WO2009091780A2

WO2009091780A2 - Device for inhaling powdered medicaments

Info

Publication number: WO2009091780A2
Application number: PCT/US2009/030929
Authority: WO
Inventors: Pothula Srinivas Naidu; Janardhanan Anand Subramony; Tallapragada Sree Ramachandra Gautam Buddha
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2008-01-14
Filing date: 2009-01-14
Publication date: 2009-07-23
Also published as: WO2009091780A3

Abstract

An inhalation device for inhalation of a medicament from an openable capsule, the device comprising: a housing unit including a dispersing chamber therein; at least one air inlet in the housing unit through which air may be admitted into the dispersing chamber during inhalation by a person; a mouthpiece removably attached to the housing unit and in communication with the dispersing chamber; a mesh provided between the dispersing chamber and the mouthpiece to prevent entry of the capsule into the mouthpiece while permitting medicament from the capsule to travel to the mouthpiece; characterized by: a port in the housing unit for inserting a medicament capsule there through such that a first portion of the capsule is captured in the port and a second portion of the capsule extends into the dispersing chamber; and an impinger located in the housing unit and adapted to engage the second portion of the capsule to open the capsule and thereby permit escape of the medicament from the capsule into the dispersing chamber.

Description

DEVICE FOR INHALING POWDERED MEDICAMENTS

INTRODUCTION

The present invention relates to devices for inhaling powdered medicaments and methods of using such devices for pulmonary administration of drugs. More particularly, the present invention relates to devices for dispersing dry powder medicaments and administering them by inhalation to a person in need of pulmonary drug delivery.

In recent times pulmonary drug delivery is attracting increasing attention of the formulation scientists. Pulmonary drug delivery relies on inhalation of a drug dispersion or aerosol by the patient so that an active drug within the dispersion can reach the distal (alveolar) regions of the lungs. It has been found that certain drugs are readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery is particularly promising for the delivery of proteins and polypeptides, which are difficult to deliver by other routes of administration. Drug delivery by the pulmonary route is effective both for systemic delivery and for localized delivery to treat diseases of the lungs.

Inhaled drug delivery systems can be divided into three categories, namely, nebulizers, metered dose inhalers ("MDIs") and dry powder inhalation devices ("DPIs"), each class having its own advantages and disadvantages. Whereas MDIs use propellants as pressurized delivery aids (and hence are less eco- friendly), DPIs are propellant-free and rely on the ability of the patient to inhale the dispersed dry powder. To deliver pharmaceuticals locally to the lungs, or systemically through the lungs, drugs must be transformed into an aerosol that can be inhaled by the patient. If an aerosol is to be delivered to the deep lung, the individual particles must be small and their velocity must be low as they pass through the upper airways and into the deep lung. With a DPI, the particle velocity is controlled by the patient's breathing, unlike the situation for metered dose inhalers that emit medication under pressure and at high speed. It is desirable to efficiently deliver the dry powders to the target region of the lungs with a minimal loss of drug. It is further desirable that any powder agglomerates present in the dry powder be sufficiently broken up prior to inhalation by the patient to assure effective systemic absorption or other pulmonary delivery. DPIs are capable of delivering formulations of both large and small molecules, either in the form of a pure drug particle or in combination with an excipient. DPIs are particularly promising for delivering protein and polypeptide drugs, which may be readily formulated as dry powders.

DPIs can be classified into two types based on their delivery mechanism, namely, passive DPIs and active DPIs. Passive DPIs have been known in the art for a few decades, and have successfully reached the marketplace as well. They are available under different brand names such as ROTAHALER® (GlaxoSmithKline), AEROLIZER® (Novartis), SPINHALER® (Aventis), DISKHALER® (GlaxoSmithKline), TURBUHALER® (AstraZeneca), TWISTHALER® (Schering-Plough Corp.), EASYHALER® (Orien), and the like. Passive DPIs do not employ any external energy to disperse the powdered medicament. Instead their functioning solely relies on the ability of the patient to fluidize or disperse the powdered medicament and inhale this dispersion by the oral or nasal route. Since the patient's aspiratory efforts to aerosolize the powdered medicament varies greatly between various patients and age groups as well as their diseased conditions, dose variability problem is frequently encountered in using passive DPIs. Some researchers have proposed modifications for these devices to minimize the dose variability, but the success is so far limited. In an attempt to overcome dose variability limitation of passive DPIs, active

DPIs (also called "energy enhanced DPIs") were proposed. They have an external energy source to aerosolize the powdered medicament, thereby forming a cloud comprising fine particles (generally less than about 5 μm in size, and sometimes described as "respirable particles") in a closed chamber, which the patient inhales in single or multiple breaths. So far, only one active DPI (EXUBERA® marketed by Pfizer for pulmonary delivery of insulin) based on the use of pressurized gas to form a cloud of dispersed powdered medicament in a chamber has been approved for commercial use in the United States.

U.S. Patent Nos. 3,991 ,761 , 4,889,1 14, 5,070,870, 5,787,881 , 6,240,918, 6,606,992, 7,143,764, 7,151 ,456, 7,219,665, 7,228,860, 7,234,464, 7,252,087 and 7,284,553 describe various drug inhalation devices.

U.S. Patent Application Publication Nos. 2005/0150492, 2005/0022812, 2007/0209661 , 2007/0295332, 2008/0251072, 2008/0105256, and 2008/0196717, and International Application Publication Nos. WO 94/006498, WO 98/58695, WO 2005/113043, WO 2006/051300, WO 2007/007110, and WO 2007/132217 disclose inhalation devices with different designs.

U.S. Patent Nos. 6,543,448 and 6,546,929 describe dry powder dispensing apparatus wherein pressurized gas is used to aerosolize the powdered medicament.

The present invention provides an alternative device for inhaling powdered medicaments. The device will provide higher delivery efficiency through a unique flow pattern with enhanced turbulence. The invention also provides methods of using such device for pulmonary administration of drugs.

SUMMARY

According to the present invention there is provided a dry powder inhalation device comprising a body defining a chamber for receiving a dose of powdered medicament, in communication with a mouthpiece through which the powdered medicament can be inhaled.

In one embodiment, the invention includes a dry powder inhalation device for inhalation of a medicament from a rupturable capsule, the device comprising: (a) a body comprising a top housing unit and a bottom housing unit and having a dispersing chamber for receiving a dose of powdered medicament; (b) a port in the top housing unit for inserting a medicament capsule; (c) an air inlet in the top housing unit through which air may be admitted into the chamber during inhalation; (d) a mouthpiece which is removably attached to the top housing unit; (e) a mesh that is present in between top housing unit and mouthpiece; and (f) an impinger, which can be moved to open the capsule, located at the end opposite the mouthpiece.

In an embodiment, the dispersing chamber has a parabolic shape, and the entire area of the dispersing chamber is linearly exposed to the mouthpiece. Further, an inlet port for air is not along the same axis as that of the powder flow during inhalation. In a particular embodiment, the angle between the air inlet and the longitudinal axis of the dispersing chamber is about 90°.

A mesh substantially covers the total top housing unit at a circumferential shoulder and functions as a filter between the mouthpiece and the dispersing chamber. However, there is no obstruction between the dispersing chamber and mouthpiece other than a mesh. In one embodiment, an air inlet is not in the same axis as that of powder flow, and there is no obstruction between the top housing unit and mouthpiece other than a mesh.

In another embodiment, the port in the top housing unit has a square- shaped hole to insert the capsule during administration.

In an embodiment, the impinger has a stem with a "C" shaped groove to open an inserted capsule.

In addition, the device optionally has inlets for retrofitting an attachment for converting into an active inhaler. In one embodiment, the dry powder inhalation device delivers a single dose, and in another embodiment, the dry powder inhalation device can deliver multiple doses. The invention includes a method of using the device of the present invention for pulmonary administration of drugs.

An embodiment of the invention includes an inhalation device for inhalation of a medicament from an openable capsule, the device comprising: a housing unit including a dispersing chamber therein; at least one air inlet in the housing unit through which air may be admitted into the dispersing chamber during inhalation by a person; a mouthpiece removably attached to the housing unit and in communication with the dispersing chamber; a mesh provided between the dispersing chamber and the mouthpiece to prevent entry of the capsule into the mouthpiece while permitting medicament from the capsule to travel to the mouthpiece; characterized by: a port in the housing unit for inserting a medicament capsule there through such that a first portion of the capsule is captured in the port and a second portion of the capsule extends into the dispersing chamber; and an impinger located in the housing unit and adapted to engage the second portion of the capsule to open the capsule and thereby permit escape of the medicament from the capsule into the dispersing chamber.

An embodiment of the invention includes a method for administering a powdered inhalation medicament, comprising: providing a medicament capsule in a dispensing chamber in a housing having air inlets positioned transversely to a first direction; opening the medicament capsule in the dispensing chamber; and inhaling through a mouthpiece connected with the dispersing chamber such that air drawn into the dispersing chamber along with medicament is inhaled through the mouthpiece in the first direction; characterized by the steps of: inserting the medicament capsule through a port in the housing unit such that a first portion of the capsule is captured in the port and a second portion of the capsule extends into the dispersing chamber; and pressing a breaking stem of an impinger located in the housing unit against the second portion of the capsule extending into the dispersing chamber to separate the second portion of the capsule from the first portion of the capsule so as to open the capsule and thereby permit escape of the medicament from the capsule into the dispersing chamber.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 (A) is a schematic top plan view of a dry powder inhalation device of the present invention.

FIG. 1 (B) is a side elevational view of the device of FIG 1 (A). FIG. 1 (C) is a bottom plan view of the device of FIG .1 (A). FIG. 1 (D) is a front elevational view of the device of FIG 1 (A).

FIG. 1 (E) is a rear elevational view of the device of FIG. 1 (A). FIG. 2(A) is a perspective view of the top housing unit with a capsule. FIG. 2(B) is an exploded perspective view of the bottom housing unit, impinger and mesh. FIG. 2(C) is a perspective view of the mouthpiece.

FIG. 3(A) is a front elevational view of the mouthpiece. FIG. 3(B) is a cross-sectional view of the mouthpiece of Fig. 3(C), taken along line 3(B)-3(B) thereof.

FIG. 3(C) is a cross-sectional view of the mouthpiece of Fig. 3(B), taken along line 3(C)-3(C) thereof.

FIG. 3(D) is a cross-sectional view of the mouthpiece of Fig. 3(B), taken along line 3(D)-3(D) thereof.

FIG. 4(A) is a front plan view of the mesh. FIG. 4(B) is a cross-sectional view of the mesh of Fig. 4(A), taken along line 4(B)-4(B) thereof.

FIG. 4(C) is a cross-sectional view of the mesh of Fig. 4(A), taken along line 4(C)-4(C) thereof. FIG. 5(A) is a top plan view of the bottom housing unit.

FIG. 5(B) is a cross-sectional view of the bottom housing unit of Fig. 5(A), taken along line 5(B)-5(B) thereof.

FIG. 5(C) is a cross-sectional view of the bottom housing unit of Fig. 5(A), taken along line 5(C)-5(C) thereof. FIG. 6(A) is a top plan view of the top housing unit.

FIG. 6(B) is a cross-sectional view of the top housing unit of Fig. 6(A), taken along line 6(B)-6(B) thereof.

FIG. 6(C) is a cross-sectional view of the bottom housing unit of Fig. 6(A), taken along line 6(C)-6(C) thereof. FIG. 7(A) is a rear elevational view of the impinger.

FIG. 7(B) is a cross-sectional view of the impinger of Fig. 7(A), taken along line 7(B)-7(B) thereof.

FIG. 7(C) is a cross-sectional view of the impinger of Fig. 7(A), taken along line 7(C)-7(C) thereof.

DETAILED DESCRIPTION

The present invention relates to devices for inhaling powdered medicaments and methods of using such devices for pulmonary administration of drugs. More particularly, the present invention relates to devices for dispersing dry powder medicaments and administering them by inhalation to a person in need of pulmonary delivery.

In accordance with one aspect, the present invention is an efficient device for administering orally a powdered composition by inhalation comprising a body defining a dispersing chamber for receiving a dose of powdered medicament and having a port for inserting a medicament capsule. During administration, the patient inserts a capsule containing medicament into a port on the top housing unit and gently presses on the impinger which is located at the rear end opposite to the mouthpiece, in order to open the capsule and empty the contents (i.e., powder comprising medicament) into a dispersing chamber, followed by inhalation of the powdered medicament through a mouthpiece. Capsule fragments will be retained by a mesh that is present between the chamber and mouthpiece and the patient will receive only the powdered medicament in a single inhalation.

An embodiment of the present invention includes a dry powder inhalation device for inhalation of a medicament from a rupturable capsule, the device comprising: (a) a body having a top housing unit and a bottom housing unit enclosing a dispersing chamber for receiving a dose of powdered medicament; (b) a port in the top housing unit for inserting a medicament capsule; (c) an air inlet in the top housing unit through which air may be admitted into the dispersing chamber during inhalation; (d) a mouthpiece which is removably attached to the top housing unit; (e) a mesh that is present between the top housing unit and the mouthpiece; and (f) an impinger, which can be moved to open the capsule, located at the rear end opposite the mouthpiece.

FIGS. 1 (A)-I (E) are schematic illustrations of a dry powder inhalation device of the present invention. The device comprises a body (4) that is defined by bottom housing unit (6) and top housing unit (8) having a dispersing chamber (10) therein and adapted for removable attachment of a mouthpiece (2). The body (4) has reversible pushing means in the form of a plunger or an impinger (12) located at the rear end opposite to the mouthpiece (2). The top housing unit (8) has a port (14) for inserting an openable capsule (18) and air inlets (16) through which the air enters the dispersing chamber (10) of the body (4) when the patient inhales through mouthpiece (2). The openable capsule (18) can be inserted in the port (14) manually. When the impinger (12) is moved toward the mouthpiece (2), it results in opening (e.g., separation) of cap and body parts of the capsule (18), thus emptying the contents (i.e., powdered medicaments) of the capsule into the dispersing chamber (10). The powdered medicament can be inhaled by the patient through mouthpiece (2).

FIGS. 2(A)-2(C) show perspective views of various parts of the dry powder inhalation device. The mouthpiece (2) has a mesh or filter (20) fitted on it at the rear end thereof that detachably attaches to the top housing unit (8). The device is held horizontally and the capsule (18) can be inserted in an upright position in the port (14) at the top housing unit (8), with the capsule crown (22) of the capsule (18) being on top. The mesh (20) prevents capsule bottom (24) or its pieces from entering into the mouthpiece (2) upon its separation from capsule crown (22), when the patient gently pushes the impinger (12) and inhales the powdered medicaments dispersed inside the dispersing chamber (10).

The device of the present invention will provide a unique air flow pattern with high turbulence as the air inlet and the inhalation port are not along the same axis. The dispersing chamber (10) has a parabolic shape that provides air flow in a parabolic path which in turn provides enhanced internal reflections to maximize turbulence and has a small volume, which will enhance the air turbulence. The dispersing chamber (10) has a volume of such size that, in use, upon a single inhalation through the chamber by a patient, the medicament within the chamber is inhaled by the patient. The whole area of the dispersing chamber (10) is linearly exposed to the mouthpiece (2) without any obstruction. The use of a mesh assists with aerosolizing and dispersing the particles during inhalation, due to vibratory forces created by a capsule portion impacting the mesh and walls of dispersing chamber. This can be evidenced by a rattling sound during the inhalation process. These unique features of the device of the present invention will contribute to improve the performance of the device in terms of higher delivery efficiency.

An embodiment of the dispersing chamber (10) in the body (4) can have a generally parabolic shape. The volume can vary, but a general range of the volume is from about 3 to 25 cm³ or from about 5 to about 20 cm³ or from about 7 to about 15 cm³. In a specific embodiment of the present invention, the volume of the dispersing chamber is about 10 cm³.

In certain embodiments, the entire area of the dispersing chamber (10) is linearly exposed to the mouthpiece. However, the port (14) for inserting a medicament capsule (18) is not in the same axis as that of powder flow during inhalation.

If the air inlet is along the axis of dispersing chamber, then powder flow will be fast and promote direct impact to the throat of the user, and will adversely affect cloud formation. Any angle from 30 to 150° may be used. Greater turbulence is expected when the inlet is normal to the longitudinal axis of the dispersing chamber at 90°. The "air loss" or "dissipation factor" component would be large at other angles, and might reduce the overall dispersion of the powder.

FIGS. 3(A)-3(D) are schematic representations of the mouthpiece. The mouthpiece (2) has an outlet end (26) through which the subject inhales the powdered medicament, and an inlet end (28), which can be detachably attached to the top housing unit.

Specifically, mouthpiece (2) includes four walls (30), namely, a substantially planar bottom wall (30a), an inwardly curved top wall (30b), and two inwardly curved side walls (30c) and (3Od) which connect together side edges of bottom wall (30a) and top wall (30b). FIG. 3(B) depicts a side cross-sectional view of the mouthpiece, wherein the mouthpiece walls (30) form a suction chamber (32) therein.

Mouthpiece (2) also includes a lower circumferential flange wall (31) which extends rearward from the rear edges of walls (30a) - (3Od). The outer surface of flange wall (31) forms a smooth continuation with the outer surfaces of walls (30). However, the thickness of flange wall (31) is less than the thickness of walls (30), whereby an inner circumferential shoulder (33) is formed between the inner surface of flange wall (31) at the forward end thereof, and the rear edges of walls (30), the purpose for which will become apparent from the discussion hereafter. Two opposing lips (31a) are formed at the inner surfaces at the rearward ends of flange wall (31) in corresponding alignment with bottom wall (30a) and top wall (30b). This flange wall, along with two opposing lips, will provide leak-resistance to powdered medicament during inhalation, as well as assisting with component fit during assembly.

FIG. 3(C) and FIG. 3(D) are cross-sectional views of the mouthpiece, taken through different axes.

In certain embodiments, the volume of the suction chamber (32) of the mouthpiece is in the range from about 3 to about 12 cm³, or from about 4 to about 10 cm³, or from about 5 to about 8 cm³. Further, a thickness of the mouthpiece walls (30) is in the range from about 0.3 to about 3 mm, or from about 0.5 to about 2 mm, or from about 1 to about 1.5 mm. In an embodiment, the volume of the mouthpiece (2) is about 6 cm³, a thickness of the mouthpiece walls (30) is about 1.5 mm, a length between the outlet end and the inlet end is about 30 mm, a width of the outlet end is about 19 mm and a width of the inlet end is about 30 mm.

FIG. 4(A) depicts the front plan view of the mesh (20) with a mesh rim (34) around it that fits in the mouthpiece (2) at the rear or base end, and specifically, fits within flange wall (31) and seats against circumferential shoulder (33). Apertures (36) of varying sizes can be made in the mesh (20) with complementary pitch (38) dimensions. FIG. 4(B) and FIG. 4(C) are cross-sectional views of the mesh taken through different axes. The mesh (20) prevents entry of capsule fragments into the mouthpiece (2) when the patient inhales the powdered medicaments dispersed inside the body chamber. The shape of the mesh (20) is designed to suit the device specifications, and can be any geometry such as but not limited to square, rectangle, round/circular, triangle, oval, pentagonal, octagonal, hexagonal, heptagonal, polygonal, trapezium, parabolic and rhombus. The size of the mesh is also designed to suit the device dimensions. Shapes of the apertures and the pitch can also be any geometry such as but not limited to round, square, rectangle, triangle, oval, pentagonal, octagonal, hexagonal, heptagonal, polygonal, parabolic, trapezium and rhombus.

In some embodiments, the mesh (20) substantially covers the dispersing chamber of the total top housing unit (8) at shoulder (33). It will be appreciated that there is no obstruction between the top housing unit (8) and mouthpiece (2), other than the mesh (20).

The thickness of the mesh (20) is in the range from about 0.3 to about 3 mm, or from about 0.5 to about 2 mm, or from about 0.8 to about 1 mm. In a specific embodiment, the length of the mesh (20) is about 28 mm, the width is about 20 mm, and the thickness is about 1 mm, with the mesh having four horizontal lines with a pitch of 4 mm and seven to nine vertical lines with a pitch of 3 mm, forming the apertures (36), which are rectangular in shape with dimensions of 3 mm^χ2 mm. In embodiments, the horizontal pitch and vertical pitch will be the same, resulting in square apertures. FIG. 5(A) is a schematic top plan view of the bottom housing unit (6).

Specifically, bottom housing unit (6) includes a proximal end (40) that attaches to the proximal end of the top housing unit (8), and a distal end (42) where movable impinger (12) is located. Bottom housing unit (6) includes a bottom cover wall (46) and an upstanding wall (44) extending up from the edges of bottom cover wall (46) at the opposite sides and at the distal end (42) thereof. Upstanding wall (44) therefore includes opposite, spaced apart upstanding side walls (44a) and (44b), as well as an upstanding distal wall (44c). A U-shaped cut-out (44d) is formed centrally in upstanding distal wall (44c) This U shaped cut-out fits to the outer walls of the dispersing chamber. There is no upstanding wall at the proximal end (40), so that a U-shaped opening (41) is formed at proximal end (40), and defined by the proximal edges of bottom cover wall (46) and side walls (44a) and (44b). Bottom cover wall (46) is cut-out to form a parabolic shaped opening (43) at proximal end (40). In addition, two adjacent securing fingers (45), each with a hook (45a) at the upper free end thereof, extend upwardly from bottom cover wall

(46) about one-third of the distance from distal end (42) to proximal end (40), although it will be appreciated that a single finger (45) can be provided. FIG. 5(B) and FIG. 5(C) are cross-sectional views of the bottom housing unit (6) taken through different axes. The thickness of the bottom cover wall (46) of the bottom housing unit (6) is in the range from about 0.3 to about 3 mm, or from about 0.5 to about 2 mm, or from about 0.8 to about 1.2 mm. In a specific embodiment of the present invention, a length of the bottom housing unit (6) is about 50 mm, a width at the center part is about 40 mm, and the thickness of the walls of the bottom housing unit (6) is about 1 mm.

FIG. 6(A) is a schematic top plan view of the top housing unit (8). FIGS. 6(B) and 6(C) are various cross-sections taken through different axes. Specifically, top housing unit (8) includes a proximal end (48) that attaches to the proximal end (40) of bottom housing unit (6) and to which mouthpiece (2) with mesh (20) therein is attached. Top housing unit (8) also includes a distal end (50), where movable impinger (12) is located for opening capsule (18) inserted through port (14) into dispersing chamber (10) when pressure is applied. In an embodiment, port (14) has a square shaped hole to insert the capsule (18) during administration. Upon capsule opening, its powdered contents are emptied in the dispersing chamber (10), to which the mouthpiece (2) with mesh (20) therein is detachably attached. Top housing unit (8) also has a passive chamber (52) rearwardly or distally adjacent the dispersing chamber (10).

This square-shaped hole is useful for retaining the cap during separation of cap and body parts of the capsule. If the hole is round, then the chances of slipping of the capsule from the hole during opening are increased. The width or diameter of the square shaped hole is variable to suit different size of capsules.

Specifically, top housing unit (8) includes a top cover wall (47) and a downwardly extending wall (49) extending down from the edges of top cover wall

(47) at the opposite sides and at the distal end (50) thereof. Air inlets (16) through which the air enters the body (4) when the patient inhales through mouthpiece (2), are provided in top cover wall (47), in surrounding relation to port (14). Downwardly extending wall (49) includes opposite, spaced apart, downwardly extending side walls (49a) and (49b), as well as a downwardly extending distal wall (49c) connected to ends of side walls (49a) and (49b). The lower edge of downwardly extending wall (49) seats flush on the upper edge of upstanding wall (44) along all three sides, such that downwardly extending wall (49) and upstanding wall (44) together form a smooth, continuous side wall of the device according to the present invention. The diameter of the air inlets can be optimized for suitability for the device specifications. Air inlets with larger diameters might produce a diffuse stream and not a sharp, focused one. Also the resistance might be small. Air inlets with too small diameters will have higher resistance and higher inspiratory force would be required. In embodiments, the diameter of air inlets (16) may range from about 1 mm to about 3 mm or from about 1.25 mm to about 2.5 mm.

An L-shaped cut-out (51) is formed centrally in downwardly extending distal wall (49c) at distal end (50) and in top cover wall (47). When top housing unit (8) is assembled with bottom housing unit (6), U-shaped cut-out (44d) in upstanding distal wall (44c) forms an opening extension of L-shaped cut-out (51). There is no downwardly extending wall at the proximal end (48), so that an inverted U-shaped opening (53) is formed at proximal end (48). When top housing unit (8) is assembled with bottom housing unit (6), inverted U-shaped opening (53), together with U-shaped opening (41), form a generally rectangular opening (3) of the device.

A generally parabolic shaped separating wall (55a) extends down from the inner surface of top cover wall (47) at proximal end (48), and opens at rectangular opening (3) at proximal end (48). Parabolic shaped separating wall (55a) is closed at its upper end by top cover wall (47), and at its lower end by a planar, parabolic shaped bottom wall (55b) which fits snugly into parabolic shaped opening (43) at proximal end (40) of bottom cover wall (46). It will therefore be appreciated that parabolic shaped separating wall (55a), top cover wall (47), and planar, parabolic shaped bottom wall (55b), together separate the interior of the device into a proximal dispersing chamber (10) and distal passive chamber (52). A small opening (55c) is provided centrally in generally parabolic shaped separating wall (55a).

Top housing unit (8) further includes a generally rectangular, forward circumferential flange wall (57) which extends forwardly from the front or proximal edges of top cover wall (47), downwardly extending wall (49) at the opposite sides of top cover wall (47) and parabolic shaped bottom wall (55b). The inner surface of flange wall (57) forms a smooth continuation with the inner surfaces of top cover wall (47), downwardly extending wall (49) and parabolic shaped bottom wall (55b). However, the thickness of flange wall (57) is less than the thickness of walls (47), (49) and (55b), whereby an outer circumferential shoulder (57a) is formed between the outer surface of flange wall (57) and the forward or proximal edges of walls (44a), (44b), (47), (49a), (49b) and (55b). Two opposing depressions or channels (57b) are formed at the outer surfaces at the rearward or distal ends of flange wall (57) in corresponding alignment with top cover wall (47) and parabolic shaped bottom wall (55b). In this manner, circumferential flange wall (31) of mouthpiece (2) is positioned snugly over circumferential flange wall (57) with opposing lips (31a) resiliently snapping into depressions or channels (57b) in order to releasably retain mouthpiece (2) thereon.

Top housing unit (8) further includes two parallel, spaced apart plunger housing walls (61) which are fixed to the underside of top cover wall (47) at distal end (50), and which extend in the lengthwise direction of the device from downwardly extending distal wall (49c) at opposite sides of L-shaped cut-out (51) at distal end (50), towards proximal end (48). The length of each plunger housing wall (61) is about one-half the distance from distal end (50) to parabolic shaped wall (55a), and has a height that extends down to bottom cover wall (46) of bottom housing unit (6). The lower edges of plunger housing walls (61) are connected together by a bottom guide wall (63), which includes a cut-out notch (63a) centrally at the forward or proximal edge thereof. When bottom housing unit (6) and top housing unit (8) are assembled together, hooks (45a) of adjacent securing fingers (45) each engage within notch (63a) to secure hold bottom housing unit (6) and top housing unit (8) together in a unitary assembly.

Two guide track walls (65) extend down from the undersurface of top cover wall (47) and extend in parallel, spaced apart relation from the forward or proximal edges of plunger housing walls (61), to the rear or distal surface of generally parabolic shaped wall (55a). However, the height of guide track walls (65) is much less than that of plunger housing walls (61).

In a specific embodiment, the volume of passive chamber (52) is in the range from about 5 to about 50 cm³, or from about 10 to about 40 cm³, or from about 15 to about 30 cm³.

The thickness of the walls of top housing unit (8) is in the range from about 0.3 to about 3 mm, or from about 0.5 to about 2 mm, or from about 0.8 to about 1.2 mm.

In a specific embodiment, the length of top housing unit (8) is about 54 mm, the width at the capsule insert port (14) is about 27 mm, the thickness of the walls is about 1 mm, and the volume of the passive chamber (52) is about 24 cm³.

FIG. 7 is a schematic rear elevational view of the impinger (12), and FIGS. 7(B) and 7(C) are various cross-sections taken through different axes. The impinger (12) includes a generally rectangular parallelepiped plunger (56). Plunger (56) includes a rear wall (56a), a top wall (56b), a parallel, spaced apart bottom wall (56c) and two parallel, spaced apart side walls (56d) and (56e). There is no front wall, so that the front face of generally rectangular parallelepiped plunger (56) is open at (56f). The width dimension of generally rectangular parallelepiped plunger (56), measured between outer surfaces of spaced apart side walls (56d) and (56e), is slightly smaller than the distance between plunger housing walls (61). In like manner, the height dimension of generally rectangular parallelepiped plunger (56), measured between outer surfaces of spaced apart top and bottom walls (56b) and (56c), is slightly smaller than the distance between top cover wall (47) and bottom cover wall (46). As a result, plunger (56) is guided for linear movement in the lengthwise direction of the device.

A breaking stem (58) has a distal end (62) fixed to the inner surface of rear wall (56a), and a free proximal end (60). The proximal end (60) slightly extends through small opening (55c) in parabolic shaped wall (55a) of top housing unit (8). As shown in FIG. 7(B), a coil spring (72) extends around breaking stem (58) such that one end thereof abuts against the inner surface of rear wall (56a) and the opposite end thereof abuts against parabolic shaped wall (55a). As a result, plunger (56) is biased by spring (72) rearwardly of the device toward distal end (50) of top housing unit (8), that is, in a direction out of the device. A user can move plunger (56) in the opposite direction toward the front of the device against the force of spring (72), and in such case, forward movement of plunger (56) is limited when plunger (56) abuts against parabolic shaped wall (55a). The impinger (12) thereby reversibly moves forward and backward when pressure is applied and released, respectively. To prevent escape of plunger (56) from the device, side walls (56d) and

(56e) are provided with openings (67), and resilient spring fingers (69) are mounted in a cantilevered manner to side walls (56d) and (56e) within openings (67). A hook end (64) is provided at the free end of each spring finger (69). When coil spring (72) moves plunger (56) rearwardly in the absence of any force applied thereto, hook ends (64) engage front edges of plunger housing walls (61) to prevent escape of plunger (56) from the device and provide a limit on rearward movement of plunger (56). The proximal end (60) of the stem (58) includes a "C"- shaped capsule opening groove (66). When plunger (56) is moved forward against the force of coil spring (72), groove (66) engages the capsule (18) which has been pushed through opening (14) into dispersing chamber (10), and separates the anchored capsule into its crown (22) and capsule bottom (24) parts, thereby spilling the contents of capsule (18) into dispersing chamber (10) where it can be inhaled through mouthpiece (2).

It will be appreciated that, among the unique features of the impinger (12) of the present invention is its stem (58) with the "C"-shaped groove (66) and the angle at which the stem (58) will break the inserted capsule (18), to make sure the capsule is broken without any failure. This "C" shaped groove acts to push the body part of the capsule uniformly during the process of separation, as the capsule is cylindrical in shape. Other shapes such as rectangles could touch only at one point and lead to formation of a dent or bend on the body part of the capsule.

The thickness or height of the stem (58) for breaking capsule (18) is in the range from about 0.2 to about 15 mm, or from about 0.5 to about 10 mm, or from about 0.8 to about 2 mm. The width of the stem (58) for breaking capsule (18) is in the range from about 3 to about 25 mm, or from about 4 to about 20 mm, or from about 5 to about 10 mm.

In a specific embodiment, the length between the proximal end and the distal end of the stem (58) is about 33 mm, the width of the stem (58) is about 6 mm and the thickness of the stem (58) is about 1.5 mm, the distance between the two hook ends (64) is about 20 mm, the width of the spring fingers (69) is about 1 mm and the thickness of the spring fingers (69) is about 2 mm.

Alternatively, in place of groove (66), impinger (12) can include a blade for cutting a bottom end portion from capsule (18) to cause emptying of the capsule, or a sharply pointed tip for piercing the capsule near its bottom end, to cause emptying of the capsule contents.

The reversible movement of the impinger (12) in an assembled condition of the device of the present invention can be brought about by various mechanisms including spring (72). Although the spring (72) is shown as a coil spring, it may be a compression spring, strip spring, tension spring, torsion spring, wire form spring, and the like or their combinations. Springs can be made of materials including but not limited to stainless steel, mild steel, aluminium, any hardened steel, plastic, any metal with powder coating or any other coating, any other elastic materials or combinations thereof. The length of the coil spring (72) varies to suit the device specifications, which can vary between about 0.5 cm to about 25 cm, or about 1 cm to about 12 cm, or about 2 cm to about 4 cm. The diameter of the spring will be determined by the device specifications and will vary between about 3 mm to about 25 mm, or about 4 mm to about 15 mm, or about 6 mm to about 7 mm. The thickness of the spring wire will also be determined by the device specifications and will vary between about 0.1 mm to about 1 mm, or about 0.2 mm to about 0.8 mm, or about 0.3 mm to about 0.5 mm.

In operation, a user inserts a capsule (18) through port (14) into dispersing chamber (10). The user then presses plunger (56) against the force of spring (72), until plunger (56) abuts against parabolic shaped wall (55a). During this operation, breaking stem (58) moves proximally with plunger (56) such that groove (66) opens capsule (18). Specifically, capsule crown (22) of the capsule (18) remains in port (14) while capsule bottom (24) is broken away and falls into dispersing chamber (10). The powder medicament from capsule (18) also falls into dispersing chamber (10) where it is inhaled through mouthpiece (2). When the user releases the force on plunger (56), after the capsule (18) has been opened, spring (72) biases plunger (56) and breaking stem (58) therewith, back to the distal position. After the medicament has been inhaled, mouthpiece (2) is removed to discard capsule bottom (24) which remained in dispersing chamber (10) because it was blocked by mesh (20). After mouthpiece (2) is reassembled, the device is ready for another dose.

It will therefore be appreciated that the present invention provides a dry powder inhalation device capable of dispensing complete doses of powdered medicament. Normally, the capsules are formed of gelatin, although any suitable material, which is both inert to the drug contained within and able to be satisfactorily ruptured or otherwise opened, may be used. The inhalation device of the present invention may be of either single dose format, requiring insertion of a new dose after each successive use, or multiple dose format in which the device contains a plurality of such doses.

Single medicament doses are generally enclosed in a separable capsule, which is normally inserted into the device just prior to use. After opening of the capsule (18), the capsule top (22) will continue to remain in the slot (14) of the top housing unit (8) to prevent moisture ingress into the device and will be pushed inwardly during the insertion of the next capsule. After every single use the mouthpiece needs to be opened to empty the separated pieces of the capsule from the dispersing chamber (10) by simple tapping, before reloading the next dose. Typically, the patient will carry a plurality of such capsules in a pop-out blister package or in some other container. In the case of a multiple dose format, there can be a design format where a disc capable of loading multiple capsules and which can be rotated to align with the capsule inlet port, will be retrofitted to the top housing unit (8). The operation will again involve adjusting the capsule to the required height as in the case of single capsules. Thus, in one embodiment, the invention includes dry powder inhalation devices for inhalation of a medicament from a separable capsule, wherein the devices deliver a single dose before reloading.

In another embodiment, the invention includes dry powder inhalation devices for inhalation of a medicament from a separable capsule, wherein the devices deliver multiple doses before reloading.

According to the present invention, the device optionally has inlets for retrofitting an attachment for converting the device into an active inhaler, by way of applying positive pressure either pneumatically or by other means so as to create a standing cloud aerosol. In such case, a one-way valve can be used to accompany such retrofits to prevent back pressure or back flow.

In certain embodiments, the dimensions of different parts of the device described will vary, and can further be manipulated according to the needs of the person skilled in the art.

Other, optional embodiments of the present invention include use of an interlock cover for the mouthpiece to prevent accidental inhalation, and a dose counter that indicates the number of doses inhaled for a device in a multi-dose format. In another embodiment of the invention, the mouthpiece can have a tortuous pathway whereby aerosol formation of the drug in the inert carrier can be enhanced.

Individual components of the inhalation device of the present invention can be made of any suitable material, including but not limited to polycarbonate (PC), polystyrene, polypropylene, polyethylene group, high density polyethylene

(HDPE), low density polyethylene (LDPE), polyvinyl chloride (PVC), rubber, glass, K-resin, acrylic, Surlyn™, styrene-acrylonitrile, acrylonithle-butadiene-styrene ("ABS"), metals such as stainless steel, and combinations thereof.

The inhalation device of the present invention can be provided as part of a kit that is provided to patients for pulmonary administration of many drugs, including but not limited to salbutamol, salmeterol, formoterol, formoterol fumarate, tiotropium, tiotropium bromide monohydrate, ipratropium bromide, fluticasone, fluticasone propionate, budesonide, ciclesonide, mometasone, mometasone furoate, apomorphine, albuterol sulfate, metaproterenol sulfate, beclomethasone dipropionate, thmcinoline acetonide, flunisolide, ergotamine tartrate, macromolecule and non-macromolecule based pharmaceuticals, insulin, interleukin-1 receptors, parathyroid hormone (PTH-34), alpha-1 antitrypsin, calcitonin, low molecular weight heparin, heparin, interferon, nucleic acids, and combinations thereof. Many drug substances can be used in the forms of salts, esters, solvates, hydrates, etc., and the above listing does not mention all of the forms of the drug compounds that are useful.

The invention includes use of packaging materials, including but not limited to polymeric bags, paper based cartons, plastic or metal boxes, wooden boxes, and any bag made of derivatives of plastic materials, etc. for packaging the inhalation device of the present invention, either alone or as a part of a kit.

The inhalation device of the present invention can be subjected to dose retention studies according to the "Uniformity of Delivered Dose" test in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP"). The content of active substance can be determined in dose retention studies using analytical techniques such as high performance liquid chromatography.

According to the USP test for "Uniformity of Delivered Dose," unless otherwise specified in an individual monograph, the drug content of at least 9 of 10 doses collected from one inhaler are between 75% and 125% of the target- delivered dose, and none is outside the range of 65% to 135% of the target- delivered dose. If the content of not more than 3 doses are outside the range of 75% to 125%, but within the range of 65% to 135%, of the target-delivered dose, select 2 additional inhalers and follow the same test for analyzing 10 doses from each. The requirements are met if not more than 3 results, out of 30 values, lie outside the range of 75% to 125% of the target-delivered dose, and none is outside a range of 65 to 125% of the target-delivered dose.

According to the MDI DPI Guidance Document ("Guidance for Industry, Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products," United States Food and Drug Administration, CDER, October 1998, Section III.F.2.h), the test for "Emitted Dose Content Uniformity" is an amount of active ingredient per determination not outside of 80-120 percent of the label claim for more than one of ten containers, none of the determinations is outside of 75-125 percent of the label claim, and the mean is not outside of 85-115 percent of the label claim. If two or three of the ten determinations are outside of 80-120 percent of the label claim, none is outside of 75-125 percent of the label claim, and the mean is not outside of 85-115 percent of the label claim, an additional 20 containers should be sampled (second tier). For the second tier of testing of a batch, the amount of active ingredient per determination is not outside of 80-120 percent of the label claim for more than 3 of all 30 determinations, none of the 30 determinations is outside of 75-125 percent of the label claim, and the mean is within 85-115 percent of the label claim. Particle size data for aerosols exiting MDIs and DPIs are usually obtained using cascade impactors, where the aerosol cloud is drawn at a pre-determined air-flow rate through an apparatus containing a series of impaction plates or stages, arranged in such a way that particles of different sizes are collected on different stages. The individual stages can then be washed quantitatively to recover collected drug, and the mass of drug associated with each size band can be determined. Cascade impactors represent the measurement devices of choice for particle size analysis in pharmaceopeias, and are recommended in guidance documents issued by regulatory authorities. The Andersen cascade impactor (ACI), multi-stage liquid impinger and Marple-Miller impactor are the three systems most often used for particle size distribution measurements. The ACI, currently a product of Thermo Fisher Scientific Inc., Waltham, Massachusetts USA, is often a preferred device, since it divides the aerosol cloud into the largest number of fractions, allowing the particle size distribution to be examined in detail. The inhalation device of the present invention can be subjected to a flow resistance study. In general, the resistance to airflow of a device restricts the inspiratory flow through the DPI that can be generated by the patient, and is a predictor of patient comfort during use. Device resistance is calculated using the following equation: Device resistance = (ΔP) ^{ϋ 5} ÷ Q

Where ΔP is pressure drop and Q is volumetric flow rate. Low resistance devices have resistance values less than 0.05 (cm H₂O)^{0 5} (L/minute), medium resistance devices have resistance values of 0.05 to 1 (cm H₂O)⁰⁵ (I/minute) and high resistance devices have resistance values of more than 1 (cm H₂O)⁰⁵ (L/minute). (A. R. Clark and A. M. Hollingworth, "The relationship between powder inhaler resistance and peak inspiratory conditions in healthy volunteers - implications for in vitro testing," Journal of Aerosol Medicine, Vol. 6, pp. 99-110, 1993).

The device can be used with methods for pulmonary administration of drugs. The present invention is not limited to specific embodiments described above. Further modifications and suitable materials will be apparent to a person skilled in the art.

The following examples further describe and explain certain specific aspects and embodiments of the invention. These examples are provided solely for purposes of illustration, and the invention is not to be limited thereto. The dose retention studies and cascade impact study results illustrate the performance of an inhalation device of the present invention.

EXAMPLE 1 : Drug retention studies.

1 ) Formoterol fumarate and Fluticasone propionate formulation.

A drug retention study was performed with a prototype formulation containing formoterol fumarate 6 μg and fluticasone propionate 500 μg, per dose. The test was performed in triplicate using a test device of the present invention and a commercial device available in the Indian market, using a glass impinger assembly, and a vacuum to obtain a of 60 L/minute air flow was applied for 5 seconds. Data averages are expressed ± standard deviation (SD) below.

2) Formoterol fumarate and Budesonide formulation.

A drug retention study was performed using a commercial formulation available in the Indian market containing formoterol fumarate 6 μg and budesonide 200 μg, per dose. The test was performed in duplicate for a test device of the invention and a commercial device (Rotahaler™), using a glass impinger assembly, and a vacuum to obtain a 60 L/minute air flow was applied for 5 seconds.

3) Formoterol fumarate and Tiotropium formulation.

A drug retention study was performed using a prototype formulation containing formoterol and tiotropium. The test was performed in triplicate for a test device of the invention and a commercial device, using a glass impinger assembly, and vacuum to obtain an air flow rate of 60 L/minute was applied for 5 seconds.

4) Salbutamol sulphate formulation. A drug retention study was performed with a commercial formulation available in the Indian market containing salbutamol sulphate 200 μg, per dose. The test was performed for a test device of the invention and a commercial device using a twin-stage glass impinger assembly at the same flow rate (60 L/minute) and the vacuum was applied for 5 seconds (n=4). There were 25.9% retained drug in the commercial device and 17.9% retained in the test device. 5) Formoterol fumarate and Budesonide formulation.

A study was performed using a prototype formulation containing formoterol fumarate 6 μg and budesonide 100 μg, per dose. The test was performed for test devices of the invention constructed of the materials polycarbonate (PC) and acrylonitrile-butadiene-styrene (ABS).

6) Formoterol fumarate and Fluticasone propionate formulation.

A study was performed using a prototype formulation containing formoterol fumarate 6 μg and fluticasone propionate 100 μg, per dose. The test was performed for test devices of the invention constructed of the materials polycarbonate (PC) and acrylonitrile butadiene styrene (ABS).

EXAMPLE 2: Cascade impactor studies.

1 ) Salbutamol sulphate formulation.

A study was performed with an Anderson cascade impactor (ACI) at 28.3 L/minute air flow for 8 seconds, using a commercial formulation available in the Indian market containing salbutamol sulphate 200 μg, per dose. The test was performed with a test device of the invention and a commercial device (Rotahaler), and the results are given below, where DD is the delivered dose, FPF is the fine particle fraction (particles <5 μm), MPF is the middle particle fraction (particles 5-7.7 μm), and LPF is the large particle fraction (particles >7.7 μm) from the large port and preseparator.

Test Device

For the test device, the average delivered dose was 128 μg with a standard deviation of 9.3 μg and a relative standard deviation of 7.3%. The calculated average value ± 15% is 108.8-147.2 μg.

Commercial Device (Rotahaler)

For the commercial device, the average delivered dose was 116.5 μg with a standard deviation of 14 μg and a relative standard deviation of 12%. The calculated average value ± 15% is 103.2-134 μg, and a calculated average value ± 20% is 93.3-139.9 μg. Delivered dose is used as a surrogate for the emitted dose (ED). For the test device, the values of delivered dose were within ±15% of the average value, whereas for the commercial device one value was outside the ±15% of average value, and no value was outside the ± 20% of average value. In the test device there was a higher ED and FPF with lower variability, whereas in the commercial device there was lower ED and FPF with higher variability.

2) Formoterol fumarate and Budesonide formulation.

A study was performed with an ACI using a prototype formulation containing formoterol fumarate 6 μg and budesonide 100 μg, per dose. The test was performed for test devices of the invention constructed of the materials polycarbonate (PC) and acrylonitrile-butadiene-styrene (ABS), and for a commercial device. An inhalation flow rate of 28.3 and 54 L/minute and an actuation time of 8 and 4.3 seconds were used in this study and the results are given below, where FPD is the fine particle dose, FPF is the fine particle fraction (<5 μm), MMAD is the mass median aerodynamic particle diameter and GSD is the geometrical standard deviation.

Results with 28.3 L/minute Flow Rate

"Based on emitted dose. Results with 54.8 L/minute Flow Rate

^*Based on emitted dose

3) Formoterol fumarate and Fluticasone propionate formulation.

A study was performed with an ACI using a prototype formulation containing formoterol fumarate 6 μg and fluticasone propionate 100 μg, per dose. The test was performed for test devices of the invention constructed of the materials polycarbonate (PC) and acrylonithle-butadiene-styrene (ABS), and for a commercial device. An inhalation flow rate of 28.3 L/minute for 8 seconds was used in this study and the results are given below.

"Based on emitted dose

4) Effect of number of air inlet holes on particle size distribution.

A study was performed with an ACI to evaluate the effect of the number of air inlet holes in the top cover wall on particle size distribution. The test was performed for test devices of the invention constructed of acrylonithle butadiene styrene (ABS), having 2 or 3 air inlet holes having 1.2 mm diameter in the top cover wall, in surrounding relation to the port. A prototype formulation containing formoterol fumarate 6 μg and budesonide 400 μg, per dose, and an inhalation flow rate of 28.3 L/minute for 8 seconds were used in this study, and the results are given below.

"Based on emitted dose.

5) Effect of mesh opening size on particle size distribution. A study was performed with an ACI to evaluate the effect of mesh size on particle size distribution. The test was performed for two test devices of the invention constructed of acrylonithle-butadiene-styrene (ABS), one device having a smaller mesh with opening size 1.5 mm^χ1.5 mm and another having a larger mesh with opening size 3 mm^χ2 mm. A prototype formulation containing formoterol fumarate 6 μg and budesonide 400 μg, per dose, and an inhalation flow rate of 28.3 L/minute for 8 seconds were used in this study, and the results are given below.

"Based on emitted dose. EXAMPLE 3: Device resistance study.

A device air flow resistance study was performed using test devices of the invention, constructed of the materials polycarbonate (PC) and acrylonitrile- butadiene-styrene (ABS), and having 2 or 3 air inlet holes in the top cover wall, in surrounding relation to the port. In order to quantify air resistance, air flow rates from a test device at different pressure drops between 1 and 8 kPa were determined by attaching the device to a dose uniformity sampling unit (DUSA, Copley, U.K.). After the pressure drop was adjusted to the pre-determined value, the flow rate across the DUSA was measured by a digital flow meter (Copley, U.K.). Plotting the square root of pressure drop (P) against volumetric flow rate (Q) resulted a straight line with an intercept at zero, and the slope indicated the actual resistance of the device. The results are given below.

Further to quantify air resistance/air flow rates from a test device of the invention, comparison with commercially available Revolizer™ and Rotahaler devices at different pressure drops between 1 and 8 kPa was determined by attaching devices to a dose uniformity sampling unit (DUSA) After the pressure drop was adjusted to the pre-determined value, the flow rate across the DUSA was measured by a digital flow meter.

EXAMPLE 4: Drug retention with dose unit sampling apparatus.

The emitted dose uniformity over the entire content of test inhalers of the invention was determined by a dose unit sampling apparatus (DUSA) described in the British Pharmacopoeia. Briefly the sampling apparatus connected to a vacuum pump running at the required air flow, the loaded inhaler (connected using a silicone adapter) was inserted into the mouthpiece of the sampling apparatus and was held for 4.4 seconds at 54.8 L/minute, (based on 4 kPa). The data represented in the tables are expressed as average ± standard deviation, for ten units.

Formeterol fumarate 6 μg + budesonide 100 μg formulation.

EXAMPLE 5: Uniformity of delivered dose.

The emitted dose was determined using a USP collecting tube (dose unit sampling apparatus (DUSA; Copley Instruments, UK). The flow was adjusted by the control device to 54.8 L/minute, and the actuation time was set to 4.4 seconds (flow rate that generated a pressure drop of 4 kPa across the device). After 4 liters of air had been drawn through the device, the drug that was collected was recovered and analyzed using a validated high performance liquid chromatography (HPLC) method. The comparative data for a test device of the invention and a commercial Rotahaler device are given below, expressed as an average of 3 units ± SD. Formoterol fumarate 6 μg+ Budesonide 100 μg formulation.

EXAMPLE 6: Andersen Cascade lmpactor study.

The pulmonary deposition of dry powder was investigated in vitro using an 8-stage ACI (Copley Instruments, UK) with a USP throat under controlled relative humidity (40-50%). Hard gelatin capsules (size '3') containing 25 mg of formulations were loaded in a test inhaler of the invention. The powder was dispersed into an ACI from the device for 8 seconds at an air flow rate of 28.3 L/minute. To determine the active ingredient distribution, the individual impactor components and the inhalation device, including the mouthpiece adapter, were rinsed quantitatively with a mixture of acetonithle and phosphate buffer pH 3.0 (65:35 by volume, 50 ml_). In each case, the individual, thoroughly mixed samples were then transferred to glass bottles, for quantitative analysis of formoterol fumarate and budesonide by HPLC. The emitted dose was defined as the percent of total powder mass exiting the inhaler. The FPF was calculated from the same plot as the fraction of powder emitted from the inhaler with an aerodynamic size <5 μm.

Formeterol fumarate 6 μg + fluticasone propionate 100 μg formulation.

A comparison of a test device of the invention and a commercial Rotahaler device was similarly conducted, and the data below are averages ± SD, from 3 units.

Formeterol fumarate 6 μg + Budesonide 100 μg formulation.

EXAMPLE 7: Effect of Material of Fabrication, Acrylonitrile-Butadiene-Styrene (ABS) vs. Polycarbonate (PC) i) Andersen Cascade lmpactor (ACI) Study: The ACI study was performed in the same manner as that of Example 6 at an air flow rate of 54.8 L/minute for 4.4 seconds.

Formeterol fumarate 6 μg + Budesonide 100 μg formulation.

ii) Drug retention:

The drug retention in the devices was determined using a USP collecting tube (dose unit sampling apparatus (DUSA; Copley Instruments, UK). The flow was adjusted by the control device to 54.0 L/minute, and the actuation time was set to 4.4 seconds (a flow rate that generated a pressure drop of 4 kPa across the device). After 4 liters of air had been drawn through the device, the drug retained in the device was collected, recovered and analyzed using a validated high performance liquid chromatography (HPLC) method. The data are expressed as an average of 10 units, ± SD.

Formeterol fumarate 6 μg + Fluticasone propionate 100 μg formulation.

EXAMPLE 8: Effect of varying mesh opening size. i) Drug Retention: Drug retention testing was conducted in the same manner as that of Example 7 (ii) using small mesh (1 .2 mm openings) and large mesh (1 .6 mm openings). The data are averages of 3 units, ± SD. Formeterol fumarate 6 μg + Fluticasone propionate 500 μg formulation.

ii) Mesh retention:

The amount of drug retained on the mesh in device was determined using a USP collecting tube (dose unit sampling apparatus (DUSA; Copley Instruments, UK). The flow was adjusted by the control device to 54.8 L/minute, and the actuation time was set to 4.4 seconds (a flow rate that generated a pressure drop of 4 kPa across the device). After 4 liters of air had been drawn through the device, the drug retained in sieve was collected, recovered and analyzed using a validated high performance liquid chromatography (HPLC) method. The data are averages of 3 units, ± SD.

Formeterol fumarate 6 μg + Fluticasone propionate 500 μg formulation.

iii) ACI Study: The ACI study was performed in the same manner as that of Example 6.

FPF (%) for Formeterol fumarate 6 μg + Fluticasone propionate 500 μg formulation.

FPF (%) for Formeterol fumarate 6 μg + Budesonide 400 μg formulation.

EXAMPLE 9: Spring selection.

The effect of spring properties on capsule opening has been studied using size '3' capsules filled with a placebo powder formulation. In this study, capsule separation was performed on hard gelatin capsules with devices having different spring thicknesses and lengths. Observations of the study are:

0.55 mm thickness and 28 mm length resulted in no chipping of cap and body, no slippage of the capsule portion from the port and no breakability issues, and no flow of powder was observed into the mouthpiece; and

0.60 mm thickness and 33 mm length resulted in no chipping of cap and body, no slippage of the capsule portion from the port and no breakability issues, but when the actuator was pressed with a relatively larger force, about 10 percent of the powder entered the mouthpiece.

EXAMPLE 10: Effect of varying number of air inlet holes.

An ACI study was performed in the same manner as that of Example 6 at a flow rate of 28.3 L/minute for 8 seconds to study the impact on FPF of 2 or 3 air inlet holes having 1.5 mm diameter.

FPF (%) for Formoterol fumarate 6 μg + Budesonide 400 μg formulation.

EXAMPLE 11 : Effect of varying air inlet hole diameter and number. i) Drug Retention Studies: Drug retention was determined in the same manner as that of Example 7 (ii).

Formoterol fumarate 6 μg + Budesonide 100 μg formulation.

ii) ACI Studies: ACI studies performed in the same manner as that of Example 6.

FPF (%) for Formoterol fumarate 6 μg + Budesonide 100 μg formulation.

FPF (%) for Formoterol fumarate 6 μg + Budesonide 400 μg formulation.

EXAMPLE 12: Effect of varying air Flow Rates.

An ACI study was performed in the same manner as that of Example 6, to study the device performance at different air flow rates.

FPF (%) for Formoterol fumarate 6 μg + Budesonide 400 μg formulation.

EXAMPLE 13: Fine particle fraction and uniformity of delivered dose.

Uniformity of emitted dose (UOED) testing has been performed in a manner similar to Example 5 and ACI testing was performed in the same manner as that of Example 6, at an air flow rate of 60 L/minute for 4 seconds. Studies have been performed for different formulations and FPF (%) and UOED results are shown below.

Formoterol fumarate 6 μg and Budesonide 100 μg.

Formoterol fumarate 6 μg and Budesonide 400 μg.

Formoterol fumarate 6 μg and Ciclesonide 200 μg.

Formoterol fumarate 6 μg and Ciclesonide 400 μg.

Formoterol fumarate 6 μg and Fluticasone propionate 100 μg.

Formoterol fumarate 6 μg and Fluticasone propionate 500 μg.

Claims

CLAIMS:

1. An inhalation device for inhalation of a medicament from an openable capsule, the device comprising: a housing unit including a dispersing chamber therein; at least one air inlet in the housing unit through which air may be admitted into the dispersing chamber during inhalation by a person; a mouthpiece removably attached to the housing unit and in communication with the dispersing chamber; a mesh provided between the dispersing chamber and the mouthpiece to prevent entry of the capsule into the mouthpiece while permitting medicament from the capsule to travel to the mouthpiece; characterized by: a port in the housing unit for inserting a medicament capsule there through such that a first portion of the capsule is captured in the port and a second portion of the capsule extends into the dispersing chamber; and an impinger located in the housing unit and adapted to engage the second portion of the capsule to open the capsule and thereby permit escape of the medicament from the capsule into the dispersing chamber.

2. An inhaler according to claim 1 , wherein an entire area of the dispersing chamber is in fluid communication with the mouthpiece without any obstruction except for the mesh.

3. An inhaler according to either of claims 1 or 2, wherein the at least one air inlet is provided in the housing unit such that an air stream that flows into dispersing chamber from the at least one air inlet is at an angle of about 90 degrees to a direction of powder flow through the mouthpiece during inhalation, to create high turbulence.

4. An inhaler according to any of claims 1 -3, further characterized in that walls defining the dispersing chamber haves a parabolic shape.

5. An inhaler according to any of claims 1 -4, wherein the impinger is movable between a first position and a second position that opens the capsule extending through the port.

6. An inhaler according to any of claims 1 -5, wherein the port has square- shaped hole to insert the capsule during administration.

7. An inhaler according to any of claims 1 -6, further characterized in that the impinger has a breaking stem with a distal end having a C-shaped capsule opening groove.

8. An inhaler according to any of claims 1 -7, wherein the housing unit is formed by a top housing unit and a bottom housing unit.

9. An inhaler according to claim 8, wherein the port is formed in the top housing unit.

10. An inhaler according to either of claims 8 or 9, wherein the at least one air inlet includes a plurality of air inlets in the top housing unit.

11. An inhaler according to any of claims 8-10, wherein the mouthpiece is removably attached to the top housing unit.

12. A method for administering a powdered inhalation medicament, comprising: providing a medicament capsule in a dispensing chamber in a housing having air inlets positioned transversely to a first direction; opening the medicament capsule in the dispensing chamber; and inhaling through a mouthpiece connected with the dispersing chamber such that air drawn into the dispersing chamber along with medicament is inhaled through the mouthpiece in the first direction; characterized by the steps of: inserting the medicament capsule through a port in the housing unit such that a first portion of the capsule is captured in the port and a second portion of the capsule extends into the dispersing chamber; and pressing a breaking stem of an impinger located in the housing unit against the second portion of the capsule extending into the dispersing chamber to separate the second portion of the capsule from the first portion of the capsule so as to open the capsule and thereby permit escape of the medicament from the capsule into the dispersing chamber.

13. A method according to claim 12, wherein the plunger is pressed against a spring force.

14. A method according to either of claims 12 and 13, further characterized by the breaking stem having a distal end with a groove thereat for breaking the capsule.