WO2002011894A1

WO2002011894A1 - Diaphragm

Info

Publication number: WO2002011894A1
Application number: PCT/GB2001/003578
Authority: WO
Inventors: Philip Braithwaite
Original assignee: Innovata Biomed Ltd
Current assignee: Innovata Biomed Ltd
Priority date: 2000-08-09
Filing date: 2001-08-09
Publication date: 2002-02-14
Anticipated expiration: 2003-02-09
Also published as: AU2001284156A1; GB0019429D0

Abstract

There is described a method of producing an aerosol which comprises placing a dispersible (9) material adjacent a surface (10) of a resiliently flexible diaphragm valve member (3) and causing the valve member to flex and disperse the material. There is also described an aerosol delivery device comprising a resiliently deformable, concave shaped member with its perimeter sealed across a discharge orifice so that it is inwardly concave in the closed position, the concave portion including at least one slit (5) extending through the thickness of the valve.

Description

Diaphragm

This invention relates to a novel method of producing an aerosol, to novel devices utilising such a method, e.g. using a flexible valve and to methods of treatment related thereto.

European Patent Application No. 0 160 336 describes a flexible container e.g. a shower gel container including a self-sealing dispensing valve. Generally, the valve comprises a flexible resilient diaphragm with at least one slot. This valve is closed until pressure is applied to the flexible container which causes the valve to take up a convex shape and the slit opens. The self-sealing valve described in the prior art is known to be used in, for example, containers for storage and dispensing of gels and/or viscous liquids since the resilient valve member will close when pressure is removed from the walls of the dispensing container. Such a valve is ideally suited for dispensing devices which are inverted in use.

However, we have considerably extended the use of such valves. Not only have we found that they may be used with solid materials, such as powders, but upon opening of the valve, the ingress of air through the open valve is an aid to the dispersion of such solid materials.

In particular, we have found that the valve of the prior art is especially advantageous in that it allows a mixture of air and powder, e.g. an aerosolised powder, to be ejected from a medicament delivery device. Thus, we have now surprisingly found that such a valve is especially suitable for use in generating an aerosol and especially a powder/air aerosol. Therefore, such a valve especially finds utility in an inhaler e.g. a dry powder inhaler (DPI) and may be suited to the delivery of a medicament into, for example, a holding chamber.

Furthermore, it is well established that asthma and other respiratory diseases can be treated with medicaments administered by inhalation. Such medicaments may be administered in the form of a dry powder with the use of a dry powder inhaler (DPI) or in the form of a solution or suspension with the use of a pressurised metered dose inhaler (MDI). A particular problem encountered with MDI's is that considerable coordination is required for the patient to actuate the pressurised aerosol, thus dispensing the medicament, and inhaling at the correct moment. The problem is exacerbated by the fact that many patients being administered such medicaments are often children or the elderly.

Furthermore, it is common practice to use a holding chamber, such that an aerosolised medicament is dispensed from an inhaler and the medicament is momentarily held in the chamber before the patient inhales. One disadvantage of such holding chambers is that, due to, ter alia, electrostatic charges, agglomeration of the aerosolised particles may occur and/or particles may be attached to the surfaces of the chamber.

Thus according to the invention we provide a method of producing an aerosol which comprises placing a dispersible material adjacent the surface of a resiliently flexible diaphragm valve member and causing the valve member to flex and disperse the material.

In the method of the invention the resiliently flexible diaphragm valve member is preferentially a valve such as described in EP 0 160 336. Thus the preferred valve comprises a resiliently deformable, concave shaped portion with its perimeter optionally sealingly secured across a discharge orifice. The valve, which will generally be self-sealing, may be secured across the orifice so that it is in a closed position. The valve may be placed in an arrangement whereby it is inwardly concave or, alternatively, it may be outwardly concave when in the closed position. The concave shaped portion of the valve may include at least one substantially linear slit extending through the thickness of the wall that comprises the concave portion of the valve. The valve requires the attainment of a threshold opening pressure to effect inversion from the concave, at rest, position in order to dispense the material. When opened, the valve will generally move to a convex arrangement, thus the valve may present an outwardly facing convex surface or an inwardly facing convex surface when open.

The circumferential wall of the valve member may be provided with a plurality of circumferential spaced apart pimples on the inside surface of the wall. The pimples are especially advantageous in the embodiment in which the valve is in an inwardly concave position at rest and an inwardly convex position when open. Thus, when the valve is urged to an open position, the pimples may react against distortion of the side wall and therefore urge the valve back to a closed position. Thus a pressure differential is essential to reopen the valve member of the invention.

The valve used in the method of the invention has utility in a variety of areas, and is particularly suited for the generation of aerosols, e.g. powder aerosols, including, for. example, medicament delivery devices, such as inhalers, air fresheners or any other devices which rely upon an aerosol generation and especially a powder aerosol. The valve and/or the method of the present invention are especially suited to use in conjunction with an inhaler, including an MDI, a DPI, an insufflator and a nebuliser. Thus, by the term inhaler used herein, it is intended to mean any of the aforementioned devices. In a preferred embodiment, the inhaler of the invention comprises a DPI.

By the term dispersible material, we particularly include a material which is aerosolisable e.g. an aerosolisable powder. The dispersible material may be positioned on or near the surface of the diaphragm valve member and the term adjacent should be construed accordingly.

Although the valve used herein is not novel per se, the use of a valve in aerosol generation is new and therefore any aerosol delivery device including such a valve is novel. Thus, according to a further feature of the invention we provide an aerosol delivery device comprising a material reservoir, a metering member and a material outlet characterised in that the delivery device is provided with a valve as hereinbefore described.

More particularly, the aerosol delivery device is provided with a resiliently flexible diaphragm valve member comprising a resiliently deformable, concave shaped member with its perimeter sealed across a discharge orifice so that it is inwardly concave in the closed position, the concave portion including at least one slit extending through the thickness of the concave portion of the valve.

According to a yet further feature of the invention aerosol delivery device is a medicament delivery device which comprises a medicament reservoir, a metering member and a medicament outlet characterised in that the delivery device is provided with a valve as hereinbefore described.

The medicament reservoir may be a bulk reservoir, in which a separate metering mechanism is provided. Such an arrangement is described in International Patent application No. WO 92/00771, which is incorporated herein by reference. Alternatively, if the medicament reservoir comprises unit dosage means, then the medicament reservoir and metering member, e.g. a metering mechanism, may comprise a single unit. Such an arrangement is described in European Patent No. 0 664 239, which is also incorporated herein by reference.

In an especially preferred embodiment of the invention the medicament delivery device is an inhaler.

In a preferred embodiment the valve is positioned adjacent to the metering mechanism. Thus, in use, a predetermined amount of medicament is dispensed adjacent to a non-dispensing surface of the diaphragm valve member when the metering mechanism is actuated. The diaphragm valve member is then flexed by a change in pressure experienced by the diaphragm valve. The pressure may be introduced by an increase in pressure on the non-dispensing surface of the valve member or, alternatively, by a decrease in pressure on the dispensing surface of the concave valve member, e.g. when a patient inhales. Upon flexing of the diaphragm the medicament is ejected through the outlet of the inhaler. In addition when the diaphragm is flexed the valve member opens, allowing air to flow through the valve towards the outlet and mixing with the medicament. Thus, the process of aerosolisation may occur by the mechanical flexing of the diaphragm or the influx of air allowed through the open valve. Alternatively the process of aerosolisation may comprise a combination of the aforementioned steps.

The valve may be mechanically or electromechanically flexed. However, in an alternative embodiment the diaphragm may be flexed manually, for example, by the use of a flexible portion of the inhaler. The pressure may be introduced by an increase in pressure on the non-dispensing surface of the valve member or, alternatively, by a decrease in pressure on the dispensing surface of the concave valve member, e.g. when a patient inhales.

The actuation of the metering mechanism and the flexing of the valve may occur separately, sequentially or together.

In the most preferred embodiment the inhaler of the invention may be provided with a holding chamber. This may be a holding chamber which is conventionally know per se. Alternatively it may be an electrically charged holding chamber such as is described by our co-pending International application No. PCT/GBO 1/01993.

In addition, the inhaler of the invention may optionally include a conventionally known breath actuated mechanism. The valve mechanism may comprise a membrane with a single aperture or a plurality of apertures. The preferred valve mechanism is such as that described in European Patent Application No. 0 160 336, which is incorporated herein by reference.

Therefore in a further embodiment of the invention we provide an inhaler system comprising an inhaler in conjunction with a chamber as hereinbefore described. The inhaler and chamber of the invention may be provided separately, together or as a kit of parts. We especially provide a dry powder inhaler as hereinbefore described.

The particle size of the medicament may be varied depending, ter alia, on the type of aerosol being formed. In the case of a dry powder medicament, the particle size of the medicament, and the carrier, if one is present, may be varied. The nature of the carrier may also be varied. Thus, the particle size of the medicament may be substantially between 1 and 100 μm. That is, at least 90% w/w of the medicament should have a particle size of between 1 and 100 μm. The preferred particle size may also depend upon the nature of the medicament being delivered. Thus, for example, for the treatment of respiratory disorders a particle size of 4 to 8 μm may be preferred, e.g. 6 μm. However, for the delivery of systematically active medicaments a smaller particle size may be desirable, for example from 1 to 5 μm, e.g. 3 μm.

In a dry powder formulation a variety of carriers may be used. Certain carriers may be mentioned, by way of example only, such as sugars, e.g. dextran, mannitol and lactose, for example α-lactose monohydrate. The particle size of the carrier may be across a wide range, between 0.1 and 500μm, preferably between 50 and 500 μm, more preferably between 50 and 400 μm. Alternatively, the carrier may itself comprise a mixture of fine and coarse particles.

According to a further feature of the invention we provide a method of drug delivery to a patient which comprises administering a medicament to a patient suffering a respiratory disorder which comprises administering a therapeutically effective amount of a medicament using an inhaler as hereinbefore described. We further provide the use of a flexible diaphragm valve in the manufacture of an inhaler as hereinbefore described. We especially provide the use of a valve as described in EP 0 160 336.

Many different materials may be used as the diaphragm valve member. The material may vary depending upon the nature of the material intended to pass through the valve. Most importantly it should be a flexible, resilient and/or elastomeric. The material may preferentially be non-porous. More particularly when the valve mechanism is used such it is actuated by a gas pressure differential, as in a breath actuated MDI, then the membrane material should be non-gas permeable. Thus, plastics materials are well suited for use as the valve member material, an elastomer such as silicone rubber being one example of such a plastics material. Other examples include, but are not limited to, polyvinyl chloride, urethane, ethylene vinyl acetate and styrene butadiene copolymer.

The inhaler of the invention is advantageous in that, ter alia, it enables the delivery of dispersions of finely divided forms of medicament and avoids some if the disadvantageous of agglomeration experienced with some known DPIs. Furthermore, conventionally known DPIs operate as passive systems, i.e. they generally act independently of a patient's inspiratory flow rate. However, the inhalers of the present invention provide an active system which is dependent on inspiratory flow rate.

A variety of medicaments may be administered by using the inhaler of the invention, such medicaments may have a systemic or non-systemic activity on the patient. Such medicaments are generally (but not limiting) antibiotics, bronchodilators or other anti-asthma drugs. Such medicaments include, but are not limited to ^β ₂-agonists, e.g. fenoterol, formoterol, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol and terbutaline; non-selective beta-stimulants such as isoprenaline; xanthine bronchodilators, e.g. theophylline, aminophylline and choline theophyllinate; anticholinergics, e.g. ipratropium bromide; mast cell stabilisers, e.g. sodium cromoglycate and ketotifen; bronchial anti-inflammatory agents, e.g. nedocromil sodium; and steroids, e.g. beclomethasone dipropionate, fmticasone, budesonide and flunisolide; and combinations thereof.

Specific combinations of medicaments which may be mentioned include combinations of steroids, such as, beclomethasone dipropionate, fluticasone, budesonide and flunisolide; and combinations of to β -agonists, such as, formoterol and salmeterol. It is also within the scope of this invention to include combinations of one or more of the aforementioned steroids with one or more of the aforementioned β₂-agonists.

Further medicaments which may be mentioned include systemically active materials, such as, proteinaceous compounds and or macromolecules, for example, hormones, such as insulin, human growth hormone, leuprolide and alpha interferon; growth factors, anticoagulants, immunomodulators, cytokines and nucleic acids.

It is within the scope of the invention to include combinations of any of the aforementioned medicaments.

When the device of the invention is used for the delivery of macromolecules, such as insulin, it is important that they be provided in a moisture resistant system. Thus, according to the invention we provide a device as hereinbefore described provided with a moisture resistant coating e.g. a paraxylylene coating.

The invention will now be described by way of example only and with reference to the accompanying drawings, in which Figure 1 is a perspective drawing of a valve of the invention in the closed position;

Figure 2 is a cross-sectional view of a valve of the invention in the closed position; Figure 3 is a perspective drawing of a valve of the invention in the open position;

Figure 4 is a cross-sectional view of a valve of the invention in the open position; Figure 5 is a cross-sectional view of a valve of the invention in the closed position with a powdered medicament in place;

Figure 6 is a cross-sectional view of a valve of the invention in the open position with medicament being discharged;

Figure 7 is a cross-sectional view of an inverted valve of the invention in the closed position with a powdered medicament in place;

Figure 8 is a cross-sectional view of an inverted valve of the invention in the open position with medicament being discharged;

Figures 9a and 9b are perspective views of a valve of the invention illustrating the pimples on the valve; and Figure 10 is a schematic representation of an inhaler comprising a valve of the invention.

With reference to Figures 1 and 2, a diaphragm valve (1) comprises a circular peripheral flange (2) surrounding a concave valve member (3). The flange is connected to an annular portion (4). The concave valve member (3) comprises a flexible material and is provided with a slit (5) or a pair of slits in its body. The version illustrated shows a pair of slits in the form of a cross, although it will be appreciated that a variety of slit arrangements may be suitable for the invention to perform satisfactorily. The concave valve member (3) is provided with a dispensing surface (6) and a non-dispensing surface (7). Generally the dispensing surface (6) is the upper surface and the non-dispensing surface (7) is the lower surface.

Referring to figures 3 and 4, when the valve (1) is actuated pressure is applied either directly or indirectly to the non-dispensing surface (7) of the valve member (3). This causes the concave valve member (3) to flex and take up a concave form. The slit (5) opens to create an aperture (8). Referring to figures 5 and 6, a powdered medicament (9) is dispensed onto the dispensing surface (6) of the concave valve member (3). Pressure is applied to the non-dispensing surface (7) of the valve member (3) causing the slit (5) to open to form aperture (8). The pressure may be introduced by an increase in pressure on the non-dispensing surface (7) of the valve member (3) or, alternatively, by a decrease in pressure on the dispensing surface (6) of the concave valve member (3), e.g. when a patient inhales. The flexing on the valve member (3) itself can cause the medicament (9) to be dispersed, alternatively, as the slit (5) opens to form an aperture (8) air is allow through the aperture (8) and the rush of air facilitates dispersion of the medicament (9). The dispersion of the aerosolised powder may utilise a combination of the flexing of the valve member and the rush of air through the aperture.

With reference to Figures 7 and 8, a powdered medicament (9) is dispensed onto a concave dispensing surface (10) of the valve member (3). Pressure is applied to the non-dispensing surface (11) of the valve member (3) causing the slit (5) to open to form aperture (8).

Referring to Figures 9a and 9b, the valve member of the invention is provided with a plurality of circumferential spaced apart pimples (12) on the inside surface (13) of the wall (4) of the valve member (3). The pimples (12) are especially advantageous in the embodiment of Figures 7 and 8. When the valve is urged to an open position, the pimples (12) react against distortion of the side wall and therefore urge the valve back to a closed position. Thus a pressure differential is essential to reopen the valve member of the invention.

Referring to Figure 10, an inhaler (14) comprises an inhalation passage (15) which comprises at one end (16) a piston (17) adjacent to a valve member (18). Downstream (in the direction of the arrow) of the valve member (18) is a medicament dispenser (19) in the form of a spool, e.g. as described in European Patent Application No. 0 626 689, in a spool cavity (20) and further downstream, the inhalation passage is provided with an outlet (21). In use, a medicament containing spool (19) is brought into coincidence with the inhalation passage (15) and medicament is dispensed into the passage (15). The piston (17) is urged towards the valve (18), which is caused by the pressure differential to flex to an open position. The medicament is therefore aerosolised and exits at an outlet (21).

Claims

1. A method of producing an aerosol which comprises placing a dispersible material adjacent a surface of a resiliently flexible diaphragm valve member and causing the valve member to flex and disperse the material.

2. A method according to claim 1 characterised in that the resiliently flexible diaphragm valve member comprises a resiliently deformable, concave shaped member in the closed position with its perimeter sealed across a discharge orifice, the concave portion including at least one slit extending through the thickness of the concave portion.

3. A method according to claim 1 in that the dispersible material is a solid material.

4. A method according to claim 3 characterised in that the solid material is a dry powder.

5. An aerosol delivery device comprising a material reservoir, a metering member and a material outlet characterised in that the delivery device is provided with a resiliently flexible diaphragm valve member wherein the device is operated by means which causes the valve member to flex to disperse the material.

6. An aerosol delivery device according to claim 5 characterised in that the valve member comprises a resiliently deformable, concave shaped member with its perimeter sealed across a discharge orifice so that it is inwardly concave in the closed position, the concave portion including at least one slit extending through the thickness of the concave portion.

7. An aerosol delivery device according to claim 5 characterised in that the material is a medicament.

8. An aerosol delivery device according to claim 5 characterised in that the device is an inhaler.

9. An aerosol delivery device according to claim 8 characterised in that the inhaler is selected from an MDI, a DPI, an insufflator and a nebuliser.

10. An aerosol delivery device according to claim 9 characterised in that the inhaler is a dry powder inhaler (DPI).

11. An aerosol delivery device according to claim 5 characterised in that the diaphragm is positioned adjacent to the metering mechanism.

12. An aerosol delivery device according to claim 5 characterised in that the diaphragm is electromechanically flexed.

13. An aerosol delivery device according to claim 5 characterised in that the actuation of the metering mechanism and the flexing of the valve may occur separately, sequentially or together.

14. An aerosol delivery device according to claim 8 characterised in that the inhaler is provided with a holding chamber.

15. An aerosol delivery device according to claim 14 characterised in that the holding chamber is an electrically charged holding chamber.

16. An aerosol delivery device according to claim 15 characterised in that the holding chamber is one described in co-pending International applications No. PCT/GB01/01993.

17. An aerosol delivery device according to claim 8 characterised in that the inhaler includes a breath actuated mechanism.

18. An aerosol delivery device according to claim 8 characterised in that the inhaler is a DPI.

19. An aerosol delivery device according to claim 6 characterised in that the diaphragm comprises a membrane with a single aperture or a plurality of apertures.

20. An aerosol delivery device according to claim 6 characterised in that the diaphragm comprises a valve mechanism as described in European Patent Application No. 0 160 336.

21. A kit comprising an aerosol delivery device according to claim 8 in conjunction with at least a holding chamber.

22. An aerosol delivery device according to claim 9 characterised in that the particle size of the medicament is substantially between 1 and 100 μm.

23. A method of delivering a medicament to a patient which comprises administering a therapeutically effective amount of a medicament using an aerosol delivery device according to claim 7.

24. A method of treating a patient with a respiratory disorder which comprises administering a therapeutically effective amount of a medicament using an aerosol delivery device according to claim 7.

25. The use of a flexible diaphragm valve in the manufacture of an aerosol delivery device according to claim 5.

26. The use according to claim 25 characterised in that the diaphragm valve is one described in European Patent Application No. 0 160 336.

27. A method or an aerosol delivery device substantially as described with reference to the accompanying examples and drawings.