from different chemical families, for non-limiting example:
Also aromatic compounds of Alcohols, Aldehydes, Esters, Ketones, Lactones, Thiols.
In preferred embodiments, the substance is contained within a capsule. The capsule can have a single compartment or it can be multi-compartment. The capsule can contain a broad range of drugs and materials. The aromatic compound can be stored in the nozzle, or the nozzle or a portion thereof can be impregnated with aromatic compound, so as to trigger the closing of the velum when the nozzle tip is being placed in the nasal cavity. The delivery can be for local effect, to the systemic circulation, to the central nerve system (CNS), to the brain, preferably via the olfactory epithelium, to the spinal cord and associated nerves, and any combination thereof.
As described hereinabove, the drugs and materials to be delivered can be, but are not limited to, pharmaceuticals, natural compounds, biologics, hormones, peptides, proteins, viruses, cells, stem cells and any combination thereof.
The stored substance or substances can be stored as a liquid, an aerosol, a powder, a slurry, a suspension, or a gel, if thin enough. The substance or substances can be stored either with or without a carrier; the carrier can be a liquid, a gas or a powder.
The substance as delivered can comprise a powder, a mixture of liquid and powder, a mixture of gas and powder, a mixture of powders, a liquid, a mixture of liquid and gas, a mixture of liquids, a gas, or a mixture of gases.
The stored substance or substances can be packaged to minimize degradation, for example, by packaging it in vacuum or under an inert atmosphere. Preferably, capsules are single-use so that a single, controllable dose can be delivered with each use of the device. Capsules can be placed in the container of the device, or the container can comprise the capsule.
Use of an inert gas for the carrier for delivery of the medication obviates the possibility of interactions between the user and the delivery carrier; allergies to carriers, especially in medications used for chronic illnesses, are a growing problem. Furthermore, the delivery carrier is in contact with the medicament for no more than a few seconds and more commonly for no more than a few milliseconds, thereby minimizing degradation of the medicament due to interactions with the delivery carrier.
Examples of drugs and materials deliverable using the device are given hereinbelow. All examples listed below are exemplary and are not limiting.
Deliverable drugs and materials include: treatments for allergic rhinitis; treatments for osteoporosis; vaccinations and immunizations; sexual dysfunction drugs; treatments for B12 deficiency; smoking cessation; treatment of gynecological problems; treatment of other women's health issues; general anesthetics; local anesthetics; opioid analgesics; agonist-antagonists and antagonists; antitussives; drugs used in the treatment of motor disorders; antiepileptics; drugs used in affective disorders; antipsychotics (neuroleptics); sedative-hypnotics, anxiolytics, and centrally acting muscle relaxants; treatments for anxiety disorders; skeletal muscle relaxants; treatments for Parkinson's disease; treatments for Alzheimer's disease; treatment for pain and anti migraine treatment.
Medicaments for treatment of allergic rhinitis include: steroids, including corticosteroids, Flonase, Patanase, Beconase, Anihistamine, Astelin, Otrivin, Livostin, Theramax, Avamys, Lufeel, Sinofresh, Nasonex, Nasocort and Veramyst.
Medicaments for treatment of osteporosis include: Miacalcin, Fortical and Stadol.
Medicaments for vaccinations and immunizations include: LAVIN, and influenza vaccines including FluMist.
Medicaments for smoking cessation include: NasalFent.
Other medicaments which can be delivered include: calcitonin and parathyroid hormone.
Neurotransmitters and neuromodulators that can be delivered include: acetylcholine (ACH), Anticholinergic drugs, adenosine triphosphate (ATP), aspartate (Asp), beta-amyloid, beta-endorphin, bradykinin, dopamine (DA), L-DOPA, Carbio-Dopa, epinephrine, dynorphins, endomorphins, enkephalins, 5-hydroxytryptamine (5-HT), Sumatriptan, Imitrex, Migranal, Zolmitriptan, Zomig, Gamma-aminobutyric acid (GABA), glutamate (glu), glycine, histamine, leptin, nerve growth factor and other growth factors), norepinephrine, nitric oxide, and Substance P.
General anesthetics which can be delivered include: alfentanil, desflurane, enflurane, etomidate, fentanyl, halothane, isoflurane, ketamine, methohexital, methoxyflurane, midazolam, lorazepam, diazepam morphine, nitrous oxide (N2O), propofol, sevoflurane, Sufentanil, Sublimase, and thiopental.
Local anesthetics which can be delivered include: benzocaine, bupivacaine, cocaine, lidocaine, prilocaine, procaine, ropivacaine, and tetracaine.
Opioid analgesics, agonist-antagonists, and antitussives which can be delivered include: agonists, codeine, diphenoxylate, fentanyl, heroin and other opiods, hydrocodone, 1-alpha-acetyl-methadol, levomethadyl acetate, loperamide, meperidine, methadone, morphine, oxycodone, d-propoxyphene, combinations of opioids plus acetaminophen and asa, and tramadol.
Agonist/antagonists and antagonists which can be delivered include: buprenorphine, butorphanol, nalbuphine, nalorphine, naloxone, naltrexone, nalmefene, pentazocine, codeine, dextromethorphan, and hydrocodone.
Drugs used in the treatment of Parkinson's disease and motor disorders which can be delivered include: amantadine, apomorphin, baclofen, benzodiazepines, benztropine, bromocriptine, carbidopa, cyclobenzaprine, dantrolene, dopamine, entacapone, haloperidol, L-DOPA, pergolide, pramiprexole, ropinerole, selegiline (deprenyl), trihexyphenidyl, rasagiline, azilect, selegiline, ladostigil, rotigotine, neupro, mono amine oxidase inhibitor, and COMT inhibitor.
Antiepileptics which can be delivered include: acetazolamide, carbamazepine, clonazepam, diazepam, ethosuximide, felbamate, gabapentin, Lamotrigine, lorazepam, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, Vigabatrin and Midazolam.
Drugs used in affective disorders which can be delivered include: antidepressants, amitriptyline, bupropion, citalopram, clomipramine, desipramine, fluoxetine, fluvoxamine, imipramine, nortriptyline, paroxetine, phenelzine, sertraline, trazodone, tranylcypromine, venlafaxine, antimanic drugs, carbamazepine, lithium carbonate and valproic acid.
Antipsychotics (neuroleptics) which can be delivered include: chlorpromazine (CPZ), clozapine, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, sertindole, thioridazine, thiothixene and ziprasidone.
Sedative-hypnotics, anxiolytics, and centrally acting muscle relaxants which can be delivered include: alprazolam, chloral hydrate, diphenhydramine, flumazenil, flurazepam, hydroxyzine, lorazepam, oxazepam, phenobarbital, temazepam, triazolam, zaleplon and zolpidem.
Anxiety disorders and skeletal muscle relaxants which can be delivered include: alprazolam, chlorazepate, chlordiazepoxide, diazepam, flumazenil (antagonist), lorazepam, and oxazepam.
Treatments for Alzheimer's disease which can be delivered include: donepezil, galantamine, rivastigmine, Tacrine, Detemir, Novolin, Humulin, Insulin, insulin like hormone, an insulin analog such as NPH Insulin, Lispro, Aspart, Detemir Insulin, Glulisin, Glargin Insulin, Insulin degludec, BDNF, GDNF, MIBG, anti cancer agents, anti cancer drugs, dopamine agonist and dopamine antagonist.
Other drugs which can be delivered include: amphetamine, caffeine, ephedrine, methamphetamine, methylphenidate, phentermine, sibutramine, disulfiram, ethanol, methanol, naltrexone, atropine, scopolamine, ketamine, lysergic acid diethylamide (LSD), MDMA (methylene dioxy-methyl amphetamine), mescaline, phencyclidine (PCP), donabinol, marijuana/THC, organic solvents, nicotine, Pentobarbital, neuroprotective compounds, neuroprotective peptides, neuroprotective factors, davunetide, anti schizophrenic drugs, anti depression drugs, comtan, Entacopone, anti ADHD agents, anti ADHD drugs such as Methylphenidrate (ritalin), and anti-autism and anti-autism symptoms drugs.
Other materials that can be delivered include: both purified natural and synthetic biologics, peptides, proteins, antibodies, cells including stem-cells, parts of cells, nanoparticles and microparticles. The nanoparticles and microparticles can comprise drugs; they can be carriers for drugs, cells or parts of cells; and any combination thereof.
In preferred embodiments, the substance comprises permeation enhancers to improve penetration of the active components of the substance through the mucosal membranes.
In some formulations, the formulation can comprise polymeric microparticles comprising at least one active agent and a permeation enhancer, where the active agent is selected from a group consisting of a peptide, a protein, an antibody, nucleic acid, small molecules, cells and any combination thereof.
A great number of penetration enhancers are known in the literature.
One such penetration enhancer is Hyaluronic acid (also referred to as HA or hyaluronan), which is a polysaccharide that occurs naturally in the body. Due to its exceptional water-binding, visco-elastic and biological properties, HA can improve the attributes, such as, but not limited to, the absorption characteristics, of existing formulations and can also add new attributes to existing formulations. Inclusion of HA can be advantageous when developing new formulations.
When used for drug delivery and targeting, HA can provide clear advantages over traditional polymeric substances such as synthetic polymers such as, but not limited to, poly(ethylene glycol), poly(lactic acid), poly(glycolic acid), poly Acrylic Acid and Poly-(N-isopropylacrylamide), or other biopolymers such as chitosan and alginate.
HA's benefits in the drug delivery area include, but are not limited to:
Other penetration enhancers include, but are not limited to the following:
A group containing: a fatty acid, a medium chain glyceride, surfactant, steroidal detergent, an acyl carnitine, Lauroyl-DL-carnitine, an alkanoyl choline, an N-acetylated amino acid, esters, salts, bile salts, sodium salts, nitrogen-containing rings, and derivatives. The enhancer can be an anionic, cationic, zwitterionic, nonionic or combination of both. Anionic can be but not limit to: sodium lauryl sulfate, sodium decyl sulfate, sodium octyl sulfate, N-lauryl sarcosinate, sodium carparate. Cationic can be but not limit to: Cetyltrimethyl ammonium bromide, decyltrimethyl ammonium bromide, benzyldimethyl dodecyl ammonium chloride, myristyltimethyl ammonio chloride, deodecyl pridinium chloride. Zwitterionic can be but not limit to: decyldimethyl ammonio propane sulfonate, palmityldimethyl ammonio propane sulfonate. Fatty acid including but not limit to: butyric, caproic, caprylic, pelargonic, capric, lauric, myristic, palmitic, stearic, arachidic, oleic, linoleic, linolinic acid, their salts, derivatives and any combinations or glyceride, monoglyceride, a diglyceride, or triglyceride of those fatty acids. Bile acids or salts, including conjugated or un conjugated bile acids, such as but not limited to: cholate, deoxycholate, tauro-cholate, glycocholate, taurodexycholate, ursodeoxycholate, tauroursodeoxycholate, chenodeoxycholate and their derivatives and salts and combinations. Permeation enhancer as comprises a metal chelator, such as EDTA, EGTA, a surfactant, such as sodium dodecyl sulfate, polyethylene ethers or esters, polyethylene glycol-12 lauryl ether, salicylate polysorbate 80, nonylphenoxypolyoxyethylene, dioctyl sodium sulfosuccinate, saponin, palmitoyl carnitine, lauroyl-1-carnitine, dodecyl maltoside, acyl carnitines, alkanoyl cjolline and combinations. Other include but not limited, 3-nitrobenzoate, zoonula occulden toxin, fatty acid ester of lactic acid salts, glycyrrhizic acid salt, hydroxyl beta-cyclodextrin, N-acetylated amino acids such as sodium N-[8-(2-hydroxybenzoyl)amino]caprylate and chitosan, salts and derivatives and any combinations.
Other enhancers include: formulations of water in oil, formulations of oil in water; emulsions, double emulsions, micro-emulsions, nano-emulsions, water in oil emulsions, oil in water emulsions; steroidal detergent, an acylse; to allow better absorption in the mucosal tissue, better permeation and absorption in the target cells, better stability of the encapsulated drug/active ingredient.
Some embodiments comprise, either alone or in combination with a penetration enhancer, a mucoadhesive agent such as, but not limited to, bioadhesive proteins, carbohydrates and mucoadhesive polymers
In the capsule of the present invention, the device comprises at least one compartment, and preferably a plurality of compartments, each containing a flowable substance. The delivery device is designed to rupture the compartments such that the flowable substances are mixed with a carrier, preferably air, and delivered to a predetermined deposition site, typically, but not exclusively, in the nasal passages.
Medicaments may be supplied as liquids, as powders, or as aerosols. In the preferred embodiment, the medicament is supplied in a single-dose capsule. In other embodiments, the medicament is supplied in a multi-dose capsule means, the multi-dose capsule adapted to provide a single dose per activation.
In preferred embodiments, the flowable-substance capsule has a plurality of compartments. A compartment can contain at least one medicament, at least one medicament precursor, carrier gas, compressed gas, and any combination thereof.
The different compartments can contain different medicaments, with the plurality of medicaments delivered to the nostril or other delivery site in a single dose. In this manner, a plurality of medicaments may be supplied to the nostril in a single injection, with interactions occurring between the medicaments at most during the short time between activation of the device and the delivery of the substances and their deposition at the target site.
In some embodiments, interactions between components are unwanted. In such embodiments, a sequential release will utilize the short time period between release of the components and their absorption in the body to prevent such unwanted interactions and/or reactions.
In other embodiments, mixing and/or reactions are desired. In such embodiments, the reactions can occur all at once, by rupturing all of the compartments at the same time and mixing/interacting the components, either in the aerosol or in at least one mixing chamber. In other embodiments, a component can be added by needle insertion at a desired time before use, either into an empty compartment or into an occupied compartment (so that a desired reaction can occur). In other embodiments, the compartment walls rupture in a predetermined order, so that mixing/interaction occurs in stages, in a predetermined order. Mixing/interaction can occur in a compartment or compartments, in a mixing chamber, in the air passages of the device, in the aerosol, in the nasal (or other) passages of the body, and any combination thereof.
As a non-limiting example, a medicament can comprise four components, stored in four compartments of a capsule. Prior to activation, a fifth component is injected into compartment 1. After a predetermined time, the device is activated and the walls between compartment 1 and compartment 2 are broken, allowing mixing of 5/1 and 2. This followed by rupture of the walls surrounding component 3, which then mixes with 5/1/2 and reacts with 2. The last walls to rupture are those surrounding compartment 4; material 4 remains in a separate part of the aerosol and deposits on the nasal passages after deposition of 5/1/2/3.
In another example, precursor A mixes with precursor B to form intermediate C, and, subsequently, intermediate C mixes with precursor D to form final product E.
Mixing or reactions or release of components from different compartments can occur simultaneously, in different linked compartments, or they can occur sequentially, as in the example above. Any combination of sequential and simultaneous reactions and/or mixing and/or release can be used. Components can arrive at the deposition site simultaneously, either mixed or unmixed, sequentially, and any combination thereof.
It should be noted that there can be a predetermined delay of some fractions of a second between rupturing of walls of different compartments, in order to, for non-limiting example, allow complete mixing of one set of components or allow a reaction between one set of components to go to completion before the next mixing/reaction starts or the delivery starts.
In some embodiments, the device or, preferably, the capsule, comprises a mixing mechanism or mixing chamber, so that, as described above, components of the composition can mix and/or react during the activation process, enabling components to be stored separately and/or to be stored as stable precursors, but to deliver a predetermined treatment comprising at least one medicament to a predetermined delivery site. An embodiment of a mixing mechanism in a mixing chamber is disclosed hereinbelow (see
An exemplary and non-limiting embodiment of part of a delivery device is illustrated in
In
In some embodiments, the capsule comprises a nosepiece (6) and at least one medicine compartment (21) as a single unit, which is removable and replaceable. In some embodiments, this a single-use unit, where the medicine compartment (21) is not refillable, the unit being discarded after use. In other embodiments, the device (21) comprises a cartridge of medicine capsules, with means to replace an exhausted capsule with an unused one. In some variants of this embodiment, the cartridge can be replaced. In other variants, the cartridge is single-use, the nosepiece unit (6) being discarded when the cartridge is exhausted. In yet other embodiments, the nosepiece (6) and capsule (21) form two units, enabling replacement of either the nosepiece (6) or capsule (21), as appropriate.
The capsule can be single-use, comprising at least one of a substance, a carrier, a compressed gas, a propellant, and any combination thereof. Similarly, a multi-dose cartridge can comprise multiple capsules, each capsule comprising at least one of a substance, a carrier, a compressed gas, a propellant, and any combination thereof.
The capsule can be single-compartment or can comprise at least two compartments. In some embodiments, at least one compartment contains a propellant such as compressed air (air compartment). In such embodiments, charging is enabled by causing the compressed air to flow from the at least one compressed air compartment into a compressed air chamber in the device, said compressed air chamber fluidly connected to an air channel (not shown). An illustrative example of a method of causing the compressed air to flow from at least one compressed air compartment into the compressed air chamber in the device comprises a port on the enclosure such that, when the flowable substance chamber is mounted to the enclosure, the port is enabled to fluidly connect the at least one compressed air compartment to the compressed air chamber. Retracting the handle (4) or placement of the capsule in its capsule retainer position causes a piercing means to pierce a wall of the at least one compartment of the capsule, causing the air to flow from the at least one compressed air compartment into the at least one flowable substance chamber of the capsule. Many other methods of causing the compressed air to flow from the at least one compressed air compartment through the other compartments and to the deposition site will be obvious to persons with ordinary skill in the art.
In any of the devices described herein, an indicator element can be used to indicate to the user that the device has been charged to the desired pressure, to the desired volume and any combination thereof.
In any of the devices described herein, active feedback with a correction element can be used to indicate to the user whether the desired volume, pressure and any combination thereof has been reached, or to ensure that the desired volume, pressure and any combination thereof have been reached and any combination thereof.
In preferred embodiments, there is a positive means of ensuring that the device is properly charged before activation. In some embodiments, proper charging is ensured by having the direction of handle movement opposite to the power produced by the pressurizing action, thus enabling the finalization of the charging of the device. In other embodiments, the user pulls a string tight to finalize the charging action of the device. In yet other embodiments, the device comprises a magnet which creates a magnetic field between the piston and the end point of charging or at another position predetermined position. This magnetic field contributes to the finalization of the charging action. An electrical field could act in a manner similar to the magnetic field.
In multi-compartment capsules, walls divide the capsule into compartments. The compartments can have approximately the same volume or different volumes, and the same thickness or different thicknesses; if circular, they can have the same diameter or different diameters. They can have the same area at the end faces, or different areas.
The compartments, taken together, can form a large fraction of the volume of the capsule, or they can form a small fraction of the volume of the capsule.
Compartment walls can be equally spaced, either angularly or linearly, or they can be unequally spaced. Spacings can be arbitrary, they can be regular, they can follow a pattern, and any combination thereof.
Compartments can be near the edge of the capsule or at other positions within the capsule.
Before use, the compartments are preferably hermetically sealed to prevent mixing of the substances contained therein.
Compartment walls can be substantially similar in shape to the capsule walls (for non-limiting example, lenticular walls within a lenticular capsule) or at least one of the compartments' walls' shape differs from the shape of the cross-section of the capsule. (For non-limiting example, a lenticular wall within a circular capsule.)
Compartment walls can be non-frangible or frangible. Frangible walls permit mixing or reaction of the contents of adjacent compartments before the substances leave the compartments.
Compartments can, but need not, have a frangible membrane at at least one end.
Any compartments can contain one substance or a mixture of substances; any two compartments can contain the same substance or mixture thereof, or different substances or mixtures thereof.
The material of any combination of capsule walls and compartment walls can be rigid, semi-flexible, flexible and any combination thereof. Flexible or semi-flexible compartment or capsule walls can reduce dead space—regions of low gas flow—in the air path during activation.
In the embodiment shown in
In the embodiment schematically illustrated in
In the embodiment schematically illustrated in
In practice, the embodiment illustrated in
In some embodiments, there is no central compartment (140).
In the exemplary embodiment shown, the auxiliary compartments are hollow, containing a substance. In other embodiments, at least one of the auxiliary compartments (150, 155) is comprised of solid material, thereby forming part of the structure of the capsule.
In preferred embodiments, the central compartment (140) and the central auxiliary compartment (155) are solid, forming a solid central core for the structure. The remaining compartments (130, 150) comprise substance, where, in preferred embodiments, the compartments (130) contain a substance such as a medicament and the auxiliary compartments (150) contain a propellant, preferably compressed gas.
In the exemplary embodiment shown in
In the exemplary embodiment shown in
These embodiments are merely exemplary; any combination of the above arrangements can be used.
In the exemplary embodiments shown, the walls separating the compartments are planar. In other embodiments, the walls can form a curve, either regular or irregularly shaped.
The main longitudinal axis of at least one of the compartments can be parallel to the main longitudinal axis of the capsule, it can be spirally disposed it can be at an angle to the main longitudinal axis of the capsule, and any combination thereof.
The main longitudinal axes of the compartments can be straight, they can form regular curve, they can form irregular curves, and any combination thereof. For any pair of compartments, the main longitudinal axes can be the same or they can be different.
In most embodiments, at least part of the upstream closure surface (not shown) and the downstream closure surface (not shown) of the capsule are frangible or otherwise removable, such that, when broken or otherwise removed, the medications can be delivered to the desired deposition site. In a variant of these embodiments, different portions at least one closure surface have different breaking strengths, such that the different portions can be broken at different times during delivery of the medication, enabling either differential mixing of medical formulations in different compartments or differential delivery of the medications in at least two of the compartments.
In some embodiments, at least part of the side surface of the capsule is frangible, enabling yet another mixing path or delivery path.
Capsules can be cylindrical with circular cross-section, as shown, cylindrical with oval, elliptical, lenticular, or polygonal cross-section, with the polygon having at least three sides and not more than about 20 sides. The polygon can be a regular or irregular.
Capsules can be spherical, elliptical, ovoid, pillow-shaped, football-shaped, stellate and any combination thereof. Capsules can form regular or irregular shapes.
Compartments can have substantially constant cross-section through the device or the cross-section can vary in area, in shape, or in any combination thereof.
In this exemplary embodiment, the mixing mechanism (1020) comprises spirally-disposed air channels (1022) at the periphery of the mixing mechanism (1020). The central part of the mixing mechanism (1020) is solid, forcing the carrier gas and the substances to pass through the channels (1022). By narrowing the channel through which the gas passes and by changing the direction of the gas flow, mixing of the substances is enhanced. The mixing mechanism (1020) fits within the tegument (110) of the capsule (100) and mixing occurs within the capsule (100).
In some embodiments, the capsule comprises two units, one comprising at least one substance and one comprising the mixing mechanism, such that the substances exit the compartments and are then mixed in the mixing mechanism.
In other embodiments, the mixing mechanism (1020) comprises channels disposed throughout its cross-section.
Channels can be arbitrarily arranged across a cross-section, regularly arranged across a cross-section, or irregularly arranged across a cross-section.
Channels can be linearly disposed, parallel to the main longitudinal axis of the capsule; or linear and disposed at an angle to the main longitudinal axis of the capsule.
The main longitudinal axis of at least one channel can be curved with respect to the main longitudinal axis of the mixing mechanism, with respect to an axis perpendicular to the main longitudinal axes, or any combination thereof.
Any combination of the above channel shapes can be used.
The shape of a channel cross-section can be substantially the same along the length of the channel, the shape can change along the length of the channel, the size of the cross-section can change along the length of the channel, and any combination thereof.
Shapes of the cross-sections of the channels can vary in the same manner along the length of the channel, or they can vary in different manners.
Shapes of the cross-sections of the channels can be the same for all the channels, or the shapes of the cross-sections of at least two channels can be different.
Sizes of the cross-sections of the channels can vary in the same manner along the length of the channel, or they can vary in different manners.
Sizes of the cross-sections of the channels can be the same for all the channels, or the sizes of the cross-sections of at least two channels can be different.
In some embodiments, the mixing mechanism (1020) comprises a plurality of longitudinal sections, with the sections having fluidly connected channels, but the channels are differently disposed longitudinally. For non-limiting example, a two-section device can have spirally disposed channels with left-handed spirals in the first section and right-handed spirals in the second section.
In some embodiments, there are different numbers of channels in the two sections. In other embodiments, there are the same number of channels in the two sections.
In other multi-section mixing mechanisms (1020), sections comprising channels are fluidly connected by substantially channel-free regions.
Mixing mechanisms can comprise between 1 and 10 regions. Individual regions can have any of the channel dispositions described hereinabove.
In some embodiments, mixing can be done by an integral mixing mechanism, either a single-section or a multi-section device. In other embodiments, mixing can be done by disposing a plurality of single-section mechanisms end-to-end, either abutting each other or with spacers to provide channel-free regions.
During the process of mixing, the first and second flowable substances can be mechanically mixed with each other and with the air, they can be reacted with each other, and any combination thereof.
In some embodiments, reaction of at least one flowable substance can be enhanced by a catalyst deposited on or part of the walls of the mixing region.
Criteria of the capsule can be optimized to include: ensuring that a single dose of the substance is delivered in its entirety, ensuring that the single dose contains the predetermined amount of the substance, ensuring that the dose is delivered to the desired region of the nose, and ensuring that delivery of the dose causes the minimum possible discomfort to the patient. Any combination of these criteria can be optimized for each particular combination giving rise to a different embodiment of the capsule.
The capsule can also be optimized for ease of insertion into a delivery device, for ease of removal from a delivery device, for stability of the contents during storage, for resistance of the capsule materials to environmental degradation, for resistance to undesired fracture, for reliability of use, for completeness of mixing, for completeness of reaction, and any combination thereof.
In some embodiments, the capsule comprises a filter adapted to remove from the air at least one selected from a group consisting of particles, particulates, bacteria, viruses, moisture, and undesired gases before the air contacts the user. Such a filter, by preventing unpleasant odors or tastes from reaching the user and by preventing particles or particulates from reaching the user, can make the experience of using the device much more pleasant for the user and much safer. By removing bacteria and viruses, infection of the user can be prevented.
In some embodiments, the capsule contains only a single dose of the substance, the capsule being replaced after each use. In other embodiments, the capsule contains multiple doses of the substance, preferably packed separately, so that the dose is fresh for each use.
It should be emphasized that any embodiment of the present invention and any variant thereof can be used for both for humans (medical use) and animals. Thus, any of the devices as disclosed above and any variant thereof can be used for veterinary applications as well as (human) medical applications.
During dispensing of the substance, the gas passing through the capsule entrains the substances contained within the compartments such that the substances have a predetermined distribution within the dispensed mixture, where the predetermined distribution can be a homogeneous distribution or a heterogeneous distribution. Heterogeneous distributions can be: an arbitrary distribution, a distribution in which the density of the at least one substance within the mixture follows a predetermined pattern, and any combination thereof.
According to another embodiment of the present invention, movement of air into the chamber during transformation of the device into said pre-activated state creates a vacuum in the region near or in the capsule.
In some embodiments the substance is a composition which can contain at least one drug, at least one chemical permeation enhancer, and any combination thereof. The composition can be a gel, a solution, a cream, a spray, a powder, a tablet and any combination thereof.
In preferred variants of this embodiment, chemical penetration enhancers, mucoadhesive agents, and any combination thereof increase the rate of absorption of at least one of the drugs in the formulation at the site of delivery, relative to rate of absorption of that drug at the site in a composition lacking the chemical permeation enhancers.
The characteristics of the formulation and/or of the chemical penetration enhancers are chosen so that the chemical permeation enhancers are unable to cause either necrosis or specific inflammation at the site of delivery and are further unable to cause symptoms associated with unwanted side effects.
In some variants of these embodiments, a chemical permeation enhancer or a combination of enhancers is adapted to deliver drugs into epithelial cells. The chemical permeation enhancer for delivery into epithelial cells can be a zwitterionic surfactant, palmityldimethyl ammonio propane sulfonate (PPS) or a structural analog thereof, a nonionic surfactant, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80 and any combination thereof.
The site of delivery of the chemical permeation enhancer for delivery into epithelial cells can be a mucosal layer selected from a group consisting of mucosa of body orifices and mainly the nasal cavity mucosa.
In some variants of these embodiments, a chemical muco-adhesive element is tailored to allow better target tissue deposition and adherence to allow better delivery with slow release characteristics for prolonged tissue exposure to the active ingredient.
An embodiment of a pressurized air carrier for providing controlled drug delivery to the nasal cavity.
Other embodiments can be used for delivery to the ear, mouth, throat and rectum.
In this embodiment of the device, the following parameters were variable, over the ranges given:
Another important consideration, not investigated in this example, is the location of the nozzle in the body orifice, for non-limiting example, the depth of insertion of the nozzle in the nasal cavity.
In practice, at least one of: the pressure, air volume and time between charging and activation can be optimized based on the characteristics of the compound, drug or medicament such as, but not limited to, the volume, density, viscosity, state of matter, drug formulation, and any combination thereof. The compound can be a liquid, a powder or any combination thereof.
Pressure, air volume, time between charging and activation, and location in the orifice interact with the characteristics of the delivered substance; all of the above contribute to the final distribution of aerosolized matter in the nasal cavity, or, in other words, the pattern of deposition of the aerosolized matter in the nasal cavity following discharge of the matter from a device with given predetermined parameters.
Other criteria which can be optimized include, but are not limited to, droplet size, droplet size distribution, droplet size as a function of time, and droplet size distribution as a function of time.
The material as delivered is then a predetermined volume of the selected medicament in a predetermined form within a carrier comprising a predetermined volume of air, with the volume of air delivered at a predetermined pressure.
Tests showing the effect of changing pressure, air volume and time between charging and activation are given below. Deposition was measured in models that mimicked at least one aspect of the human nasal cavity (structure, friction, air flow, surface area or surface mucosa).
Model 1
A 36 cm long plastic tube with an inner diameter of 0.6 cm was used as a model for nasal friction and air resistance in the nasal cavity. The length of the aerosol distribution was measured, as well as the characteristics of the aerosol distribution.
2 mg/ml Methylene Blue in saline was used. The dye distribution pattern in the tube and the amount of dye that reached the end of the tube were observed.
In reference to
In reference to
Delivery of the liquid dye through the end of the tube (2620), as determined by its deposition on the absorbent (2630), was more efficient for the air volume of 18 cc, as shown by the stronger color (showing more deposited material) and more-even distribution in
In reference to
In reference to
In reference to
Model 2
A nasal cast model was used to provide a more realistic comparison to the average human nasal cavity. Material dispersion and penetration into the nasal cavity layers was found to be dependent on the pressure and air volume and the form and characteristics of the material deposited.
Model 3
The effects of air volume and air pressure on the distribution of 99mTC-DTPA aerosol in the nasal cavity and nasopharynx were examined using SPECT-CT for two human volunteers.
In both cases, the deposited material comprised 300 microliters of DTPA; 1.75 mc (milli Ciri) and the air volume was 20 ml. A pressure of 6 bar was used for the results shown in
In
The pressure affected the distribution and thus the absorption of the aerosolized drug in the human body.
As shown hereinabove, the location and distribution of deposition of a desired substance and the characteristics of the substance on deposition are controllable by controlling parameters such as pressure, air volume, substance volume and nozzle shape.
In contrast to prior-art nasal delivery devices and technologies, the devices of the present invention can produce a fine aerosol in the nasal cavity or other desired body orifice at the target area and at the location of the target tissue instead of within the device or immediately after exit from the device. Utilizing the pressure as a driving force and the air as a carrier allows the material to be released from the nozzle as a combination of material in a pre-aerosolized state and an aerosol. The properties of the resultant aerosol are typically dependent on the properties of the device and of the medium into which the device is discharged. The properties of the device which affect the aerosol characteristics are the delivery pressure, the volume of the delivery gas, and the characteristics of the delivery orifice.
In some embodiments, the aerosol properties are fairly independent of the delivered substance, in other embodiments, the pressure, volume, orifice characteristics and delivered substance properties can be co-optimized.
In prior-art devices the aerosol is produced at the exit to the device. Typically, the aerosol comprises a wide dispersion of particle sizes, a wide “fan” of aerosol and a low driving force. Therefore, the large droplets typically deposit very close to the exit from the device; smaller droplets tend to quickly contact the walls of the passage, so that deposition is typically predominantly close to the exit from the device, with little of the substance reaching desired sites deeper in the orifice, such as the turbinates of the nose,
In contrast, in the present device, the pre-aerosolized mixture of gas and substance exits the device with a significant driving force, when the preaerosolized fluid hits the walls of the nasal passages, it “explodes” into a fine aerosol that is capable of being driven by the pressure deep into the nasal passages to deposit in the desired region.
The following example will illustrate a typical aerosol dispersions.
In all known other mechanisms of creating aerosols, an orifice is placed at the end of a nozzle and the inner diameter of the device's nozzle and, especially, its orifice, is the main parameter that influences aerosol formation and the aerosol's characteristics. In contrast, in the present invention, no orifice is needed. More than that, putting a conventional orifice at the end of the nozzle will actually limit the pressure and the forces reaching the liquid or powder being dispensed, and thus will reduce the ability to create the desired fine aerosol at the target site. Thus, the large diameter tubing that can be used in the present invention, about an order of magnitude larger than the diameter of commonly-used tubes and orifices, results in the desired fine aerosol, carried efficiently into the nasal cavity with droplet diameters on the order of 0.1-50 micrometer.
In the present invention, the aerosol is created as a result of the nasal cavity resistance and is influenced by the air volume-pressure parameters of the device rather than primarily by the orifice diameter.
In order to model nasal friction and air resistance and as a model for aerosol formation in the nasal cavity, a 36 cm long glass tube with an inner diameter of 2 cm, filled with oil up to 22 cm of its length, was used.
Theoretical analysis has indicated that 5 cm of tube is equivalent to about 0.1-0.5 cm of the nasal passages; therefore the 22 cm. tube would approximately simulate the full depth of a nasal passage.
The test material was 200 microliter of Methylene Blue liquid solution.
The liquid solution was discharged from a device into the base of the tube and pictures and videos were taken in order to be able to follow the process of aerosol formation. The length of the deposition region, the aerosol distribution and the diameter of the aerosol droplets were determined as a function of time.
The Methylene blue solution was injected into the tube using a syringe.
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A comparison of
| Number | Date | Country | Kind |
|---|---|---|---|
| 2020131057150 | Dec 2013 | DE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL2014/050752 | 8/21/2014 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2015/025324 | 2/26/2015 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 462990 | Oppenheimer | Nov 1891 | A |
| 3921637 | Bennie et al. | Nov 1975 | A |
| 4114615 | Wetterlin | Sep 1978 | A |
| 4620670 | Hughes | Nov 1986 | A |
| 5740794 | Smith | Apr 1998 | A |
| 6123228 | Hippensteel | Sep 2000 | A |
| 6398074 | Bruna et al. | Jun 2002 | B1 |
| 7497390 | Beller | Mar 2009 | B2 |
| 7726308 | Flora | Jun 2010 | B1 |
| 7802569 | Yeates et al. | Sep 2010 | B2 |
| 7900659 | Whitley et al. | Mar 2011 | B2 |
| 20020023641 | Stadelhofer | Feb 2002 | A1 |
| 20020092520 | Casper | Jul 2002 | A1 |
| 20030079743 | Genova et al. | May 2003 | A1 |
| 20030187404 | Waldenburg | Oct 2003 | A1 |
| 20030209455 | Pynson et al. | Nov 2003 | A1 |
| 20050028812 | Djupesland | Feb 2005 | A1 |
| 20060067911 | Nilsson et al. | Mar 2006 | A1 |
| 20060107957 | Djupesland | May 2006 | A1 |
| 20060151629 | Vedrine et al. | Jul 2006 | A1 |
| 20060213514 | Price et al. | Sep 2006 | A1 |
| 20070060868 | Tsutsui | Mar 2007 | A1 |
| 20070125371 | Djupesland | Jun 2007 | A1 |
| 20070151562 | Jones | Jul 2007 | A1 |
| 20070154407 | Peters et al. | Jul 2007 | A1 |
| 20080092887 | Hodson et al. | Apr 2008 | A1 |
| 20080210229 | Corbacho | Sep 2008 | A1 |
| 20090285849 | Barsanti et al. | Nov 2009 | A1 |
| 20090314293 | Djupesland | Dec 2009 | A1 |
| 20100282246 | Djupesland | Nov 2010 | A1 |
| 20110048414 | Hoekman | Mar 2011 | A1 |
| 20110088690 | Djupesland et al. | Apr 2011 | A1 |
| 20110168172 | Patton | Jul 2011 | A1 |
| 20110283996 | Abrams | Nov 2011 | A1 |
| 20120291779 | Haartsen et al. | Nov 2012 | A1 |
| 20130096495 | Holmqvist et al. | Apr 2013 | A1 |
| 20130180524 | Shahaf et al. | Jul 2013 | A1 |
| 20130267864 | Addington et al. | Oct 2013 | A1 |
| 20130299607 | Wilkerson et al. | Nov 2013 | A1 |
| 20130345673 | Ferreri et al. | Dec 2013 | A1 |
| 20140060532 | Hodges et al. | Mar 2014 | A1 |
| 20150122257 | Winkler et al. | May 2015 | A1 |
| 20150144129 | Djupesland et al. | May 2015 | A1 |
| 20150174343 | Muellinger et al. | Jun 2015 | A1 |
| 20150209325 | Najarian et al. | Jul 2015 | A1 |
| 20150297845 | Shahaf et al. | Oct 2015 | A1 |
| 20160129205 | Shahaf et al. | May 2016 | A1 |
| 20180072480 | Genosar | Mar 2018 | A1 |
| 20180110922 | Dunki-Jacobs et al. | Apr 2018 | A1 |
| 20190015613 | Shahaf et al. | Jan 2019 | A1 |
| 20190060168 | Koska | Feb 2019 | A1 |
| 20200197631 | Stedman et al. | Jun 2020 | A1 |
| 20200289768 | Shahaf et al. | Sep 2020 | A1 |
| 20200306463 | Shahaf et al. | Oct 2020 | A1 |
| Number | Date | Country |
|---|---|---|
| 202013105715 | Feb 2014 | DE |
| 1 023 098 | Sep 2004 | EP |
| 1 752 176 | Feb 2007 | EP |
| 2030645 | Mar 2009 | EP |
| 724974 | Feb 1955 | GB |
| 2415376 | Dec 2005 | GB |
| 9012567 | Nov 1990 | WO |
| 2012029064 | Mar 2012 | WO |
| 2013128447 | Sep 2013 | WO |
| WO-2015025324 | Feb 2015 | WO |
| WO-2016199135 | Dec 2016 | WO |
| WO-2019003216 | Jan 2019 | WO |
| WO-2019079335 | Apr 2019 | WO |
| WO-2019220443 | Nov 2019 | WO |
| Entry |
|---|
| Israeli Patent Office, “International Search Report and Written Opinion dated Dec. 18, 2014 in corresponding International Application No. PCT/IL2014/050752”, Dec. 18, 2014, Israel. |
| Damm et al., “Intranasal Volume and Olfactory Function”, Chemical Senses, 2002, pp. 831-839, vol. 27, Oxford University Press. |
| Derendorf et al., “Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications”, Allergy, 2008, pp. 1292-1300, vol. 63, 2008 Blackwell Munksgaard. |
| Doose et al., “Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, A novel antiepileptic drug”, Journal of Clinical Pharmacology, 1996, pp. 884-891, vol. 36. |
| Ganger et al., “Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa”, Pharmaceutics, 2018, pp. 1-28, vol. 10, No. 116. |
| International Preliminary Report on Patentability for International Application No. PCT/IL2014/050752, dated Feb. 23, 2016. |
| International Search Report & International Written Opinion of the International Searching Authority issued in International Application No. PCT/IL2014/050752, dated Dec. 18, 2014. |
| Khan et al., “Progress in brain targeting drug delivery system by nasal route”, Journal of Controlled Release, 2017, pp. 364-389, vol. 268, Elsevier B.V. |
| Lammi et al., “Treatment with intranasal iloprost reduces disease manifestations in a murine model of previously established COPD”, The American Journal of Physiology-Lung Cellular and Molecular Physiology, 2016, pp. L630-L638, vol. 310, 2016 American Physiological Society. |
| Leombruni et al., “Treatment of obese patients with binge eating disorder using topiramate: a review”, Neuropsychiatric Disease and Treatment, 2009, pp. 385-392, vol. 5, Dove Medical Press Ltd. |
| Massolt et al., “Appetite suppression through smelling of dark chocolate correlates with changes in ghrelin in young women”, Regulatory Peptides, 2010, pp. 81-86, vol. 161, 2010 Elsevier B.V. |
| Puhakka et al., “The common cold: Effects of intranasal fluticasone propionate treatment”, The Journal of Allergy and Clinical Immunology, 1998, pp. 726-731, vol. 101, No. 6, Part 1, Mosby, Inc. |
| Ramaekers et al., “Odors: appetizing or satiating? Development of appetite during odor exposure over time”, International Journal of Obesity, 2014, pp. 650-656, vol. 38, 2014 Macmillan Publishers Limited. |
| Scheibe et al., “Intranasal Administration of Drugs”, Archives of Otolaryngology—Head & Neck Surgery, Jun. 2008, pp. 643-646, vol. 134, No. 6, 2008 American Medical Association. |
| Schiffman et al., “Taste and smell perception affect appetite and immunity in the elderly”, European Journal of Clinical Nutrition, 2000, pp. S54-S63, Suppl 3, 2000 Macmillan Publishers Ltd. |
| Schriever et al., “Size of nostril opening as a measure of intranasal volume”, Physiology & Behavior, 2013, pp. 3-5, vol. 110-111, 2012 Elsevier Inc. |
| Yeomans, “Olfactory influences on appetite and satiety in humans”, Physiology and Behavior, 2006, pp. 1-14, vol. 89, No. 1. |
| Number | Date | Country | |
|---|---|---|---|
| 20150258287 A1 | Sep 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61868614 | Aug 2013 | US | |
| 61868627 | Aug 2013 | US |
