Patent Grant
9889953
The present invention relates to systems for filling containers with dry powder such as drugs, chemicals and toners and may be particularly suitable for filling multi-dose disks or other containers for dry powder inhalers.
Known dry powder dose filling devices use injectors, pistons or sleeves, such as described in U.S. Pat. Nos. 3,847,191, 4,116,247, 4,850,259, and 6,886,612. Despite the above, there remains a need for alternate dose filling systems.
Embodiments of the invention provide dosing heads with a plurality of spaced apart elongate channels that communicate with a dry powder bed to concurrently directly fill a plurality of aligned dose containers.
Embodiments of the invention provide a relatively high-speed filling process for concurrently filling all the dose containers held by a dose container member, such as a disk, in sub-second time.
In some embodiments, the dosing head has at least one row of circumferentially spaced apart elongate channels (e.g., 30) and can directly fill an underlying dose container disk with an aligned row of spaced apart concentric dose containers (typically in less than about 1 second). In particular embodiments, the dosing head has two radially spaced apart circular rows of elongate channels, e.g., two rows of 30 channels arranged in a circle.
The dosing head can include at least one plate that provides the elongate channels. The dosing head can be configured to interchangeably hold different plates with different elongate channel geometries for accommodating specific dose container form factors and/or for use with different dry powder formulations. The dosing head plate can be substantially circular.
The dosing systems can be configured to fill a dose container disk with 30, 60 or, in particular embodiments, even 120 dose containers in less than about 1 second.
Some embodiments are directed to an apparatus for dispensing a defined amount of dry powder concurrently to a plurality of spaced apart dose receiving containers. The apparatus includes: (a) a dosing head comprising a support body with a plurality of spaced apart elongate channels having a channel length with an upper end defining an entry orifice and a lower end defining an exit port; (b) a dry powder bed residing above and in communication with the dosing head; and (c) at least one vibration source in communication with the dosing head channels configured to controllably apply a vibration flow signal. The channels are sized and configured to prevent a free-flow of dry powder therefrom. When the vibration flow signal is applied to the dosing head channels, dry powder from the dry powder bed flows through the elongate channels and out of the exit port. When the vibration flow signal is removed, dry powder does not flow through the dosing head elongate channels.
The spaced apart channels can be arranged so that the respective entry orifices are substantially circumferentially spaced apart in at least one circle. In some particular embodiments, the channel entry orifices are arranged in two substantially concentric circles.
The vibration source can include a substantially cylindrical body actuator mechanism with a radially extending flange having an array of circumferentially extending apertures extending therethrough. The apparatus can further include a tube plate with an array of upwardly extending tubes having upper and lower ends. The tube plate can be positioned between the actuator body flange and the dose head body so that each tube extends through a respective flange aperture with upper ends of the tubes in communication with dry powder in a dry powder hopper and lower ends of the tubes residing proximate the dosing head channels.
The channels can have orifices that have a diameter of about 3 mm or less and a geometry that defines a miniature-hopper selected to provide an on/off flow pattern and mass flow rate to deliver a defined dose amount in the range of between about 0.5-15 mg.
The channels can be sloped along at least a major portion of the channel length. For example, the channels can slope downward at an angle that is between about 30 degrees to about 45 degrees for at least a major portion of the length of the channel. The channels may have a first portion that angles downwardly to merge into a second portion that is substantially vertical at the exit port.
In some embodiments, the dosing head includes a holder with upstanding sidewalls and a lower inwardly extending ledge. The dosing head can include a plate that mounts to the holder and resides on the ledge and the plate defines the channels.
In some embodiments, the dosing head includes at least one substantially circular plate that defines the channels, the plate having a center. The apparatus can include an upstanding rod that is aligned with the center of the plate. The rod is in communication with the plate and the vibration source to apply the vibration flow signal to the plate.
In some embodiments, the apparatus includes a substantially circular tube plate with an array of circumferentially spaced apart tubes. The dosing head body can be defined by a substantially circular orifice plate that includes at least one row of circumferentially spaced apart elongate channels. The vibration source can include an actuator mechanism with a substantially cylindrical body with a vertically extending centerline aligned with a vertical linear vibration axis of the orifice plate. The actuator mechanism can have a radially extending flange that is attached to the orifice plate and the tube plate. The actuator mechanism can include a plurality of linear actuators that cause the tubes to vibrate in a vertical direction to feed dry powder to the orifice plate and to apply the vibration signal to the orifice plate.
The dosing head can have a lower primary surface that is horizontally oriented. The vibration source can be substantially in-line with a vertical axis associated with the dosing head and is configured to apply energy so that the dosing head operates with a vertical displacement that is less than about 100 microns, and wherein the target dose container is a disk that is closely spaced apart from a lowermost surface of the dosing head.
The vibration source can include: (a) a plurality of actuators, one residing proximate each channel to individually apply the flow signal; (b) a single actuator that is configured to apply the flow signal to all the flow channels; or (c) a plurality of actuators, at least one for sub-groupings of the channels.
The dry powder bed can hold a dry powder having a pharmaceutically active agent including, but not limited to, bronchodilators and the bronchodilator may be used in the form of salts, esters or solvates to thereby optimize the activity and/or stability of the medicament.
The dosing head can include at least one plate that defines at least some of the channels, and wherein the dosing head is configured to releasably engage different plates having different channel geometries to thereby allow a user to dispense different dry powders.
The apparatus channels communicate with the dry powder bed to define miniature hoppers that each hold a plurality of bolus amounts of dry powder and controllably directly dispense a bolus amount to an aligned dose container in response to the on and off application of the vibration flow signal.
Other embodiments are directed to methods of filling a dose container disk assembly. The methods include: (a) providing a dose container disk having upper and lower primary surfaces with a plurality of circumferentially spaced apart apertures associated with dose containers; (b) placing the dose container disk under a dosing head that resides below a dry powder bed, the dosing head having a plurality of circumferentially spaced apart dose filling channels with respective exit ports over the dose container disk so that the exit ports are aligned with the dose disk apertures; (c) applying a vibration flow signal to the dosing head to cause the dry powder to concurrently flow out of the channels into the dose disk apertures; (d) directly filling the dose container disk with a defined amount of dry powder in response to the applying step; and (e) ceasing the applying step to stop the flow of dry powder thereby filling a dose container disk with a defined amount of dry powder in each of the dose containers.
The flow vibration signal can be in-line and can be a frequency modified (modulated) signal. The dose container disk can have at least 30 apertures and the dosing head has at least 30 dose filling channels, and the filling step is carried out to fill at least 30 dose containers on a disk or other substrate in less than 1 second, typically in less than 0.5 seconds.
The dosing head can be attached to a tube plate that includes an array of upwardly extending tubes that communicate with the dry powder bed. The applying step can be carried out to also cause the tubes to vibrate up and down to feed the dosing head channels (which may optionally reside in a lower orifice plate).
Yet other embodiments are directed to dosing heads for a powder filling system that include a plurality of circumferentially spaced apart filling channels with exit ports residing on inner and outer radially spaced apart rows.
The dosing head can include a circular orifice plate that holds the filling channels.
The dosing head can be in combination with a tube plate attached to the orifice plate and an actuator mechanism with a radially extending flange with an array of apertures attached to the tube plate and the orifice plate.
The tube plate can have upper and lower planar surfaces with the upper surface having at least one row of upwardly extending circumferentially spaced apart tubes positioned so that the upwardly extending tubes of the tube plate extend through the flange apertures and the tube plate resides between the orifice plate and the actuator flange.
It is noted that aspects of the invention described with respect to one embodiment, may be incorporated in a different embodiment although not specifically described relative thereto. That is, all embodiments and/or features of any embodiment can be combined in any way and/or combination. Applicant reserves the right to change any originally filed claim or file any new claim accordingly, including the right to be able to amend any originally filed claim to depend from and/or incorporate any feature of any other claim although not originally claimed in that manner. These and other objects and/or aspects of the present invention are explained in detail in the specification set forth below.
The present invention will now be described more fully hereinafter with reference to the accompanying figures, in which embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Like numbers refer to like elements throughout. In the figures, certain layers, components or features may be exaggerated for clarity, and broken lines illustrate optional features or operations unless specified otherwise. In addition, the sequence of operations (or steps) is not limited to the order presented in the figures and/or claims unless specifically indicated otherwise. In the drawings, the thickness of lines, layers, features, components and/or regions may be exaggerated for clarity and broken lines illustrate optional features or operations, unless specified otherwise. Features described with respect to one figure or embodiment can be associated with another embodiment of figure although not specifically described or shown as such.
It will be understood that when a feature, such as a layer, region or substrate, is referred to as being “on” another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when an element is referred to as being “directly on” another feature or element, there are no intervening elements present. It will also be understood that, when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other element or intervening elements may be present. In contrast, when a feature or element is referred to as being “directly connected”, “directly attached” or “directly coupled” to another element, there are no intervening elements present. Although described or shown with respect to one embodiment, the features so described or shown can apply to other embodiments.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation or relative descriptor only unless specifically indicated otherwise.
It will be understood that although the terms “first” and “second” are used herein to describe various components, regions, layers and/or sections, these regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one component, region, layer or section from another component, region, layer or section. Thus, a first component, region, layer or section discussed below could be termed a second component, region, layer or section, and vice versa, without departing from the teachings of the present invention. Like numbers refer to like elements throughout.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Well-known functions or constructions may not be described in detail for brevity and/or clarity.
In the description of the present invention that follows, certain terms are employed to refer to the positional relationship of certain structures relative to other structures. As used herein, the term “front” or “forward” and derivatives thereof refer to the general or primary direction that the dry powder travels from a powder bed to a receiving container such as a dose disk; this term is intended to be synonymous with the term “downstream,” which is often used in manufacturing or material flow environments to indicate that certain material traveling or being acted upon is farther along in that process than other material. Conversely, the terms “rearward” and “upstream” and derivatives thereof refer to the direction opposite, respectively, the forward or downstream direction.
The term “deagglomeration” and its derivatives refer to flowing or processing dry powder to inhibit the dry powder from remaining or becoming agglomerated or cohesive.
The term “free-flow” refers to the ability of a channel to allow dry powder to flow therethrough when in an operative position and in the absence of any vibratory flow signal.
The filling systems can be particularly suitable for filling a partial or bolus dose or doses of one or more types of particulate dry powder substances that are formulated for in vivo inhalant dispersion (using an inhaler) to subjects, including, but not limited to, animal and, typically, human subjects. The inhalers can be used for nasal and/or oral (mouth) respiratory inhalation delivery, but are typically oral inhalers.
The terms “sealant”, “sealant layer” and/or “sealant material” includes configurations that have at least one layer of at least one material and can be provided as a continuous layer that covers the entire upper surface and/or lower surface or may be provided as strips or pieces to cover portions of the device, e.g., to reside over at least one or more of the dose container apertures. Thus, terms “sealant” and “sealant layer” include single and multiple layer materials, typically comprising at least one foil layer. The sealant or sealant layer can be a thin multi-layer laminated sealant material with elastomeric and foil materials. The sealant layer can be selected to provide drug stability as they may contact the dry powder in the respective dose containers.
The sealed dose containers can be configured to inhibit oxygen and moisture penetration to provide a sufficient shelf life.
The term “primary surface” refers to a surface that has a greater area than another surface and the primary surface can be substantially planar or may be otherwise configured. For example, a primary surface can include protrusions or recesses, such as where some blister configurations are used. Thus, a component such as a disk and/or plate can have upper and lower primary surfaces and a minor surface (e.g., a wall with a thickness) that extends between and connects the two.
The dry powder substance may include one or more active pharmaceutical constituents as well as biocompatible additives that form the desired formulation or blend. As used herein, the term “dry powder” is used interchangeably with “dry powder formulation” and means that the dry powder can comprise one or a plurality of constituents, agents or ingredients with one or a plurality of (average) particulate size ranges. The term “low-density” dry powder means dry powders having a density of about 0.8 g/cm3 or less. In particular embodiments, the low-density powder may have a density of about 0.5 g/cm3 or less. The dry powder may be a dry powder with cohesive or agglomeration tendencies.
The term “filling” means providing a bolus or sub-bolus metered or defined amount of dry powder. Thus, the respective dose container is not required to be volumetrically full.
The term “direct” with respect to filling means that no additional components are required to carry out the operation, e.g., the dry powder is directly deposited from the dosing head channel into a blister or other dose container.
As will be appreciated by one of skill in the art, embodiments or aspects of the invention may be embodied as a method, system, data processing system, or computer program product. Accordingly, the present invention may take the form of an entirely software embodiment or an embodiment combining software and hardware aspects, all generally referred to herein as a “circuit” or “module.”
In any event, individual dispensable quantities of dry powder formulations can comprise a single ingredient or a plurality of ingredients, whether active or inactive. The inactive ingredients can include additives added to enhance flowability or to facilitate aerosolization delivery to the desired target. The dry powder drug formulations can include active particulate sizes that vary. The systems may be particularly suitable for filling dry powder formulations having particulates which are in the range of between about 0.5-50 μm, typically in the range of between about 0.5 μm-20.0 μm, and more typically in the range of between about 0.5 μm-8.0 μm. The dry powder formulation can also include flow-enhancing ingredients, which typically have particulate sizes that may be larger than the active ingredient particulate sizes. In certain embodiments, the flow-enhancing ingredients can include excipients having particulate sizes on the order of about 50-100 μm. Examples of excipients include lactose and trehalose. Other types of excipients can also be employed, such as, but not limited to, sugars which are approved by the United States Food and Drug Administration (“FDA”) as cryoprotectants (e.g., mannitol) or as solubility enhancers (e.g., cyclodextrine) or other generally recognized as safe (“GRAS”) excipients.
“Active agent” or “active ingredient” as described herein includes an ingredient, agent, drug, compound, or composition of matter or mixture, which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized and/or systemic effect in a patient.
The active ingredient or agent that can be delivered includes antibiotics, antiviral agents, anepileptics, analgesics, anti-inflammatory agents and bronchodilators, and may be inorganic and/or organic compounds, including, without limitation, drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system, and the central nervous system. Suitable agents may be selected from, for example and without limitation, polysaccharides, steroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, anti-Parkinson agents, analgesics, anti-inflammatories, muscle contractants, antimicrobials, antimalarials, hormonal agents including contraceptives, sympathomimetics, polypeptides and/or proteins (capable of eliciting physiological effects), diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, fats, antienteritis agents, electrolytes, vaccines and diagnostic agents.
The active agents may be naturally occurring molecules or they may be recombinantly produced, or they may be analogs of the naturally occurring or recombinantly produced active agents with one or more amino acids added or deleted. Further, the active agent may comprise live attenuated or killed viruses suitable for use as vaccines. Where the active agent is insulin, the term “insulin” includes natural extracted human insulin, recombinantly produced human insulin, insulin extracted from bovine and/or porcine and/or other sources, recombinantly produced porcine, bovine or other suitable donor/extraction insulin and mixtures of any of the above. The insulin may be neat (that is, in its substantially purified form), but may also include excipients as commercially formulated. Also included in the term “insulin” are insulin analogs where one or more of the amino acids of the naturally occurring or recombinantly produced insulin has been deleted or added.
It is to be understood that more than one active ingredient or agent may be incorporated into the aerosolized active agent formulation and that the use of the term “agent” or “ingredient” in no way excludes the use of two or more such agents. Indeed, some embodiments of the present invention contemplate filling a single dose container or a single disk with combination drugs that may be mixed in situ.
Examples of diseases, conditions or disorders that may be treated using dry powder filled with the filling systems of embodiments of the invention include, but are not limited to, asthma, COPD (chronic obstructive pulmonary disease), viral or bacterial infections, influenza, allergies, cystic fibrosis, and other respiratory ailments as well as diabetes and other insulin resistance disorders. The dry powder may be used to deliver locally-acting agents such as antimicrobials, protease inhibitors, and nucleic acids/oligionucleotides as well as systemic agents such as peptides like leuprolide and proteins such as insulin. For example, inhaler-based delivery of antimicrobial agents such as antitubercular compounds, proteins such as insulin for diabetes therapy or other insulin-resistance related disorders, peptides such as leuprolide acetate for treatment of prostate cancer and/or endometriosis and nucleic acids or ogligonucleotides for cystic fibrosis gene therapy may be performed. See e.g. Wolff et al., Generation of Aerosolized Drugs, J. Aerosol. Med. pp. 89-106 (1994). See also U.S. Patent Application Publication No. 20010053761, entitled Method for Administering ASPB28-Human Insulin and U.S. Patent Application Publication No. 20010007853, entitled Method for Administering Monomeric Insulin Analogs, the contents of which are hereby incorporated by reference as if recited in full herein.
Typical dose amounts of the unitized dry powder mixture dispersed by inhalers may vary depending on the patient size, the systemic target, and the particular drug(s). The dose amounts and type of drug held by a dose container (also known as a “dose container system”) may vary per dose container or may be the same on a platform such as a disk. In some embodiments, the dry powder dose amounts can be about 100 mg or less, typically less than 50 mg, and more typically between about 0.1 mg to about 30 mg.
In some embodiments, such as for pulmonary conditions (i.e., asthma or COPD), the dry powder can be provided as about 5 mg total weight (the dose amount may be blended to provide this weight). A conventional exemplary dry powder dose amount for an average adult is less than about 50 mg, typically between about 10-30 mg and for an average adolescent pediatric subject is typically from about 5-10 mg. A typical dose concentration may be between about 1-5%. Exemplary dry powder drugs include, but are not limited to, albuterol, fluticasone, beclamethasone, cromolyn, terbutaline, fenoterol, β-agonists (including long-acting β-agonists), salmeterol, formoterol, cortico-steroids and glucocorticoids.
In certain embodiments, the bolus or dose can be formulated with an increase in concentration (an increased percentage of active constituents) over conventional blends. Further, the dry powder formulations may be configured as a smaller administrable dose compared to the conventional 10-25 mg doses. For example, each administrable dry powder dose may be on the order of less than about 60-70% of that of conventional doses. In certain particular embodiments, using the dispersal systems provided by certain embodiments of the DPI configurations of the instant invention, the adult dose may be reduced to under about 15 mg, such as between about 10 μg-10 mg, and more typically between about 50 μg-10 mg. The active constituent(s) concentration may be between about 5-10%. In other embodiments, active constituent concentrations can be in the range of between about 10-20%, 20-25%, or even larger. In particular embodiments, such as for nasal inhalation, target dose amounts may be between about 12-100 μg.
In certain particular embodiments, the dry powder in the filling system for a particular dose container, drug compartment or blister may be formulated in high concentrations of an active pharmaceutical constituent(s) substantially without additives (such as excipients). As used herein, “substantially without additives” means that the dry powder is in a substantially pure active formulation with only minimal amounts of other non-biopharmacological active ingredients. The term “minimal amounts” means that the non-active ingredients may be present, but are present in greatly reduced amounts, relative to the active ingredient(s), such that they comprise less than about 10%, and preferably less than about 5%, of the dispensed dry powder formulation, and, in certain embodiments, the non-active ingredients are present in only trace amounts.
In some embodiments, the target unit dose amount of dry powder for a respective drug compartment or dose container is between about 5-15 mg, typically less than about 10 mg, such as about 5 mg of blended drug and lactose or other additive (e.g., 5 mg LAC), for treating pulmonary conditions such as asthma. Insulin may be provided in quantities of about 4 mg or less, typically about 3.6 mg of pure insulin. The dry powder may be inserted into a dose container/drug compartment in a “compressed” or partially compressed manner or may be provided as free flowing particulates.
The filling can be carried out to fill dose containers in any suitable number of doses, typically between about 30-120 doses, and more typically between about 30-60 doses.
Certain embodiments may be particularly suitable for dispensing medication to respiratory patients, diabetic patients, cystic fibrosis patients, or for treating pain. The inhalers may also be used to dispense narcotics, hormones and/or infertility treatments.
The dose filling systems may be particularly suitable for dispensing medicament for the treatment of respiratory disorders. Appropriate medicaments may be selected from, for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen or nedocromil; antiinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti-inflammatories, e.g., beclomethasone dipropionate, fluticasone propionate, flunisolide, budesonide, rofleponide, mometasone furoate or triamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, or (−)-4-amino-3,5-dichloro-α-[[6-[2-(2-pyridinyl)ethoxy]hexyl]methyl]benzenemethanol; diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium, tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin or glucagon. It will be clear to a person of skill in the art that, where appropriate, the medicaments may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament.
Some particular embodiments of the filling system can be used to dispense meted quantities of medicaments that are selected from the group consisting of: albuterol, salmeterol, fluticasone propionate and beclometasone dipropionate and salts or solvates thereof, e.g., the sulphate of albuterol and the xinafoate of salmeterol. Medicaments can also be delivered in combinations. Examples of particular formulations containing combinations of active ingredients include those that contain salbutamol (e.g., as the free base or the sulphate salt) or salmeterol (e.g., as the xinafoate salt) in combination with an anti-inflammatory steroid such as a beclomethasone ester (e.g., the dipropionate) or a fluticasone ester (e.g., the propionate).
Turning now to the figures,
The geometry of the channel 20ch, including one or more of the size of the orifice 20a, size (volume and cross-sectional area) of the channel between entry orifice 20a and the exit port 20e, shape and length of the channel and the size and shape of the exit port can be selected so that there is no “free flow” of powder out of the exit port 20e when dispensing is not desired (e.g., when the vibratory flow signal is “off” or not transmitted to the flow channels).
The channel geometry and the flow signal 28s can be selected to define a reliable flow rate with the “on” and “off” flow control corresponding to when the flow signal is applied or withheld without requiring any physical barrier or valving of the exit ports 20e. The flow rates can be within a range of between about 5 mg/second to about 100 mg/second, typically between about 10 mg/second to about 30 mg/second. It may be desired to have the channel geometry and the vibration provide a sub-second filling rate, e.g., a suitable flow rate for an “on” time for the vibratory flow signal of less than about 1 second, typically about 0.5 seconds or less to fill all 30 or 60 doses (or other numbers of dose containers).
As shown in
The dry powder bed 23 with the dry powder 23p can be enclosed in a housing or open to atmosphere but is not required to be sealed in a pressurized chamber. That is, as the geometry of the channel and the vibratory flow signal directly dispense the dry powder into aligned dose containers 30c. The system 10 does not require either pressure or vacuum to dispense the dry powder and the dry powder bed can be environmentally protected from exposure but is not sealed in a pressure-tight manner.
Referring to
The dry powder 23p in the channel can be replenished via a powder bed residing directly above the channels 20ch (contacting the upper primary surface the dosing head 20 and the entry orifices 20a). The powder 23p in the powder bed 23 can be maintained at a desired level or may be allowed to fluctuate in levels, typically between defined upper and lower limits, such as between a 3 mm to a 150 mm bed height above the entry orifices 20a, typically between 3 mm and 15 mm. The powder 23p in the powder bed 23 can be continuously replenished or may be replenished based on a level sensor and/or after a defined number of dose container members 20 have been filled.
In particular embodiments, the channels 20ch can be sloped and/or angled to inhibit “rat-holing” or undesired trapping of the dry powder. Rat-holing refers to circumstances in which powder is retained against the walls of a length of the channel. Bridging and rat-holing can both be caused by a reduction in the channel width or cross sectional area. This may lead to the powder becoming compacted and forming stresses within the body of the powder. These stresses can lead to stable structures that are difficult to break up. This problem is usually amplified by high wall friction and a head of powder above the blockage. Although vibration can be used to break a bridge or to cause a rat hole to collapse, it can also have the adverse effect of compacting the powder.
To facilitate controlled flow, in some embodiments, as shown in
In some embodiments, the channels 20ch can have an offset geometry that can help prevent the undesired plugging or rat-holing of powder flow. That is, as shown in
It is also noted that although shown as angling down in the right hand direction in several figures, the channels 20ch can slope the opposite way. Indeed, different channels in a dosing head or plate can be oriented to angle in the opposite directions, e.g., the channels 20ch associated with exit ports 20e on the outer row can angle down and outward while the channels associated with exit ports 20e on the inner row can angle down and inward (where two rows of concentric/circular channels are used) or vice versa. See, for example,
The vibration signal 28s can be generated by any suitable vibratory source, including electrical means, mechanical means, electromagnetic means and/or electro-mechanical means. As shown, the vibration source 25 includes at least one actuator 25 in communication with the dosing head 20 and a vibration control circuit 28. It is contemplated that more than one actuator may be used for each set of dosing channels or for each plate 20p (the dosing plate is shown in various figures, e.g.,
The actuator(s) 25 can be configured to be substantially in-line with the dosing head 20 and one-directional. The actuator 25 can apply the flow signal (e.g., flow energy) in a substantially vertical (only) direction. As shown in
In other embodiments, a piezoelectric material (e.g., crystal or ceramic) with an opening that aligns to the entry orifice 20a can be attached to each dosing channel. This can provide an individual actuator for each channel (not shown).
The vibration signal 28s is selected to dispense dry powder at a defined flow rate (with acceptable variation, typically +/−5-10%) for a particular channel geometry. As noted above, the channel geometry can be selected so that the flow is controllable, e.g., there is no free-flow of powder out or through the channels 20ch without the flow signal 28s. In operation, a continual vibration signal or signals can be applied to the dosing head (or individually to the channels 20ch), and a “burst” of energy can be applied as the flow signal 28s for a short duration to carry out the filling process. For example, a vibratory signal can be applied to the dosing head/powder bed to help avoid powder segregation. A high frequency can be modulated “on” and “off” as impulses for providing the vibratory flow signal. In other embodiments, no “background” vibration is used and the vibration can be applied only to generate the flow signal. The vibration signal 28s can include, for example, a saw tooth, square or sine wave associated with a waveform generator. The signal 28s can be configured to generate less than about an 80 micron vertical displacement of the head 20 and/or plate 20p. The frequency or frequencies of the flow signal 28s can be between about 100 Hz to about 5000 Hz, but other frequencies may be used. The vibration signal can be frequency modified, e.g., a frequency modulated sinusoidal signal. Powder-specific signals may be used. See, e.g., U.S. Pat. No. 6,985,798, the content of which is hereby incorporated by reference as if recited in full herein.
The dosing head 20 can have integrated dosing channels 20ch or the dosing channels 20ch can be provided in a plate 20p (
In some embodiments, as shown in
In some embodiments, the dosing channel exit ports 20e (e.g., orifice) can have a cross-sectional length or width (e.g., diameter) that is about 3.2 mm or less.
As shown in
In other embodiments, the bottom of the dose container 30c may be provided by a closed floor of the substrate rather than a sealant layer. In yet other embodiments, the dose disk 30 can have a blister configuration which is filled by the dose head 20.
As shown in
As shown in
The dose container disk 30 can have an outer diameter of between about 50-100 mm, typically about 65 mm and a thickness of between about 2-5 mm, typically about 3 mm. The disk 30 can comprise a cyclic olefin (COC) copolymer. The apertures 30a can have a diameter of between about 2-5 mm, typically about 3 mm and the sidewalls 30w of the dose containers 30c may have an angle or draft of about 1-3 degrees per side, typically about 1.5 degrees, as shown in
Referring to
As shown in
The actuator 25′ can include a radially extending planar flange 225 with a plurality of circumferentially spaced apart apertures 226. The vibrating tubes 326 extend through these apertures 226 to communicate with the power bed 23. The tubes 326 are free to vibrate up and down in response to the vibration input from the actuator 25′ during operation as there is a non-contact clearance around each vibrating tube 326, actuator flange 225 and hopper bottom 123f. As before, the actuator 25′ can be configured to be substantially in-line with the dosing head 20 and one-directional. The actuator 25′ can apply the flow signal (e.g., flow energy) in a substantially vertical (only) direction. The flow signal/energy 28s can be applied so that the displacement is substantially all vertical but typically so that there is limited physical vertical displacement during the dispensing step. The actuator 25′ can be an in-line magnetostrictive actuator or any other suitable actuator or controllable vibrating member. In some embodiments, the actuator 25′ includes a plurality of, typically three, spaced-apart precision linear actuators that vibrate at least 3 points on a plane concurrently. For example, Model PI P/N S-900C002 actuator from PI (Physik Instrumente) L.P., Auburn, Mass. The stimulation or vibration motion can have a defined displacement profile, such as a non-harmonic displacement profile. The stimulation/vibration flow signal 28s can be generated in-line with a vertical axis associated with the dosing head (“A”) so as to apply the flow energy so that the dosing head with a vertical displacement that is less than about 25 microns. As noted above, the target dose container member 30 can be closely spaced apart from a lowermost surface of the dosing head 20, such as between about 20-100 microns, during filling.
The actuator 25′ can be configured to have a pre-load tensioning/compression to achieve a desired bipolar action in a dynamic mode. Actuator power wiring 25p can be provided via the top of the cylindrical body 25′ as shown in
As shown in
As shown in
Bolts 27, 227, 327 can be used to releasably attach the tube plate 325, the actuator flange 225, the orifice plate 20 and/or the floor 123f together. However, in other embodiments, two or more of the components may be bonded, brazed, welded or otherwise be integrally attached together. It is contemplated that the assembly configuration used should be allow the tubes 326 to be free moving so as to not disrupt the vibration of the orifice plate/dosing head 20p, 20 and allow for uniformity of vibration over the ring of orifices in the dosing head/plate.
In some embodiments particularly suited for filling a dose disk with 60 dose containers in two concentric rows with the dose containers in each row having circumferentially offset centers, the tubular plate 325 can include 20 equally circumferentially spaced apart tubes 326 positioned at a common defined radial distance. The underlying orifice plate 20p can include 60 channels 20ch that align with 60 dose container apertures 30c for one dose disk 30 as described above (
In other embodiments, a single tube 326 can feed a single orifice plate channel 20ch or more than one tube 326 can feed a respective one channel 20ch. As noted above, the dose filling system 10′ may be configured to concurrently fill all dose containers 30c on a disk 30 or other configuration and the disk can include different numbers of dose containers 30c, such as 30 dose containers. The orifice dispensing channels 20ch can feed one or more underlying dose containers 30c or more than one channel 20ch can be used to fill an underlying dose container 30c as discussed above.
As shown in
The holder 40 can be configured to hold a plurality of dose container members 30 in alignment with each other and with the dose containers 30c in position for alignment with the corresponding dose channels 20ch. As shown in
The system 100 can also include proximity sensors 125 or other sensors that provide feedback on the position of the dose containers which can be electronically monitored to facilitate the timing of the on-off flow signal for automated filling.
As shown in
The application programs 454 are illustrative of the programs that implement the various features of the data processing system 405 and preferably include at least one application which supports operations according to embodiments of the present invention. Finally, the data 456 represents the static and dynamic data used by the application programs 454, the operating system 452, the I/O device drivers 458, and other software programs that may reside in the memory 414.
While the present invention is illustrated, for example, with reference to the signal generator module 450 being an application program in
The I/O data port can be used to transfer information between the data processing system 405 and the dispensing system 420 or another computer system or a network (e.g., an intranet and/or the Internet) or to other devices controlled by the processor. These components may be conventional components such as those used in many conventional data processing systems which may be configured in accordance with the present invention to operate as described herein.
While the present invention is illustrated, for example, with reference to particular divisions of programs, functions and memories, the present invention should not be construed as limited to such logical divisions. Thus, the present invention should not be construed as limited to the configuration of
The flowcharts and block diagrams of certain of the figures herein illustrate the architecture, functionality, and operation of possible implementations of dry powder-specific dispensing and/or vibratory energy excitation means according to the present invention. In this regard, each block in the flow charts or block diagrams represents a module, segment, or portion of code, which comprises one or more executable instructions for implementing the specified logical function(s). It should also be noted that in some alternative implementations, the functions noted in the blocks may occur out of the order noted in the figures. For example, two blocks shown in succession may in fact be executed substantially concurrently or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved.
In certain embodiments, the present invention can provide computer program products for operating a flowing dry powder dispensing system having channels 20ch and a vibration energy source associated therewith to facilitate controlled flow. The computer program product can include a computer readable storage medium having computer readable program code embodied in the medium. The computer-readable program code can include: (a) computer readable program code that a plurality of different vibration energy signals associated with a “recipe” that correlates the formulation to the dosing head/dosing plate geometry and/or dose container geometry; and (b) computer readable program code that directs the dispensing system to operate using the vibration energy signal for defined “on” and “off” times to dispense the desired dose amount (at the desired flow rate).
The invention will now be described in more detail in the following non-limiting example.
“On/off” flow control evaluation data was obtained using a laboratory system. To deliver the vibratory signal, the laboratory system included a harmonic signal drive configuration with a HP33120A function generator that can provide a carrier signal source connected to a timer (such as a Panasonic LT4H timer) to gate the drive signal, connected to a power amplifier connected to an electromagnetic (linear) actuator from Ling Dynamic Systems, model number V203. Preliminary results indicate relatively limited powder bed depth sensitivity, at least between about 3 mm to about 6 mm of initial bed depth. Powder bed depth for most trials was set to 6 mm and replenished if dropped below about 3 mm for a particular trial.
The following exemplary claims are presented in the specification to support one or more devices, features, and methods of embodiments of the present invention. While not particularly listed below, Applicant preserves the right to claim other features shown or described in the application.
The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. In the claims, means-plus-function clauses, where used, are intended to cover the structures described herein as performing the recited function and not only structural equivalents but also equivalent structures. Therefore, it is to be understood that the foregoing is illustrative of the present invention and is not to be construed as limited to the specific embodiments disclosed, and that modifications to the disclosed embodiments, as well as other embodiments, are intended to be included within the scope of the appended claims. The invention is defined by the following claims, with equivalents of the claims to be included therein.
This application is a second divisional application of U.S. patent application Ser. No. 13/029,356, filed Feb. 17, 2011, which claims the benefit of and priority to U.S. Provisional Patent Application Ser. No. 61/306,291, filed Feb. 19, 2010, through first divisional application, U.S. patent application Ser. No. 14/221,648, filed Mar. 21, 2014, the contents of which are hereby incorporated by reference as if recited in full herein.
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| Number | Date | Country | |
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| Child | 14221648 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14221648 | Mar 2014 | US |
| Child | 15013329 | US |
