WO2008024728A2

WO2008024728A2 - Aerosol inhaler with airflow introduced into mouthpiece

Info

Publication number: WO2008024728A2
Application number: PCT/US2007/076347
Authority: WO
Inventors: Junguo Zhao
Original assignee: Glaxo Group Limited
Priority date: 2006-08-22
Filing date: 2007-08-21
Publication date: 2008-02-28
Also published as: WO2008024728A3

Abstract

A metered dose inhaler comprising a canister configured to contain a pharmaceutical aerosol formulation therein; an actuator comprising: (1) a housing portion, wherein the housing portion is configured to slidably engage the canister upon actuation of the canister and (2) a mouthpiece for engagement by an end user. The inhaler is configured such that the pharmaceutical aerosol formulation does not substantially accummulate on the inner surfaces of mouthpiece or the throat.

Description

AEROSOL INHALER WITH AIRFLOW INTRODUCED INTO MOUTHPIECE

CROSS-REFERENCE TO RELATED APPLICATIONS

The disclosures of the following U.S. Provisional Applications, commonly owned and simultaneously filed herewith, are all incorporated by reference in their entirety: U.S. Provisional Application No. 60/823,139 entitled DRUG DISPENSER (Attorney Docket No. PB61970P); U.S. Provisional Application No. 60/823,141 entitled DRUG DISPENSER (Attorney Docket No. PB62048P); U.S. Provisional Application No. 60/823,143 entitled ACTUATOR FOR AN INHALER (Attorney Docket No. PB62087P); U.S. Provisional Application No. 60/823,146 entitled ACTUATOR FOR AN INHALER (Attorney Docket No. PB62088P); U.S. Provisional Application No. 60/823,151 entitled ACTUATOR FOR AN INHALER (Attorney Docket No. PB62089P); and U.S. Provisional Application No. 60/823,134 entitled ACTUATOR FOR AN INHALER (Attorney Docket No. PB61515P).

FIELD AND BACKGROUND OF THE INVENTION

The present invention generally relates to metered dose inhalers for dispensing pharmaceutical aerosol formulations therefrom.

Metered dose inhalers (MDIs) deliver inhaled medicine in the form of aerosol plumes. MDI aerosol plumes are typically generated under high pressure through a small orifice in a short time with high velocity. The aerosol plume interacts with airflow of patient inhalation in the oral cavity that is believed to influence significantly the drug deposition in the oral cavity and throat, often resulting in variable drug delivery efficiency. The airflow pattern through the MDI device generated through patient inhalation is capable of altering the interaction with the aerosol plumes and thus the aerosol plume behaviour inside patient oral cavity. (In particular, deposition along the inner surfaces of an MDI can be detrimental to consistent drug dosing to the patient. The airflow control general has no advantage to reduce device deposition, but to reduce the throat deposition)

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a metered dose inhaler (MDI). The metered dose inhaler comprises a canister configured to contain a pharmaceutical aerosol formulation therein; an actuator comprising: (1 ) a housing portion, wherein the housing portion is configured to slidably engage the canister upon actuation of the canister, (2) an orifice block to atomize the liquid formulation under pressure into fine aerosol plume, and (3) a mouthpiece for engagement by an end user, wherein the mouthpiece includes structures to define an airflow passage (includes an inner surface defining an airflow passage and an external surface); a valve stem in communication with said canister and orifice block, (wherein the valve stem comprises a dispensing passage) producing an aerosol plume in communication with the airflow passage through the mouthpiece and throat, the plume comprising the pharmaceutical aerosol formulation.

Advantageously, the inhaler is configured to allow sufficient airflow through/around the mouthpiece such that an air layer forms surrounding the aerosol plume such that medicament from the pharmaceutical aerosol formulation does not substantially accumulate on the inner surface of the mouthpiece or induction port (ie, "throat") of a Cascade lmpactor per USP.

These and other aspects of the invention are described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional side view of a metered dose inhaler configured in accordance with the present invention. FIG. 2 is a cross-sectional side view of a metered dose inhaler configured in accordance with the present invention.

FIG. 3 is a cross-section front view of a tubular member for use with a metered dose inhaler in accordance with the present invention. FIG. 4 is a cross-sectional view of an end user employing a metered dose inhaler according to the present invention.

FIG. 5 is a cross-sectional side view of a metered dose inhaler configured in accordance with the present invention. FIG. 6 is a cross-sectional view of an end user employing a metered dose inhaler according to the present invention.

FIG. 7 is a graph illustrating the mean plume intensity profile as a function of time inside a throat of a Cascade lmpactor for various inhaler structures. FIG. 8 is a graph illustrating particles detected by an Aerosizer subsequent to a Cascade Impaction throat at 28 Liters per Minute.

DETAILED DESCRIPTION OF THE INVENTION

Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified systems or process parameters as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to limit the scope of the invention in any manner.

All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an", "the" and "one" include plural referents unless the content clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although a number of methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein. In one aspect, the present invention provides a metered dose inhaler (MDI). The metered dose inhaler comprises a canister configured to contain a pharmaceutical aerosol formulation therein; an actuator comprising: (1 ) a housing portion, wherein the housing portion is configured to slidably engage the canister upon actuation of the canister, (2) an orifice block to atomize the liquid formulation under pressure into fine aerosol plume, and (3) a mouthpiece for engagement by an end user, wherein the mouthpiece includes structures to define an airflow passage (includes an inner surface defining an airflow passage and an external surface); a valve stem in communication with said canister and orifice block, (wherein the valve stem comprises a dispensing passage) producing an aerosol plume in communication with the airflow passage through the mouthpiece and throat, the plume comprising the pharmaceutical aerosol formulation. The inhaler is configured to allow sufficient airflow through/along the mouthpiece such that an air layer forms around the outside of the aerosol plume (at the inner surface of the mouthpiece) such that pharmaceutically active agent from the pharmaceutical aerosol formulation does not substantially accumulate on the inner surface of the mouthpiece or the throat of a Cascade Impactor.

For the purposes of the invention, a number of metered dose inhalers can be employed. The pharmaceutical aerosol formulations delivered from such inhalers also are numerous. In various embodiments, the formulations may be employed in or as suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, a chlorofluorohydrocarbon (e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, 1 ,1 ,1 ,2-tetrafluoroethane), as carbon dioxide or other suitable gases. Such formulations may be delivered via a pressurized inhaler, e.g., a Metered Dose Inhaler (MDI).

Exemplary MDIs typically include canisters suitable for delivering the pharmaceutical aerosol formulations. Canisters generally comprise a container capable of withstanding the vapor pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example, an aluminum can which may optionally be anodised, lacquer-coated and/or plastic- coated, which container is closed with a metering valve. Aluminium cans which have their inner surfaces coated with a fluorocarbon polymer are particularly preferred. Such polymers can be made of multiples of the following monomehc units: tetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluoroalkoxyalkane (PFA), ethylene tetrafluoroethylene (EFTE), vinyldienefluoride (PVDF), and chlorinated ethylene tetrafluoroethylene. Additionally, in other embodiments, cans having inner surfaces coated with blends of fluorocarbon polymers and non-fluorocarbon polymers may also be employed. Embodiments of coatings used on all or part of the internal surfaces of an MDI are set forth in U.S. Patent Nos. 6,131 ,566; 6,143,277; 6,149,892; 6,253,762; 6,511 ,652; 6,511 ,653; 6,524,555; 6,532,955; and 6,546,928.

MDIs may also include metering valves designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve. The gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, black and white butadiene-acrylonithle rubbers, butyl rubber and neoprene.

Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK356) and 3M-Neotechnic Ltd, UK (e.g. SpraymiserTM) Embodiments of metering valves are set forth in U.S. Patent Nos. 6,170,717; 6,315,173; and 6,318,603.

In various embodiments, the MDIs may also be used in conjunction with other structures such as, without limitation, overwrap packages for storing and containing the MDIs, including those described in U.S. Patent No. 6,119,853; 6,179,118; 6,315,112; 6,352,152; 6,390,291 ; 6,679,374, as well as dose counter units such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431 ,168.

Medicaments, for the purposes of the invention, include a variety of pharmaceutically active ingredients, such as, for example, those which are useful in inhalation therapy. In general, the term "medicament" is to be broadly construed and include, without limitation, actives, drugs and bioactive agents, as well as biopharmaceuticals. Various embodiments may include medicament present in micronized form or soluble form. Appropriate medicaments may thus be selected from, for example, analgesics, (e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine); anginal preparations, (e.g., diltiazem); anti- allergies, (e.g., cromoglicate, ketotifen or nedocromil); antiinfectives (e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine); antihistamines, (e.g., methapyrilene); antiinflammatories , (e.g., anti-inflammatory steroids, beclomethasone (e.g. beclomethasone dipropionate), fluticasone (e.g. fluticasone propionate), flunisolide, budesonide, rofleponide, mometasone (e.g. mometasone furoate), ciclesonide, triamcinolone (e.g. triamcinolon acetonide), 6α, 9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α- propionyloxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3- yl) ester), (6a, 11 b,16a, 17a)-6,9-difluoro-17-{[(fluoromethyl)thio]carbonyl}-11 - hydroxy-16-methyl-3-oxoandrosta-1 ,4-dien-17-yl 2-furoate, and (6a,11 b,16a,17a)- 6,9-difluoro-17-{[(fluoromethyl)thio]carbonyl}-11 -hydroxy-16-methyl-3- oxoandrosta-1 ,4-dien-17-yl 4-methyl-1 ,3-thiazole-5-carboxylate); antitussives, (e.g., noscapine); bronchodilators, (e.g., albuterol (e.g. as sulphate), salbutamol (e.g. as the free base or the sulphate salt), salmeterol (e.g. as xinafoate), ephedrine, adrenaline, fenoterol (e.g as hydrobromide), bitolterol, formoterol (e.g., as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g., as acetate), reproterol (e.g., as hydrochloride), rimiterol, terbutaline (e.g., as sulphate), isoetharine, tulobuterol, 4-hydroxy-7-[2-[[2-[[3-(2- (henylethoxy)propyl]sulfonylurea]ethyl]-amino]ethyl-2(3H)-benzothiazolone), 3-(4- {[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl}amino)hexyl]oxy}butyl) benzenesulfonamide, 3-(3-{[7-({(2R)-2- hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl] oxyjpropyl) benzenesulfonamide, 4-{(1 R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy] ethoxy}hexyl)amino]-1 -hydroxyethyl}-2-(hydroxymethyl)phenol, 2-hydroxy-5-((1 R)- 1-hydroxy-2-{[2-(4-{[(2R)-2-hydroxy-2-phenylethyl]amino} phenyl)ethyl]amino}ethyl)phenylformamide, and 8-hydroxy-5-{(1 R)-1 -hydroxy-2- [(2-{4-[(6-methoxy-1 ,1'-biphenyl-3-yl)amino]phenyl}ethyl)amino]ethyl}quinolin-

2(1 H)-one); diuretics, (e.g., amiloride) ; anticholinergics, (e.g., ipatropium (e.g., as bromide), 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). In addition to those stated above, it will be clear to a person skilled 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. It will be further clear to a person skilled in the art that where appropriate, the medicaments may be used in the form of a pure isomer, for example, R-salbutamol or R-formoterol. Particular medicaments for administration using pharmaceutical formulations in accordance with the invention include anti-allergies, bronchodilators, beta agonists (e.g., long-acting beta agonists), and antiinflammatory steroids of use in the treatment of respiratory conditions, as defined herein, by inhalation therapy, for example, cromoglicate (e.g. as the sodium salt), salbutamol (e.g. as the free base or the sulphate salt), salmeterol (e.g. as the xinafoate salt), bitolterol, formoterol (e.g. as the fumarate salt), terbutaline (e.g. as the sulphate salt), 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide, 3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) heptyl]oxy}propyl)benzenesulfonamide, 4-{(1 f?)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy] ethoxy}hexyl)amino]-1 -hydroxyethyl}-2-(hydroxymethyl)phenol, 2-hydroxy-5-((1 R)- 1-hydroxy-2-{[2-(4-{[(2R)-2-hydroxy-2-phenylethyl]amino}phenyl)ethyl]amino} ethyl)phenylformamide, 8-hydroxy-5-{(1 R)-1 -hydroxy-2-[(2-{4-[(6-methoxy-1 ,V- biphenyl-3-yl)amino]phenyl}ethyl)amino]ethyl}quinolin-2(1 H)-one, reproterol (e.g. as the hydrochloride salt), a beclomethasone ester (e.g. the dipropionate), a fluticasone ester (e.g. the propionate), a mometasone ester (e.g., the furoate), budesonide, dexamethasone, flunisolide, triamcinolone, tripredane, (22R)-6α,9α- difluoro-11 β, 21 -dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione. Medicaments useful in erectile dysfunction treatment (e.g., PDE-V inhibitors such as vardenafil hydrochloride, along with alprostadil and sildenafil citrate) may also be employed. It should be understood that the medicaments that may be used in conjunction with the inhaler are not limited to those described herein. Salmeterol, especially salmeterol xinafoate, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof are especially preferred.

It will be appreciated by those skilled in the art that the formulations according to the invention may, if desired, contain a combination of two or more of any of the above medicaments. As an example, formulations containing two active ingredients are known for the treatment and/or prophylaxis of respiratory disorders such as those described herein, for example, formoterol (e.g. as the fumarate) and budesonide, salmeterol (e.g. as the xinafoate salt) and fluticasone (e.g. as the propionate ester), salbutamol (e.g. as free base or sulphate salt) and beclomethasone (as the dipropionate ester) are preferred.

In one embodiment, a particular combination that may be employed is a combination of a beta agonist (e.g., a long-acting beta agonist) and an antiinflammatory steroid. One embodiment encompasses a combination of salmeterol, or a salt thereof (particularly the xinafoate salt) and fluticasone propionate. The ratio of salmeterol to fluticasone propionate in the formulations according to the present invention is preferably within the range 4:1 to 1 :20. The two drugs may be administered in various manners, simultaneously, sequentially, or separately, in the same or different ratios. In various embodiments, each metered dose or actuation of the inhaler will typically contain from 25 μg to 100 μg of salmeterol and from 25 μg to 500 μg of fluticasone propionate. The pharmaceutical formulation may be administered as a formulation according to various occurrences per day. In one embodiment, the pharmaceutical formulation is administered twice daily.

Embodiments of specific medicament combinations that may be used in various pharmaceutical formulations are as follows:

1 ) fluticasone propionate 100 μg/ salmeterol 50 μg

2) fluticasone propionate 250 μg/ salmeterol 50 μg

3) fluticasone propionate 500 μg/ salmeterol 50 μg

Optionally, the aerosol formulations may include surfactant (e.g., oleic acid), as well as other excipients (e.g., ethanol). In various embodiments, however, the aerosol formulations are free or substantially free of surfactant and/or excipient.

The invention is highly advantageous. By virtue of a layer of air forming along the inner surface of inhaler mouthpiece, deposition of medicament along the inner surface of the mouthpiece as well as the throat (oral cavity) is believed to be capable of being substantially reduced in comparison to conventional inhalers. As a result, an increased amount of medicament may be available to the end user, and the inhalation drug delivery will be less sensitive to the aerosol plume release orientation. A typical MDI aerosol plume leaving the mouthpiece has a forward central velocity up to 40-50 m/s with peak radial velocity around 2-5 m/s. To provide adequate buffer between the aerosol plume and the throat surface, the annular airflow should be as thick as possible with a linear velocity around 2-5 m/s surrounding the aerosol plume entering the throat. The design of the device is to provide such an annular airflow for maximum buffering capacity between the aerosol plume and the surfaces of the device as well as the throat. Meanwhile, a fraction of the airflow is distributed from the atomization orifice through to the edge of the mouthpiece to minimize the device deposition.

The invention will now be described in reference to the embodiments set forth in the drawings. It should be understood that these embodiments serve to illustrate the invention, and do not limit the scope of the invention as described by the claims. In the drawings, like numbers refer to like elements throughout.

Various embodiments of the inhaler of the invention are set forth in FIGS. 1 and 2. Metered dose inhaler 10 includes a canister 20 configured to contain a pharmaceutical aerosol formulation therein (not shown) and an actuator 30. The actuator 30 includes a housing portion 40 which is configured to slidably engage canister 20 upon actuation of the canister. The actuator 30 also includes mouthpiece 50 for engagement by an end user. The mouthpiece 50 includes an inner surface 60 defining an airflow passage 65 in the mouthpiece 50 and an external surface 70. Valve stem 80 is also present and is in communication with canister 20, wherein the valve stem 80 includes a dispensing passage 90 in communication with airflow passage 65 for delivering a plume 100 therethrough. The plume 100 includes the pharmaceutical aerosol formulation.

As shown in FIG. 1 , a tubular member 110 is present which extends along the length I of the mouthpiece 50. Tubular member 110 extends around the external surface 70 of mouthpiece 50 such that a gap g1 is present between tubular member 110 and external surface 70. In this embodiment, the size of gap g1 is substantially uniform throughout the circumference of the mouthpiece external surface; however it should be appreciated that the size of gap g1 may vary in accordance with the circumference. As an example, gap g1 may be larger at the portion of mouthpiece 50 proximal to dispensing passage 90 versus the portion of mouthpiece 50 distal to dispensing passage 90 or vise versa. In addition, to facilitate the intake of air exclusively through gap g1, the space between the housing and canister (indicated by s) is closed off by employing member 115. Although shown in a predetermined position in FIG. 2 , it should be appreciated that member 115 may be located at other positions along the vertically-extending length of canister 20, including the surface interfacing with the valve stem 80.

Tubular member 110 may be formed from a number of materials and fabricated according to known techniques. Exemplary materials include, without limitation, metals such as aluminium and stainless steel, as well as thermoplastics including, without limitation, polypropylene, polyethylene, nylon, polycarbonate, and the like, along with combinations thereof. The materials for member 110 can be the same as or different from the actuator body material.

The tubular member 110 may have various dimensions, the selection of which is made to facilitate formation of the air layer on the inner surface of the mouthpiece to eliminate or substantially reduce accumulation of pharmaceutically active agent on the inner surfaces of the mouthpiece as well as the throat. As an example, the tubular member 110 may have an annular thickness t of no greater than about 1 mm. Moreover, the tubular member may be present such that gap g1 ranges from about 0.5 mm to about 3 mm in one embodiment. Further, in an embodiment, gap g1 may range from about 1 mm to about 2.5 mm, in another embodiment, from about 2 mm to about 2.5 mm. Also, in an embodiment, gap g1 may be about 1.5 mm.

The tubular member 110 may be attached to mouthpiece 50 according to various techniques known to one skilled in the art. As illustrated in FIG. 3, a plurality of members 120a, 120b, 120c and 12Od serve to connect tubular member 110 to mouthpiece 50. In this embodiment, the members 120a, 120b, 120c and 12Od are equally spaced; however, it should be appreciated that such members may be spaced at different intervals than those illustrated. Moreover, a greater or lesser number of connecting members may be employed while remaining within the scope of the invention.

FIG. 4 illustrates an inhaler 10 with tubular member 110 employed by an end user 130. As shown, a plume 100 containing a pharmaceutical aerosol formulation is emitted from dispensing passage 90. During utilization of the inhaler 10, air is inhaled by end user 130 resulting in the air entering the inhaler 10 via gap g1, depicted by arrows Ai and A₂. As a result, and in accordance with the invention, a layer of air I₃ forms surrounding the aerosol plume 100 such that pharmaceutically active agent from the pharmaceutical aerosol formulation does not substantially accumulate on the inner surface of the mouthpiece 110 and/or the throat of a Cascade Impactor. It should be noted that the aerosol plume 100 travels continuously and uninterrupted through the length of the mouthpiece 50, i.e., there are no structural impediments in passage 65 which might cause excessive turbulence of the plume. Thus, the invention is believed to be highly advantageous.

Other embodiments of the present invention are shown in FIGS. 5-6. As shown in FIG. 5, longitudinal member 160' extends from the valve stem 80 in a parabolic fashion. The member 160' terminates in a front portion 160". As seen in FIG. 5, front portion 160" is positioned with the dispensing passage 90 and in particular the exit portion 90' of the dispensing passage 90. Moreover, member 160 forms a gap g2 against the inner surface 60 of mouthpiece ranging from about 0.5 mm. to about 3 mm in one embodiment. Further, in an embodiment, gap g2 may range from about 1 mm to about 2.5 mm. Also, in an embodiment, gap g2 may be about 1.5 mm. Member 160' may have a thickness t ranging from about 0.5 mm to about 1.5 mm. Dimensions other than these are within the scope of the invention. Advantageously, the distance that member 160' extends beyond the exit portion 90' of dispensing passage 90 (g_x) is at least 3 times the distance of gap g2. In one embodiment, longitudinal member 160' may be fabricated from a number of materials, the selection known to one skilled in the art. As an example, longitudinal member 160' can be formed from metals such as aluminium and stainless steel, as well as various thermoplastics including, without limitation, polypropylene, polyethylene, nylon, polycarbonate, and the like, along with combinations thereof. The materials for member 160' can be the same as or different from the actuator body material.

FIG. 6 illustrates an inhaler 10 with member 160' employed by an end user 130. As shown, a plume 100 containing a pharmaceutical aerosol formulation is emitted from dispensing passage 90. During utilization of the inhaler 10, air is inhaled by end user 130 resulting in the air entering the inhaler 10 via gap g1 , depicted by arrows A₁ and A₂. As a result, and in accordance with the invention, a layer of air I₃ forms surrounding the aerosol plume 100 such that pharmaceutically active agent from the pharmaceutical aerosol formulation does not substantially accumulate on the inner surface of the mouthpiece 110 and/or the throat of a Cascade Impactor. Thus, the invention is believed to be highly advantageous.

The invention will now be described with respect to the following examples. It should be understood that these examples are set forth for the purpose of illustrating the invention and do not limit the invention as defined by the claims. In the examples: "Cl" is defined as Cascade Impactor

"LPM" is defined as liters per minute "FPS" is defined as feet per second

Example 1 Mean Plume Intensity Inside Cl Throat

The intensity of an aerosol plume was evaluated in the transparent throat of a Cl at 28 LPM total airflow. The images were collected at 923 FPS at a 35° forward angle using the OxforLasers High Speed Image System. A single Ventolin actuator (Bespak of United Kingdom) is used. FIG. 7 is a graph measuring mean plume intensity as a function of time. In this figure, the following definitions apply: Inserted open = normal control, actuator mouthpiece inserted into rubber adapter of Cl throat such that air flows through the actuator body into the throat. Designated as the regular position of the Aerosizer test.

Position 0-open = actuator withdrawn from the rubber adapter such that a portion of airflow was leaked around the outside of the mouthpiece

Position 0-seal = airflow through actuator body was blocked using parafilm, all airflow into the throat was along the outside of the mouthpiece. Air whistle noticed

Position 1 -seal = actuator withdrawn from the rubber adapter to address air whistle (see above)

Position 2-seal = actuator withdrawn to a greater extent relative to the scenario described in "position 1 -seal" to increase the gap between the mouthpiece and the rubber adapter sealer to facilitate easier airflow into the throat. This is the position used in the Aerosizer test.

The mean intensity of the shaded area (with less device reflection) after background subtraction is set forth in FIG. 7. Example 2 Aerosizer Particle Detection

Particles emitted from an MDI were detected via an Aerosizer with throat and e-cylinder at 0 V. The total airflow was 28 LPM.

As shown from the results set forth in FIG. 8, positions in accordance with the invention, namely SeaM and Seal2 (actuator sealed with airflow along the outside mouthpiece into the throat, ie repetitions of Position 2-seal) suggest that throat deposition is reduced relative to scenarios analogous to conventional inhalers, namely Regular! and Regular2.

The invention has been described with respect to the embodiments above, including, without limitation, those set forth in the drawings and examples. It should be noted that such embodiments are meant to illustrate the invention, and do not serve to limit the scope of the invention as set forth in the following claims.

Claims

THAT WHICH IS CLAIMED:

1. A metered dose inhaler comprising: a canister configured to contain a pharmaceutical aerosol formulation therein; an actuator comprising: (1 ) a housing portion, wherein the housing portion is configured to slidably engage the canister upon actuation of the canister and (2) a mouthpiece for engagement by an end user, wherein the mouthpiece includes an inner surface defining an airflow passage and an external surface; a valve stem in communication with said canister, wherein the valve stem comprises a dispensing passage in communication with the airflow passage for delivering a plume therethrough, the plume comprising the pharmaceutical aerosol formulation; wherein the inhaler is configured to allow sufficient airflow through the mouthpiece such that an air layer forms at the inner surface of the mouthpiece such that pharmaceutically active agent from the pharmaceutical aerosol formulation does not substantially accumulate on the mouthpiece inner surface.

2. The inhaler according to Claim 1 , further comprising a tubular member extending along the length of the mouthpiece such that a gap is present between the tubular member and the outer surface of the mouthpiece, and wherein the gap allows sufficient airflow into the mouthpiece to facilitate formation of the air layer on the inner surface of the mouthpiece, and wherein the gap between the tubular member and the mouthpiece provides the sole access of air into the inhaler.

3. The inhaler according to Claim 2, wherein the gap between the tubular member and the outer surface of the mouthpiece has a thickness ranging from about 1 mm to about 3 mm.

4. The inhaler according to Claim 2, wherein the tubular member has an annular thickness no greater than about 1 mm.

5. The inhaler according to Claim 4, wherein the annular thickness of the tubular member is substantially uniform.

6. The inhaler according to Claim 2, wherein the tubular member has a length ranging from about 1cm to about 4 cm.

7. The inhaler according to Claim 2, wherein the pharmaceutical aerosol formulation is present in said canister.

8. The inhaler according to Claim 7, wherein the pharmaceutical aerosol formulation comprises a hydrofluoroalkane (HFA) propellant and at least one pharmaceutically active agent.

9. The inhaler according to Claim 8, wherein the propellant is selected from the group consisting of 1 ,1 ,1 ,2-tetrafluoroethane and 1 , 1 ,1 , 2,3,3, 3-n- heptafluoropropane, or a mixture thereof.

10. The inhaler according to Claim 9, wherein the propellant is 1 ,1 ,1 ,2- tetrafluoroethane.

11. The inhaler according to Claim 1 , wherein the housing has a lower end, and wherein the inhaler further comprises a member attached to the lower end located proximal to the dispensing passage and extending longitudinally outward from the lower end to form a gap between the inner surface of the mouthpiece and the member, and wherein the gap is sized to allow for formation of the air layer, the longitudinal member extending a distance beyond the end of the dispensing passage at least three times the distance of the gap between the inner surface of the mouthpiece and the longitudinal member.

12. The inhaler according to Claim 11 , wherein the longitudinal member extends parabolically from the lower end located proximal to the dispensing passage.

13. The inhaler according to Claim 11 , wherein the pharmaceutical aerosol formulation is present in said canister.

14. The inhaler according to Claim 13, wherein the pharmaceutical aerosol formulation comprises a hydrofluoroalkane (HFA) propellant and at least one pharmaceutically active agent.

15. The inhaler according to Claim 14, wherein the propellant is selected from the group consisting of 1 ,1 ,1 ,2-tetrafluoroethane and 1 , 1 ,1 , 2,3,3, 3-n- heptafluoropropane, or a mixture thereof.

16. The inhaler according to Claim 15, wherein the propellant is 1 ,1 ,1 ,2-tetrafluoroethane.