Breath Actuated Inhaler

Abstract

A breath actuated metered dose inhaler may comprise a canister fire system configured to fire a medicament containing canister in response to patient inhalation. The canister fire system may comprise a pneumatic force holding unit and having a rest configuration in which a metering valve of the canister is in a refill configuration; a prepared configuration in which a canister actuation force is retained by the pneumatic force holding unit and the canister fire system is actuatable by patient inhalation induced airflow; and a fire configuration in which the metering valve is in a dose delivery position. When in the prepared configuration, the force retained by the pneumatic force holding unit may be reduced by less than about 6% over a period of 5 minutes, preferably less than about 3% over a period of 5 minutes.

Claims

1. A valve port for a pneumatic force holding unit in a breath actuated metered dose inhaler, said valve port comprising a valve seal surface, which in use is sealably engaged by a movable valve seal, wherein the valve seal surface has a surface roughness average (RA) of less than about 0.15 m.

2. The valve port of claim 1, wherein the valve seal comprises an elastomer.

3. The valve port of claim 2, wherein the valve seal comprises a thermoplastic elastomer.

4. The valve port of claim 2, wherein the elastomer has a hardness of from about 80 to 90 Shore A.

5. The valve port of claim 1, wherein the valve port is injection molded.

6. The valve port of claim 5, comprising: an annular boss defining a valve orifice channel; and one or more radially outwardly extending projections defining a path through which polymer passes to form the annular boss during injection molding.

7. The valve port of claim 6, wherein the one or more radially outwardly extending projections comprises at least two radially outwardly extending projections and the at least two radially outwardly extending projections are substantially uniformly circumferentially separated, wherein the annular boss has a longitudinal axis which passes through the valve orifice channel, and wherein the at least two radially outwardly extending projections and the valve orifice channel lie in a common plane coincident with the longitudinal axis.

8. The valve port of claim 6, wherein an upper surface of the one or more radially outwardly extending projections and an upper surface of the annular boss are contiguous.

9. The valve port of claim 8, wherein the upper surface of the annular boss and the upper surface of the projection are at an angle between about 90 degrees and about 180 degrees.

10. The valve port of claim 9, wherein the angle is obtuse.

11. The valve port of claim 6, wherein the valve port is located on a planar body and a portion of the planar body immediately adjacent the annular boss has a depth that is less than or equal to a thickness of the one or more radially outwardly extending projections, and wherein the portion of the planar body immediately adjacent the annular boss circumferentially surrounds the annular boss between the one or more radially extending projections.

12. The valve port of claim 7, further comprising: a canister fire system including a flap valve, wherein the flap valve comprises: a chassis for pivotal mounting within the inhaler; a valve port seal mounted on the chassis configured to selectively engage the valve port in a sealing relation; and a vane for moving the valve port seal away from the valve port in response to inhalation induced airflow.

13. The valve port of claim 1, wherein the valve port comprises acrylonitrile butadiene styrene.

14. The valve port of claim 1, comprising an annular boss with an inner wall defining a valve orifice channel wherein: a volume of the orifice channel is greater than about 12.7% of a volume of the annular boss, or the inner wall defines a frustum of an imaginary cone with an apex angle of greater than about 20 degrees.

15. The valve port of claim 14, wherein the apex angle is within a range of about 22 degrees to about 35 degrees.

16. The valve port of claim 1, further comprising at least one of: a diaphragm for a pneumatic force holding unit in a canister fire mechanism of a breath actuated metered dose inhaler; and a flap valve comprising: a chassis for pivotal mounting within the inhaler; a valve port seal mounted on the chassis configured to selectively engage the valve port in a sealing relation; and a vane for moving the valve port seal away from the valve port in response to inhalation induced airflow, wherein the diaphragm comprises a rigid disk portion and flexible membrane, and wherein the valve port is unitarily formed with the rigid disk portion.

17. A diaphragm for a pneumatic force holding unit in a canister fire mechanism of a breath actuated metered dose inhaler comprising at least one of: the valve port of claim 7; or a flap valve comprising: a chassis for pivotal mounting within the inhaler; a valve port seal mounted on the chassis configured to selectively engage the valve port in a sealing relation; and a vane for moving the valve port seal away from the valve port in response to inhalation induced airflow, wherein the diaphragm comprises a rigid disk portion and flexible membrane, and wherein the valve port is unitarily formed with the rigid disk portion.

18. A mold for injection molding a diaphragm for a breath actuated metered dose inhaler wherein the mold comprises cavities configured to produce the valve port of claim 6, wherein the mold has a surface average roughness in a region of a valve port sealing surface of less than 0.1 m.

19. A breath actuated metered dose inhaler comprising a pneumatic force holding unit, wherein the pneumatic force holding unit comprises a valve port in accordance with claim 1.

20. The breath actuated metered dose inhaler of claim 19, wherein the valve port is injection molded.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0064] Preferred features of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:

[0065] FIG. 1-3 show a known multi-material diaphragm for a breath actuated inhaler;

[0066] FIG. 4 shows a multi-material diaphragm according to the invention;

[0067] FIG. 5-7 show cross-sections of a valve port according to the invention;

[0068] FIG. 8-9 shows a breath actuated metered dose inhaler according to the invention;

[0069] FIG. 10 shows an alternative diaphragm according to the invention;

[0070] FIG. 11 shows surface roughness testing results of a known valve port sealing surface;

[0071] FIG. 12 shows surface roughness testing results of a valve port sealing surface according to the invention.

[0072] FIG. 13 shows the locations at which surface roughness measurements may be taken.

[0073] FIG. 14 shows the volume of the boss and the valve orifice channel.

DETAILED DESCRIPTION OF THE INVENTION

[0074] The invention provides a valve port for a pneumatic force holding unit in a breath actuated metered dose inhaler, breath actuated metered dose inhalers, and methods of manufacturing and assembling the same.

[0075] FIG. 8 shows a breath actuated inhaler which is merely an example of an inhaler in accordance with the present invention. The inhaler includes a force holding unit housing 12, a main body 14, a mouthpiece dust cap 16 and a dose counter door 18 having a dose counter window. In other embodiments comprising nasal inhalers, the mouthpiece 66 may be replaced with a nose piece.

[0076] As shown by the exploded view of FIG. 8, a dose counter chamber 22 includes a dose counter system 24 closed within it by the dose counter door 18. The dose counter system includes an actuating pin 26 and return spring 28. The dose counter can take various forms and may, for example, be as described in EP2135199A or EP2514464A.

[0077] As also shown in FIG. 8, the inhaler 10 includes a force holding unit 30 which includes: a filter 32, flap valve housing 34, flap valve 36, flap valve spring 38, compression spring 40, retaining ring 42, diaphragm 44 and lower cap 46. The inhaler also includes a canister 50 with a metering valve 52 and a valve stem 54; as well as a yoke 56 with drive rods or legs 58 having distal ends 59 which are driven by respective cams 60 on the pivotally-connected mouthpiece dust cap 16. The valve stem 54 may be fitted into an inner bore of a valve stem block which communicates with a nozzle (not shown) for ejection of inhalable substances through a central bore of a mouthpiece 66 (FIG. 8) of the main body 14 of the inhaler.

[0078] In embodiments, the arrangement of openings in the metering valve of the present invention is similar to those described in US2016/0084385, which is incorporated by reference herein. In particular, the metering valve of the present invention may be similar to the embodiment shown in FIG. 4 of US2016/0084385, in which the valve body includes at least one first opening (i.e., at least one first side hole 100 that is arranged in a cylindrical portion of the valve body) and at least one second opening (i.e., at least one second side hole 111 that, as with the first hole(s), is arranged in a cylindrical portion of the valve body), the second opening(s) being axially offset relative to the first opening(s) along a longitudinal axis that extends between a first axial end and a second axial end of the valve body. The first opening(s) and second opening(s) that are axially offset from each other along the valve body enable the metering chamber to be filled and emptied.

[0079] The force holding unit 30 operates substantially as disclosed with reference to FIGS. 1 to 3 of EP1289589A and the yoke 56 and mouthpiece dust cap 16 substantially as described in EP2514465A, including but not limited to FIG. 22 thereof, which are incorporated herein by reference.

[0080] FIG. 9 shows the flap valve 36 and diaphragm 44 in situ, in a patient inhalation configuration, so at the spring 38, the upper surface of the boss 80, and the valve orifice channel 78 are visible.

[0081] The canister 50 is operable by a force holding unit 30 having a cap housing 12 attachable to a main body 14 of the inhaler. In use, a mouthpiece cap 16 is opened to prime the inhaler ready for inhalation and then after inhalation the mouthpiece cap 16 is closed to reset the force holding unit 30, i.e. return it to a rest configuration.

[0082] In more detail, when the mouthpiece cap 16 is opened, the lower cap 46 is forced downwards under the action of the compression spring 40. Then, as the lower cap 46 moves down, an enclosed volume between the diaphragm 44 and the lower cap 46 is increased by a linear amount, and whilst valve port remains closed, this creates a pressure difference in the enclosed volume.

[0083] The offset of the differential between the pressure in the enclosed volume and atmospheric pressure results in the lower cap 46 resisting action of the compression spring 40. Downward movement of the lower cap 46 continues until the force is balanced between the force of the compression spring 46 and the opposing forces of the pressure difference and metering valve 52.

[0084] The geometry of the mechanism is arranged such that the balance occurs before the valve has been actuated.

[0085] Upon inhalation, air enters the inhaler through approximately ten air inlets 72 formed on the cap housing 12. Flow of air across a vane 74 on the flap valve 36 during inhalation causes the valve 36 to pivot, moving the flap valve seal 76 out of its rest position, and opening a valve orifice channel 78 in the diaphragm 44. The subsequent passage of air into the volume between the diaphragm 44 and the lower cap 46 allows the volume to reach atmospheric pressure. The resulting imbalance of forces acting on the lower cap 46 and canister 50 produces the downward (forward) motion of the canister 50 and actuation of the aerosol metering valve 52: releasing a measured dose through the dispensing nozzle and into the mouthpiece 66.

[0086] The force holding unit 30 relies on the described pressure difference to maintain the prepared configuration, and release thereof for firing the canister 50 under the action of the compression spring 40. The force holding unit 30 is therefore considered pneumatic within the normal meaning of the term.

[0087] Referring to FIG. 4, a diaphragm 1000 according to the present invention for use with the medicament dispenser of FIGS. 8 and 9 is shown.

[0088] The moulded flexible diaphragm 1000 includes a rigid disc-like section 1041, a flexible generally cylindrical wall section, or annular flexure 1045, and a thicker connector section, or peripheral attachment ring 1047. A central portion (not shown) is unitarily formed with and extends radially inwardly from the annular flexure 1045. The central portion preferably is provided in the form of a disk bonded along a top surface to a bottom surface of the rigid disc-like section 1041.

[0089] The relatively thick disk-portion which includes the disc-like section 1041 of the diaphragm 1000, is moulded from acrylonitrile butadiene styrene, which is particularly resistant to flexural deformation. The relatively thin flexure portion which includes the central portion, the annular flexure 1045 and the peripheral attachment ring 1047, is moulded from thermoplastic polyurethane, permitting high performance flexibility. The multi-material diaphragm 1000 may be made using a multi-shot moulding process wherein the rigid disc-like section is moulded in a first step, and the second flexible portion is moulded in a second step, and at the same time bonded to the first portion.

[0090] As shown in FIG. 4, the rigid disc-like section 1041 defines a central upwardly extending boss 1002 for additional strength. In addition, the rigid disc-like section 1041 includes an outer axial wall 1004 which provides further strength to the diaphragm 1000.

[0091] The valve port 1095 of the diaphragm 1000 passes through the rigid disc-like section 1041 and the central portion of the diaphragm. The valve port 1095 is closed by the valve port seal 76, which is biased closed by a flat spring 38, as shown in FIG. 9. Although not shown, the rigid disc-like section 1041 of the diaphragm may include protrusions extending upwardly therefrom that receive the flat spring 38. The rigid disc-like section 1041 of the diaphragm 100 also includes a baffle 1014 on a top surface thereof for substantially preventing air flow between the valve port seal 76 and the diaphragm.

[0092] As illustrated in FIG. 4 the valve port 1095 comprises an annular boss 1100 projecting from an upper surface of the rigid disk-like portion 1041 of the diaphragm. Typically, the annular boss 1100 and rigid disk-like portion 1041 are a single unitary structure. The annular boss 1100 comprises a lower generally cylindrical body portion 1101 and an upper portion 1102 in the form of a truncated cone. The frustum of the truncated cone provides the upper surface 1103 of the annular boss 1100. The upper surface 1103 includes an annular projection 1104 which surrounds the entrance to the valve orifice channel and provides the sealing surface 1103, which in use engages the valve port seal in a sealing relation. Whilst the illustrated annular boss 1100, including both its upper 1102 and lower portions 1101, and the annular projection 1104, all have a circular circumference, it will be appreciated that other boss shapes may also be employed without departing from the invention. Accordingly, unless stated otherwise, for the purposes of the invention the use of annular, circumference, circumferential and/or radial, or the like, do not restrict the invention to circular cross-sectioned bodies. Equally, substantially circular cross-sectioned and/or circumferenced bodies are not excluded.

[0093] As illustrated, the valve port 1095 further comprises two radially outwardly extending projections 1106 and 1107. A first projection 1106 extending from outer wall 1004 to the annular boss 1100. The second projection extending from the baffle 1014 to the annular boss 1100. During moulding molten polymer, or prepolymer, flows along a path defined by the mould corresponding to each of the two projections 1106 1107 into the annular boss mould cavity. Typically, the projections are of substantially the same thickness T. In this illustrated embodiment 0.64 mm. The illustrated projections 1106 1107 are substantially uniformly circumferentially separated. That is to say, each and every projection is separated from its adjacent projections by substantially the same central angle. The illustrated projections 1106 1107 are separated from each other by a central angle of 180 degrees. They are diametrically opposed. As illustrated by reference to FIG. 5 and FIG. 6, an imaginary straight-line Y running along a central axis of the projections passes through the central longitudinal axis X of the valve orifice channel. This arrangement concentrates polymer flow towards the centre of the boss 1100 during moulding, improving the surface finish of the upper surface 1103 and in particular its sealing surface 1105.

[0094] As better illustrated in FIG. 6, the upper surfaces of the first 1107 and the second projections 1106 are both contiguous with the upper surface 1103 of the annular boss 1100. The upper surface 1110 of the first projection 1107 and the upper surface 1103 of the annular boss 1100 are at an angle (a) of greater than 90 degrees but less than 180 degrees. The upper surface 1109 of the second projection 1106 and the upper surface 1103 of the annular boss 1100 are at an angle (p) of approximately 180 degrees: preferably there is no discernible joint between the two.

[0095] As a result of each of the upper surfaces 1109 1110 of the projections 1106 1107 and the upper surface 1103 of the annular boss 1100 joining directly, during moulding, molten polymer is able to flow directly along the mould surface from projection upper surface to boss upper surface without stalling, improving the finish of the upper surface 1103 of the annular boss 1100 and in particular the sealing surface 1105.

[0096] As illustrated in FIG. 6 a portion of the valve orifice channel forms the frustum of an imaginary cone with an apex angle of 28 degrees. With reference to FIG. 14, the valve orifice channel 78 has a volume of 1.91 mm.sup.3 and the annular boss 80 has a volume of 12.02 mm.sup.3.

[0097] As better illustrated in FIGS. 5 and 7, the annular boss 1100 is surrounded by a circumferential channel 1111 formed in the upper surface of the diaphragm 1041 surrounding the annular boss 1100. The channel 1111 has two sections 1112 and 1113 each extending between the two projections 1106 and 1107 around opposite sides of the annular boss 1100. The channel sections 1112 and 1113 reduce the depth of the relatively rigid disk-like portion 1041 of the diaphragm immediately adjacent to the annular boss; typically, to a depth D less than the thickness T of the projections 1106 and 1107. This arrangement concentrates polymer flow towards the centre of the annular boss 1100 during moulding, improving the smoothness of the upper surface 1103 and in particular the sealing surface 1105.

[0098] FIG. 10 shows an alternative diaphragm central disk 1041 according to the invention. As illustrated, this embodiment differs from that illustrated in FIG. 4 in that one of the radially outwardly extending projections 1210 of the valve port 1095 extends from the annular boss 1100 to the central upwardly extending boss 1002. As with the valve port 1095 shown in FIG. 4, this arrangement concentrates polymer flow towards the centre of the annular boss 1100 during moulding, improving the smoothness of the upper surface 1003 and, in particular, the sealing surface 1005.

[0099] Advantageously, it has been found that injection moulded diaphragms according to the invention provide an increased yield during manufacturing compared to those illustrated in FIGS. 1-3 and improved surface finish immediately adjacent the valve channel orifice. In embodiments, the yield has increased from about 50% to about 85%.

[0100] In embodiments the breath actuated metered dose inhaler comprises a reservoir, particularly a pressurized canister, comprising an active pharmaceutical ingredient (API).

[0101] Preferably the active pharmaceutical ingredient is presented in a pharmaceutical composition comprising a propellant, optionally a co-solvent and optionally other pharmaceutically acceptable excipients.

[0102] Preferred propellants include hydrofluroalkanes, in particular 1,1,1,2-tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA227), or combinations thereof. Most particular propellant is HFA134a. Most particular HFA134a concentration is from about 91.8% w/w to 92.9% w/w.

[0103] HFA134a has a low boiling point (26.1 C.) and correspondingly high vapor pressure (572 kpa) at 20 C.

[0104] Particular co-solvents are selected from the list of aliphatic alcohols (particularly ethanol), glycerols and glycols. Most particular co-solvent is ethanol. Most particular ethanol concentration is about 8% w/w.

[0105] Ethanol is well known to be compatible with HFA-134a and increases the solubility of BDP. Ethanol (anhydrous) is used as a co-solvent to aid solubility of BDP in HFA134a. A concentration of around 8% w/w of ethanol is known to provide necessary stability, preventing precipitation and achieving correct aerosol performance.

[0106] Other pharmaceutically acceptable excipients include surfactants, particularly oleic acid.

[0107] Preferably, the active pharmaceutical ingredient is suspended in the propellant. Alternatively, the active pharmaceutical ingredient is dissolved in the propellant. The active pharmaceutical ingredient may also be partly suspended and partly dissolved in the propellant.

[0108] A particular active pharmaceutical ingredient is selected from the group consisting of anti-inflammatory agents, 2-adrenoreceptor agonists, anti-cholinergic agents, anti-histamines, serotonin agonists, and combinations thereof.

[0109] Suitable anti-inflammatory agents include corticosteroids and NSAIDs.

[0110] Suitable corticosteroids which may be used include those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples of suitable corticosteroids include methyl prednisolone, dexamethasone, fluticasone propionate, fluticasone furoate, beclomethasone, beclomethasone esters such as e.g. the 17-propionate ester or the 17,21-dipropionate ester, budesonide, flunisolide, mometasone, mometasone esters such as e.g. the furoate ester, triamcinolone acetonide, rofleponide, ciclesonide, and butixocort propionate.

[0111] A particular corticosteroid is beclomethasone dipropionate (BDP).

[0112] Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e. g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2-integrin antagonists and adenosine receptor agonists or antagonists (e. g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis.

[0113] Suitable 2-adrenoreceptor agonists are selected from SABA (short-acting 2-adrenoreceptor agonists), LABA (long-acting 2-adrenoreceptor agonists), ultra-LABA (ultra-long-acting 2-adrenoreceptor agonists), and combinations thereof.

[0114] Suitable SABA include bitolterol, fenoterol, isoprenaline, orciprenaline, pirbuterol, procaterol, salbutamol, levosalbutamol, terbutaline, and pharmaceutically acceptable salts and esters thereof.

[0115] Suitable LABA include bambuterol, clenbuterol, formoterol, arformoterol, protokylol, salmeterol, and pharmaceutically acceptable salts and esters thereof.

[0116] Suitable ultra-LABA include indacaterol, olodaterol, vilanterol, and pharmaceutically acceptable salts and esters thereof.

[0117] Particularly suitable 2-adrenoreceptor agonists include salmeterol xinafoate, salbutamol sulphate, salbutamol free base, formoterol fumarate, fenoterol or terbutaline.

[0118] A particular 2-adrenoreceptor agonist is salbutamol sulphate.

[0119] Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds, which are antagonists of the M1 and M2 receptors. Compounds include the alkaloid of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines.

[0120] Particularly suitable anticholinergics include ipratropium (e.g. as the bromide), oxitropium (e. g. as the bromide) and tiotropium (e. g. as the bromide). Further suitable anticholinergics of interest are methantheline, propantheline bromide, anisotropine methyl bromide, clidinium bromide, copyrrolate, isopropamide iodide, mepenzolate bromide, tridihexethyl chloride, hexocyclium, cyclopentolate hydrochloride, tropicamide, trihexyphenidyl hydrochloride, pirenzepine, telenzepine, and methoctramine.

[0121] Suitable antihistamines (also referred to as H1-receptor antagonists) include carbinoxamine maleat, clemastine fumarate, diphenylhydramine hydrochloride, dimenhydrinate, pyrilamine maleate, tripelennamine HCl, tripelennamine citrate, chlorpheniramine, chlorpheniramine maleate, acrivastine, hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl, cyclizine lactate, meclizine HCl, cetirizine HCl, astemizole, levocabastine HCl, loratadine, loratadine descarboethoxy analogue, terfenadine, fexofenadine hydrochloride, azelastine hydrochloride.

[0122] In a particular embodiment of the invention, the active pharmaceutical ingredient is selected from beclomethasone dipropionate (BDP), salbutamol sulphate and dihydroergotamine.

[0123] In a particular embodiment the breath actuated metered dose inhaler comprises a pressurized canister comprising beclomethasone dipropionate as active pharmaceutical ingredient, HFA134a as propellant and ethanol as co-solvent.

[0124] In a particular embodiment the breath actuated metered dose inhaler comprises a pressurized canister comprising beclomethasone dipropionate as active pharmaceutical ingredient at about 1.0 mg/ml, HFA134a as propellant at about 1090.20 mg/ml and ethanol as co-solvent at about 94.80 mg/ml.

[0125] In a particular embodiment the breath actuated metered dose inhaler comprises a pressurized canister comprising beclomethasone dipropionate as active pharmaceutical ingredient at about 0.084% w/w, HFA134a as propellant at about 91.9% w/w and ethanol as co-solvent at about 8.0% w/w.

[0126] In a particular embodiment the breath actuated metered dose inhaler comprises a pressurized canister comprising beclomethasone dipropionate as active pharmaceutical ingredient at about 0.169% w/w, HFA134a as propellant at about 91.8% w/w and ethanol as co-solvent at about 8.0% w/w.

[0127] In a particular embodiment the breath actuated metered dose inhaler comprises a pressurized canister comprising salbutamol sulphate as active pharmaceutical ingredient, HFA134a as propellant and ethanol as co-solvent.

[0128] In a particular embodiment the breath actuated metered dose inhaler comprises a pressurized canister comprising about 0.1098 mg of salbutamol sulphate as active pharmaceutical ingredient, about 27.8 mg of HFA134a as propellant and about 3.6 mg of ethanol as co-solvent.

[0129] One embodiment relates to a breath actuated metered dose inhaler as described herein comprising an active pharmaceutical ingredient.

[0130] One embodiment relates to a breath actuated metered dose inhaler as described herein comprising an active pharmaceutical ingredient for therapeutic use.

[0131] One embodiment relates to a breath actuated metered dose inhaler as described herein comprising an active pharmaceutical ingredient for use in the treatment or prevention of a respiratory disease, particularly COPD or Asthma.

[0132] One embodiment relates to an active pharmaceutical ingredient for use in the treatment or prevention of a respiratory disease, particularly COPD or Asthma, wherein the active pharmaceutical ingredient is delivered to a patient using a breath actuated metered dose inhaler as described herein.

[0133] One embodiment relates to a method for the treatment or prevention of respiratory diseases, particularly COPD or Asthma, which method comprises administering an active pharmaceutical ingredient to a human being or animal using a breath actuated metered dose inhaler as described herein.

[0134] One embodiment relates to the use of a breath actuated metered dose inhaler as described herein comprising an active pharmaceutical ingredient for the treatment or prevention of respiratory diseases, particularly COPD or Asthma.

[0135] The invention will now be illustrated by the way of the following examples which are intended to be non-limiting.

EXAMPLES

Sample Preparation

[0136] Two groups of Easi-Breathe inhaler force holding unit diaphragms were prepared for use in the following examples.

[0137] The diaphragms in both groups shared the following common features.

[0138] The diaphragms of both groups were injection moulded on a Nestal 120 2-shot apparatus with 8+8 cavity mould and 25 mm/25 mm screw and barrel. In both groups the rigid disk-like portion was made from ABS Sabic Cycolac HMG47MD, and the central portion, the annular flexure and the peripheral attachment ring were moulded from an elastomer comprising 96% BASF Elastollan 1185A with 4% BASF Konz 950/1 additive as release agent.

[0139] The first control group diaphragms (M30579) were manufactured according to FIGS. 1 to 3, with the injection moulding parameters as set out in Table 1.

[0140] Whereas, the second test group diaphragms (M24406) were manufactured according to FIG. 4, with the injection moulding parameters as set out in Table 2.

TABLE-US-00001 TABLE 1 Diaphram-M24406 Process Minimum Maximum Parameter Value Value Value Injection Time .13 sec. .12 sec. .14 sec. Hold Pressure 750 bar 675 bar 825 bar Pack and Hold 1.0 sec .9 sec 1.1 sec Time Cool Time 6.0 sec 5.4 sec 6.6 sec Barrel Temp. 210 C. 205 C. 215 C. Mold Water 75 F. 65 F. 85 F. (Front/Cavities) Mold Water 75 F. 65 F. 85 F. (Back/Cores) 2nd Shot Process Minimum Maximum Parameter Value Value Value Injection Speed 10 mm/s 9 mm/s 11 mm/s Pack and Hold 700 bar 630 bar 770 bar Pressure Total Pack and 1.0 sec. 1.0 sec. 1.0 sec Hold Time Cool Time 6.0 sec. 6.0 sec. 6.0 sec. Barrel Temp. 245 C. 240 C. 250 C.

TABLE-US-00002 TABLE 2 Diaphram-M30579 Process Minimum Maximum Parameter Value Value Value Injection Time 1.26 sec. 1.13 sec. 1.39 sec. Hold Pressure 10153 psi 8122 psi 12183 psi 700 bar 560 bar 840 bar Pack and Hold 1.0 sec 1.0 sec 1.0 sec Time Cool Time 6.0 sec 6.0 sec 6.0 sec Melt Temp. 473 F. 463 F. 483 F. 245 C. 240 C. 250 C. Mold Water 110 F. 100 F. 120 F. (Front/Cavities) 43 C. 38 C. 48 C. Mold Water 110 F. 100 F. 120 F. (Back/Cores) 43 C. 38 C. 48 C. 2nd Shot Process Minimum Maximum Parameter Value Value Value Injection Time 0.12 sec. 0.108 sec. 0.132 sec. Pack and Hold 10153 psi 8122 psi 12183 psi Pressure 700 bar 560 bar 840 bar Total Pack and 1.0 sec. 1.0 sec. 1.0 sec Hold Time Cool Time 6.0 sec. 6.0 sec. 6.0 sec. Melt Temp. 410 F. 400 F. 420 F. 210 C. 205 C. 215 C.

Surface Roughness

[0141] The surface roughness of the sealing surface of each diaphragm was analysed using Bruker Contour GT white light interferometry machine at a magnification of 27.5. Three areas of were scanned on each sealing surface, i.e. those indicated by the three-pronged arrow in FIG. 13. Each scanning area was 230 m172 m. The areas were selected so as to avoid any weld line.

[0142] The results are summarised in Table 3. The results show that the test diaphragms are less rough than control diaphragms.

Weld Line Measurements

[0143] Using the Bruker Contour GT, the step height measurement mode was used to measure the depth of the weld line of the diaphragm samples and the step width measurement mode and Cross Sectioning was used to measure the width of the weld line. The location of the measurements are indicated in FIG. 13 by rectangles 4 and 5: labelled Step Height Locations. The weld line (200) is indicated. Example results are illustrated in FIGS. 11 and 12, and summarised in Table 3.

TABLE-US-00003 TABLE 3 Control Test Diaphragm Diaphragm Design Design (n = 2) (n = 2) Mean Roughness 0.162 0.095 Average (RA/m Mean Weld Line Depth/ 11 13.95 m

Force Holding Unit Performance

[0144] Otherwise identical EasiBreathe force holding units (FHUs) were assembled comprising either the control or test diaphragms mentioned above. The ability of both types of FHU to retain a pressure difference after priming was then assessed using an Instron 5564 force testing unit according to the following method. The Instron was equipped with an Instron 1 kN load cell and operated using Bluehill 2.33.895 software.

[0145] The FHU to be tested was secured in the Instron, with the Instron gripping the unit housing and the lower cap. The Instron was then used to compress the FHU until a force of 90N was achieved. Then the Instron was backed off 2.6 mm and a first, F1, force reading was recorded. The Instron was held in the same position for a period of 5 minutes, after which time a second force reading, F2, was taken.

[0146] The results are summarised in Tables 4 and 5.

TABLE-US-00004 TABLE 4 Control Diaphragm Design (n = 10) F1 (N) F2 (N) Delta F1-F2 (N) Mean 23.14 27.39 4.25 Minimum 22.72 24.34 1.48 Maximum 23.63 34.35 11.52

TABLE-US-00005 TABLE 5 Test Diaphragm Design (n = 10) F1 (N) F2 (N) Delta F1-F2 (N) Mean 21.701 22.034 0.333 Minimum 20.74 21.33 0.18 Maximum 22.2 22.42 0.59

[0147] As demonstrated, FHUs containing the test diaphragms according to the invention were able to maintain a pressure difference more effectively over the allotted time period.