WO2002089884A1

WO2002089884A1 - Aerosol medication delivery system with breath activated means

Info

Publication number: WO2002089884A1
Application number: PCT/GB2002/002102
Authority: WO
Inventors: Philip Braithwaite
Original assignee: Innovata Biomed Limited
Priority date: 2001-05-10
Filing date: 2002-05-10
Publication date: 2002-11-14
Also published as: GB0111328D0

Abstract

There is described a medicament delivery device for delivery of an aerosolised medicament provided with an exhalation/inhalation trigger. There is also described a method of treatment which comprises the administration of a medicament using a such a medicament delivery device.

Description

AEROSOL MEDICATION DELIVERY SYSTEM WITH BREATH ACTIVATED MEANS

This invention relates to a novel inhalation device and to novel methods related thereto.

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) or a nebuliser. A particular problem encountered with inhaled medicaments delivered by a DPI is that a patient's inspiration may not be sufficient to aerosolise and inhale a medicament into a desired part of the lung. Whilst a particular problem encountered with MDIs is that a patient's inspiration may be too strong, leading to the medicament particles impacting at the back of the throat rather than reaching the upper or lower respiratory tract.

Moreover, a general problem encountered with inhalation devices is the need to coordinate the action of inhalation with the action of inhalation with the actuation of the device. Further, with, for example, a DPI it is necessary to achieve a specific flow rate prior to effective aerosolisation so as to enable the powdered medicament to reach the desired part of the lungs.

US Patent No. 5,404,871 describes apparatus for delivering an aerosolised medicine. In particular, there is described apparatus which includes a control for detecting changes in a patient's breathing pattern during inspiration to determine the optimum point for release of the medicament to the patient.

US Patent No. 5,408,994 describes an inhalation device for administration of an aerosolised medicament to the respiratory system of a patient. The inhalation device is activated by the use of an inhalation trigger. International Patent Application No. WO 01/58514 describes a drug delivery apparatus which includes a monitor which indicates whether a patient's breathing pattern is effective for inhaling drug laden air. The apparatus monitors the duty cycle of a patient on, for example, a nebuliser.

US Patent No. 6,129,080 describes an atomiser which is provided with means to prevent or stop atomisation in response to a positive pressure.

However, although a variety of inhalation activated devices are available. Existing inhalation actuated devices have not been entirely successful in overcoming the problem of timing the delivery of a medicament with the inspiration of a patient.

Such devices are usually triggered on crossing a fixed threshold inspiratory effort.

However, even though an inspiration effort sufficient to release a metered dose might be achieved, the inspiration of the patient immediately following the release of the medicament may not be sufficient to cause the medicament to pass into the desired portion of the patient's airways. A yet further problem with such devices is that with some patients whose inspiratory effort may not be sufficient to rise above the threshold to trigger the release valve at all. In addition, patients often are unable to use devices correctly and may not exhale sufficiently prior to exhalation.

Thus, in all situations, for a patient to inhale effectively, it is a pre-requisite that they should first exhale to empty the lungs sufficiently.

Therefore, there has long been a need for a delivery system which is capable of overcoming the aforementioned disadvantages.

We have now surprisingly found a novel breath actuated system, winch does not rely on the inspiration of the patient for the inhaler to be actuated and the medicament to be delivered. Thus, one object of this invention is to provide an inhalation device constructed to enable the patient to place the mouthpiece in their mouth and first exhale through the mouthpiece to, for example, an exhaust port or an exhalation channel and then, with the mouthpiece still in place, to inhale. Thus, the present invention may overcome or mitigate some of the disadvantages of prior art devices.

Thus, according to the invention we provide a medicament delivery device for delivery of an aerosolised medicament provided with an exhalation/inhalation trigger.

According to a preferred aspect of the invention we provide a medicament delivery device for delivery of an aerosolised medicament provided with a breath activated means which means is adapted to be activated at or a short time after the end of exhalation by a patient.

In a preferred embodiment of the invention, the breath activated actuation means is adapted to dispense the medicament either substantially at the point when exhalation by the patient terminates or, preferably a short time, e.g. milliseconds, after the end of exhalation, i.e. the patient has begun to inhale.

Preferably, the activation means may comprise a pair of valves, wherein a first valve is openable upon exhalation by a patient and a second valve is openable upon inhalation by a patient. Most preferably the second valve will be prevented from opening until the first valve has closed or at least partially closed. Therefore in a particularly preferred embodiment the first and second valves, which may be defined as an exhalation valve and an inhalation valve, may be operably linked. The link between the two valves may be a mechanical link, electromechanical link or an electronic link.

Although a variety of valves maybe used in the device of the invention, one example of such valves is a poppet valve, slidable within an inhalation and an exhalation channel respectively. Thus, according to the invention we provide a medicament delivery device comprising a medicament reservoir, a metering member and a medicament delivery passage wherein the delivery device is provided with an exhalation valve as hereinbefore described.

When the device of the invention is a medicament delivery device, the device may have utility in a variety of medicament delivery areas, including, for example, as an oral delivery device, e.g. an inhaler and especially a metered dose inhaler (MDI), or a dry powder inhaler (DPI). Furthermore, although oral administration is referred to, it would be well understood by the skilled man that the delivery device may be suitable for use in relation to other routes of administration, e.g. nasal administration.

Thus, according to a further feature of the invention we provide an inhaler characterised in that it incorporates an exhalation activation means as hereinbefore described.

The inhalation device of the invention may comprise any conventionally known inhalation devices, including, for example, and insufflator, a nebuliser or an inhaler, e.g. an MDI or a DPI. hi one embodiment, the inhaler is a DPI. In a further embodiment, the inhaler is an MDI.

An example of a conventional DPI is a CUCKHALER (available from Innovata Biomed in the UK and described in European Patent application No. 0 539 469) which is provided with an inhalation passage. The delivery device of the invention may optionally he attached, for example, at the outlet end of such an inhaler, to a spacer device. Alternatively, the inhaler may comprise a TECHNOHALER (available from Innovata Biomed in the UK and described in European Patent Application No. 0 626689). A variety of medicaments maybe administered by using the inhaler of the invention. By way of example only, such medicaments may generally include drugs for the treatment of asthma, COPD and/or infections, including antibiotics, bronchodilators or other anti-asthma drugs. Furthermore, such medicaments include, but are not limited to β₂-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 chorine 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, fluticasone, budesonide and flunisolide; and combinations thereof.

It is within the scope of this invention for two or more medicaments to be administered.

Specific combinations of medicaments which may be mentioned include combinations of steroids, such as, beclomethasone dipropionate, fluticasone, budesonide and flunisolide; and combinations of to β₂-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 and mediators, such as insulin, human growth hormone, leuprolide and alpha interferon; growth factors, anticoagulants, immunomodulators, cytokines and nucleic acids.

It is within the scope of this invention to include combinations of any of the aforementioned medicaments . The particle size of the medicaments maybe varied depending, inter alia, on the type of aerosol being formed. In the case of a dry powder medicament, the particle size of the powder, 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 powder may be substantially between 1 and 100 μm. That is, at least 90% w/w of the powder 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 powders a smaller particle size maybe desirable, for example from 1 to 5 μm, e.g. 3 μm.

hi 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 1 and 200 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 administering a medicament which comprises the use of a medicament delivery device as hereinbefore described.

As previously mentioned the medicament delivery device of the invention is especially suited for use as an inhaler and most especially a dry powder inhaler.

Therefore, we further provide a method of treatment of a patient with a respiratory disorder which comprises the administration of a medicament using an inhaler as hereinbefore described.

hi a preferred embodiment we provide a method of treatment of a patient with a systemic disorder which comprises the administration of a medicament using an inhaler as hereinbefore described. The medicament delivery device of the invention is especially suited for the efficient delivery of macromolecules, such as insulin. Thus, according to a particular feature of the invention we provide a method of treating insulin dependent diabetes which comprises administration of an effective amount of insulin using a medicament delivery device as hereinbefore described.

When the device of the invention is used for the delivery of moisture sensitive molecules, e.g. certain 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. However, it should be noted that a moisture resistant coating may be desirable for use in connection with other molecules, e.g. small molecules.

The inhaler of the invention is especially advantageous in that, inter alia, it ensures the lungs are sufficiently empty at the beginning of inhalation and this improves the potential for the drug to reach the lower lung.

The device of the invention may have a mechanism for active deaggregation the mechanism can be activated as early as necessary to ensure deaggregation takes place at the most efficient time in the inhalation cycle.

The invention will now be described by way of example only and with reference to the accompanying drawings, in which Figure 1 is a schematic representation of a patient exhaling into a device;

Figure 2 is a schematic representation of a patient inhaling from the device;

Figure 3 is an enlarged cross-sectional representation of the inhalation/exhalation trigger;

Figure 4 is a cross-sectional representation of the trigger in the rest position;

Figure 5 is a cross-sectional representation of the trigger during exhalation by a patient;

Figure 6 is a cross-sectional representation of the trigger at the end of exhalation, and Figure 7 is a cross-sectional representation of the trigger at the start of inhalation.

Referring to Figure 3, an inhalation/exhalation trigger (1) comprises an exhalation tube (2) and an inhalation tube (3) connected by a conduit (4).

Referring to Figure 4, the exhalation tube (2) is provided with an exhalation poppet (5) which is biased by a spring (6) to the closed position. The end (7) of the exhalation tube (2) is provided with a pair of air vents (8 and 9). The poppet (5) is provided with an annular shoulder (10) which, when in the closed position, abuts an annular rim (11) in the exhalation tube (2) to form a closed seal. The poppet (5) is biased in a direction towards the exhalation end (12) of the exhalation tube (2).

The inhalation tube (3) is provided with an inhalation poppet (13) which is biased by a spring (14) to the closed position. The inhalation end (15) of the inhalation tube (3) is provided with a pair of air vents (16 and 17). The poppet (13) is provided with an annular shoulder (18) which, when in the closed position, abuts an annular rim (19) in the inhalation tube (3) to form a closed seal. The poppet (13) is biased in a direction away from the inhalation end (12) of the inhalation tube (3).

The exhalation poppet (5) is provided with a guide rod (20), the distal end (21) of the rod (20) rests in a slide (22) housed in a slide assembly (23). The slide (22) is shaped such that it comprises a substantially triangular groove. The slide assembly (23) sits in the joining conduit (4) and is moveable (slidable) within the joining conduit.

The inhalation poppet (13) is also provided with an inhalation guide rod (26). The distal end (25) of the inhalation guide rod (26) cooperates with a latch (24) in the slide assembly (23). The latch (24) is provided at the end (29) of the slide assembly (23). Beneath the latch (24), the slide assembly (23) is also provided with a guide aperture (30). The inhalation guide rod (26) protrudes through the guide aperture (30) so as to engage with the latch (24). The slide assembly (23) is also provided with a lever (27) to allow manual override if necessary. When the inhalation/exhalation trigger is in the rest position the exhalation spring (6) and the inhalation spring (14) are both uncompressed. Therefore the exhalation poppet (5) and the inhalation poppet (13) are both in the closed position whereby the exhalation poppet (5) abuts the annular rim (11) of the exhalation tube (2) and the inhalation poppet (13) abuts the annular rim (18) of the inhalation tube (3).

Referring to Figure 5, as the patient exhales, the exhalation spring (6) is compressed and the exhalation poppet (5) is urged away from the annular rim (11) of the exhalation tube (2). Exhaled air therefore is allowed to flow through the vents (8, 9). When the exhalation spring (6) is compressed, the movement of the exhalation poppet (5) causes the end (21) of the guide rod (20) to be urged towards a first corner (28) of the triangular slide (22). The slide assembly (23) is therefore urged to slide within the conduit (4) away from the exhalation poppet (5) and towards the inhalation tube (3) and the inhalation poppet (13). This causes the inhalation guide rod (26) to begin to disengage from the latch (24) of the slide assembly (23).

Referring to Figure 6, when exhalation stops, the exhalation poppet (5) is urged by the decompression of the exhalation spring (6) to return to the closed position. The exhalation guide rod (26) is urged to a second corner (31) of the guide triangle (22) thus the slide assembly (23) is therefore urged to slide further within the conduit (4) away from the exhalation poppet (5) and towards the inhalation tube (3) and the inhalation poppet (13). As a result, the inhalation guide rod (26) is completely disengaged from the latch (24) and the inhalation guide rod (26) is free to move in the guide aperture (30). Therefore, the inhalation poppet (13) is also free to move within the inhalation tube (3) e.g. to compress the inhalation spring (14).

Referring to Figure 7, as the patient inhales the inhalation poppet (13) is urged away from the annular rim (18) of the inhalation tube (3) and the inhalation spring (14) is compressed. Inhaled air is therefore allowed to flow through the vents (16, 17).

When the inhalation spring (14) is compressed the inhalation guide rod (26) is free to slide in the guide aperture (30) and therefore the inhalation poppet (13) is able to slide in the inhalation tube (3).

The slide assembly (23) may be biased or may be provided with biasing means (not shown) which urges the slide assembly (23) back to the rest position once a cycle of exhalation and inhalation has been completed

Claims

1. A medicament delivery device for delivery of an aerosolised medicament provided with an exhalation/inhalation trigger.

2. A medicament delivery device for delivery of an aerosolised medicament provided with a breath activated actuation means characterised in that the actuation means is adapted to be activated a short time after the end of exhalation by a patient.

3. A medicament delivery device according to claim 1 characterised in that the breath activated actuation means is adapted to dispense the medicament substantially at the point when exhalation by the patient terminates.

4. A medicament delivery device according to claim 1 characterised in that the device comprises a medicament reservoir, a metering member and a medicament delivery passage wherein the delivery device is provided with an exhalation valve.

5. A medicament delivery device according to claim 1 characterised in that the activation means comprises a pair of valves.

6. A medicament delivery device according to claim 5 characterised in that a first valve is openable upon exhalation by a patient and a second valve is openable upon inhalation by a patient.

7. A medicament delivery device according to claim 6 characterised in that the second valve is prevented from opening until the first valve has closed.

8. A medicament delivery device according to claim 5 characterised in that the first and second valves are operably linked.

9. A medicament delivery device according to claim 8 characterised in that the link is a mechanical link.

10. A medicament delivery device according to claim 5 characterised in that the each of the valves are slidable within an inhalation and an exhalation channel respectively.

11. A medicament delivery device according to claim 10 characterised in that the valves are poppet valves.

12. A medicament delivery device according to claim 1 characterised in that the device is an inhaler.

13. A medicament delivery device according to claim 12 characterised in that the inhaler is a DPI.

14. A medicament delivery device according to claim 12 characterised in that the inhaler is an MDI.

15. A medicament delivery device according to claim 12 characterised in that the device is a nebuliser.

16. A medicament delivery device according to claim 1 characterised in that the medicament is suitable for the treatment of asthma, COPD and/or infections.

17. A medicament delivery device according to claim 1 characterised in that the medicament is selected from the group, antibiotics, bronchodilators, anti-asthma drugs, such as β -agonists; fenoterol, formoterol, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol and terbutaline; non-selective beta-stimulants such as isoprenaline; xanthine bronchodilators; theophylline, aminophylline and choline theophyllinate; anticholinergics such as ipratropium bromide; mast cell stabilisers, such as sodium cromoglycate and ketotifen; bronchial anti-inflammatory agents, such as nedocromil sodium; steroids, such as beclomethasone dipropionate, fluticasone, budesonide and flunisolide; and combinations thereof.

18. A medicament delivery device according to claim 1 characterised in that the combination of medicaments is selected from steroids, such as beclomethasone dipropionate, fluticasone, budesonide and flunisolide; and combinations of to β₂- agonists, such as, formoterol and salmeterol.

19. A medicament delivery device according to claim 1 characterised in that the medicament is systemically active.

20. A medicament delivery device according to claim 1 characterised in that the medicament is selected from a proteinaceous compound and/or macromolecules, such as hormones and mediators, such as insulin, human growth hormone, leuprolide and alpha interferon; growth factors, anticoagulants, inimunomoduϊators, cytokines and nucleic acids.

21. A medicament delivery device according to claim 1 characterised in that the medicament is a combination selected from a medicament of claim 17 and a medicament of claiml 8.

22. A method of measuring when an optimum inspiration level has been achieved by a patient which comprises the use of a delivery device according to claim 1.

23. A method of administering a medicament which comprises the use of a medicament delivery device according to claim 1.

24. A method of treatment of a patient with a respiratory disorder which comprises the administration of a medicament using an inhaler according to claim 5.

25. A method of treatment of a patient with a systemic disorder which comprises the administration of a medicament using an inhaler according to claim 12.

26. A medicament delivery device substantially as described with reference to the accompanying drawings.