WO2001097887A1

WO2001097887A1 - Delivery of bronchially provocative agents

Info

Publication number: WO2001097887A1
Application number: PCT/GB2001/002648
Authority: WO
Inventors: Philip Braithwaite; Leslie Hendeles
Original assignee: Innovata Biomed Ltd; University of Florida
Current assignee: Innovata Biomed Ltd; University of Florida
Priority date: 2000-06-19
Filing date: 2001-06-19
Publication date: 2001-12-27
Anticipated expiration: 2002-12-19
Also published as: AU2001266143A1; GB0014898D0

Abstract

There is described a method of conducting a bronchial challenge test which comprises metering and subsequently administering a provocatively effective amount of a bronchially provocative agent to a patient. There is also described a medicament delivery device which comprises a sealed medicament reservoir containing a predetermined dosage of a medicament delivery passage and means for opening the sealed reservoir.

Description

DELIVERY OF BRONCHIALLY PROVOCATIVE AGENTS

This invention relates to a novel delivery system and to a novel method of treating patients.

Methacholine, or a salt thereof, is used in the clinical diagnosis of respiratory disorders, e.g. asthma, and for the evaluation of treatment effects. Conventionally, methacholine chloride is delivered as an aqueous solution via a nebuliser or a dosimeter to a patient. The methacholine chloride causes bronchoconstriction and the concentration at which bronchoconstriction occurs reflects the degree to which the patient may be suffering from a respiratory disorder. Thus, the concentration that causes a 20% decrease in lung function (FENi) is- usually measured as the provocative concentration, or PC o or the provocative dose, PD o. For example, a healthy patient will have a high PC o or PD₂o.

In carrying out these tests, a medical practitioner will prepare a range of methacholine chloride solutions in saline, with a concentration of from 0.03 mg ml^"1 to lό mg ml^"1.

However, there are several disadvantages with the current techniques. It is time consuming for a medical practitioner to make up the necessary solutions and generally inefficient and wasteful of methacholine in that much of the solutions are discarded. More importantly, the diagnostic technique can be inaccurate, particularly when investigating severely asthmatic patients, since, inter alia, only- very low concentrations, e.g. 0.03 mg ml^"1, of methacholine chloride are required and such low concentration solutions are difficult to prepare accurately.

A further disadvantage of the conventionally used diagnostic technique is that a patient must use a "communal" nebuliser or dosimeter. We have now surprisingly found a novel system for delivering methacholine, or a salt thereof, and other bronchially provocative agents, which comprises the metering of the provocative agent in the delivery system used. Thus for example, a single concentration of solution may be used and the amount of solution delivered may be varied.

Thus, according to the invention we provide a method of conducting a bronchial challenge test which comprises metering and subsequently administering a provocatively effective amount of a bronchially provocative agent to a patient.

By the term "bronchial challenge test" it is intended to include a bronchial diagnostic test and/or evaluation of bronchial treatment effects, for example, PC₂o or PD₂o.

According to a further feature of the invention we provide a method of delivery a provocatively effective amount of a bronchially provocative agent to the lung of a patient which comprises the use of a metering inhaler.

By the term metering inhaler we mean any conventionally known inhaler which is capable of delivering combined metering and delivery of an active agent. Thus for example, the inhaler may be a metered dose inhaler, a dry powder inhaler, an insufflator or nebuliser, or any other conventionally known type of inhaler. However, a preferred inhaler is a dry powder inhaler (DPI).

By the term bronchially provocative agent we mean any conventionally known materials used in a challenge test, e.g. PC₂o or PD₂₀ tests. Such materials are well known to those skilled in the art. However, certain agents which may be mentioned include, by way of example only, methacholine, or a salt thereof, histamine, or a salt thereof, adenosine monophosphate, sodium metabisulphite and conventionally known allergens. We especially prefer methacholine, or a salt thereof. Conventionally known salts of methacholine may be used in accordance with the invention;, but the halide salts are preferred, e.g. the bromide or chloride and especially the chloride.

The bronchially provocative agent may delivered alone, however, it may be advantageous for the bronchially provocative agent to be administered in conjunction with a carrier material. Thus according to a further feature of the invention we provide a formulation suitable for administration in dry powder form which comprises an effective amount of a bronchially provocative agent in admixture with a suitable adjutant diluent or carrier. Any conventionally known adjuvant, diluent or carrier materials may be used, such materials which may be mentioned include, but are not limited to, sugars, e.g. dextran, mannitol and lactose.

The amount of the bronchially provocative agent in such an admixture may vary and may therefore range from the pure bronchially provocative agent to an admixture containing up to 0.1 % w/w of the bronchially provocative agent.

It is a particularly novel aspect of the invention to administer a bronchially provocative agent in a dry powder composition and thus this use of the bronchially provocative agent is novel per se.

Therefore, according to a yet further aspect of the invention we provide the use of a bronchially provocative agent in the manufacture of a composition as hereinbefore described. We especially provide the use of methacholine, or a salt thereof, e.g. methacholine chloride, in the manufacture of a composition as hereinbefore described.

The amount of the bronchially provocative agent administered may vary, but will generally be in the range of from 0.008 to 6.56mg, preferably from 0.008 to 4.2mg. The method and composition of the inventions is especially advantageous in that, inter alia, it provides an efficient and accurate technique for the measurement of PC₂o or PD₂o in a patient.

Conventional inhalers generally deliver a predetermined dose of medicament and are intended to be used by a patient for long periods of time e.g. up to one month. However, for use in tests such as the PC₂₀ or PD₂₀ test such inhalers would prove expensive and inappropriate. Thus, we have also developed an inexpensive, disposable inhaler which is especially suitable for use in a challenge test. However, such disposable inhalers may also have utility in delivery of conventionally known medicaments.

Thus according to a further feature of the invention we provide a medicament delivery device which comprises a sealed medicament reservoir containing a predetermined dosage of a medicament delivery passage and means for opening the sealed reservoir.

More specifically, the medicament reservoir preferentially comprises a chamber, one wall of which comprises a thin material.^" The thin material may be frangible, however it is preferred the thin material is, for example, a thin film which is bonded to the chamber and may be removed by breaking the bond, e.g. by peeling away. Thus the film may be a thin plastics material or, preferably, a thin foil such as aluminium foil. The film may be conventionally bonded to the medicament chamber, e.g. by adhesive, heat bonding or crimping. The medicament reservoir preferably is a strip comprising a plurality of medicament chambers. The number of chambers may vary, however for use in the delivery of a bronchially provocative agent, the optimum number of chambers is five since, conventionally, a patient is required to receive, for example, five doses of the bronchially provocative agent.

The delivery device is preferably an inhaler and especially a dry powder inhaler. By the term dry powder we mean an agent in finely divided form. As well as delivering the aforementioned bronchially provocative agents, a variety of medicaments may be separately administered by using the inhaler of the invention, optionally with a conventionally known pharmaceutically acceptable adjuvant, diluent or carrier. Such medicaments are generally, bronchodilators of other anti- asthma drugs and antibiotics. 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 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, fluticasone, 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.

The inhaler of the invention is especially suitable for use in conjunction with a bronchially provocative agent, e.g. in Challenge tests. However, it is also useful in the treatment or alleviation of respiratory disorders. Thus according to the invention we also provide a method of administering a dry powder inhalation medicament using an inhaler as hereinbefore described.

We further provide a method of treatment of a patient with a respiratory disorder which comprises the administration of a combination of medicaments using an inhaler as hereinbefore described. It is an especially advantageous feature of the invention to provide a prefilled inhaler in accordance with invention. We especially provide a prefilled DPI and particularly a DPI prefilled with a bronchially provocative agent, e.g. methacholine or a salt thereof.

According to yet further feature of the invention we provided a Challenge test kit which comprises a prefilled DPI as hereinbefore described. The kit may optionally include a plurality of such DPIs which may be individually wrapped and sealed. The kit may also include colour coding to signify the dosage contained in the prefilled DPI.

The invention will now be described by way of example only and with reference to the accompanying drawings in which

Figure 1 is a cut-away perspective representation of an inhaler of the invention;

Figure 2 is a perspective representation of an inhaler of the invention; and Figure 3 is a schematic representation of the use of the kit of the invention in a methacholine test.

With reference to Figures 1 and 2, an inhaler (1) is provided with a mouthpiece (2) and an operating handle (3). The inhaler (1) comprises a first end (4) and a second, mouthpiece end (12). The first end (4) is provided with a conduit (5) for receiving a cartridge ship (6) of medicament chambers (7). The cartridge strip (6) is provided with a foil seal (8) along one wall. The foil is crimped (8a) to provide a traction point. Part way along the cartridge receiving conduit (5), the inhaler (1) is provided with a lip (9) which partially protrudes into the conduit (5). The lip (9) is positioned at the open end (10) of a closed passage (11).

Towards the second end (12) of the inhaler (1), and beyond the lip (9) the conduit (5) divides into a closed cavity (13) and an airway or inhalation passage (14). Adjacent to lip (9) the inhaler (1) is provided with a foil collection drum (15) which is mounted on a rotatable axis (16). The drum (15) is provided with an operating handle (3) which itself comprises a shaft (18) attached a moveable wall portion (19) of the inhaler (1). i

Thus, by way of example only, in use, a cartridge (6) is placed in the conduit (5) and pushed up against the lip (9). The lip (9) is positioned such that it slides between the foil cover (8) and the chamber walls of the cartridge (6). When the medicament (not shown) in the first chamber is exposed, the patient inhales through the mouthpiece (12). The medicament is drawn from the chamber (7), through the inhalation passage (14) and exits the passage through the mouthpiece (12).

The patient then raises the moveable wall (19) and is able to rotate the foil collection drum (15). Once the end (8b) of the foil (8) has engaged with the drum (15), rotation of the drum (15) winds the foil (8) in, which acts to pull the cartridge (6) down the conduit (5) and exposes the medicament in the next chamber (7). The patient inhales and the process is repeated.

Referring to Figure 3, Figures 3 a) and b) illustrate an inhaler (1) and a medicament cartridge (6) respectively. The correct dosage cartridge is inserted in the conduit (Fig. 3c) and the inhaler is primed ready for use and then sealed in a foil package (Fig. 3d). The packs and/or inhalers may preferentially be colour coded (Fig. 3e) to identify the dosage of drug filled into the cartridge chambers. Similarly colour coded packs may then be placed in a holding tray (Fig. 3f). In use, a patient is provided with the relevant dosage indicated inhaler. The foil seal is broken (Fig. 3g) and the inhaler removed from the package. The patient lifts the lever (Fig. 3h) to prime the first chamber and then inhales through the mouthpiece (Fig. 3i).

Claims

1. A method of conducting a bronchial challenge test which comprises metering and subsequently administering a provocatively effective amount of a bronchially provocative agent to a patient.

2. A method of delivery a provocatively effective amount of a bronchially provocative agent to the lung of a patient which comprises the use of a metering inhaler.

3. A method according to Claim 1 characterised in that the test includes the measurement of the PC₂o or PD o of a patient.

4. A method according to either of claims 1 or 2 characterised in that the bronchially provocative agent is in dry powder form.

5. A method according to claim 4 characterised in that the inhaler is a dry powder inhaler.

6. A method according to either of claims 1 or 2 characterised in that the bronchially provocative agent is selected from one or more of methacholine, or a salt thereof, histamine, or a salt thereof, adenosine monophosphate and sodium metabisulphite.

7. A method according to claim 6 characterised in that the bronchially provocative agent is methacholine, or a salt thereof.

8. A method according to claim 7 characterised in that the bronchially provocative agent is methacholine chloride.

9. A formulation suitable for administration in dry powder form which comprises an effective amount of a bronchially provocative agent in admixture with a suitable adjuvant, diluent or carrier.

10. A formulation according to claim 9 characterised in that the amount of the bronchially provocative agent present ranges from the pure bronchially provocative agent to an admixture containing up to 0.1 % w/w of the bronchially provocative agent.

11. The use of a bronchially provocative agent in the manufacture of a formulation according to claim 9.

12. The use according to claim 11 characterised in that the bronchially provocative agent is methacholine, or a salt thereof.

13. The use according to claim 12 characterised in that the bronchially provocative agent is methacholine chloride.

14. A medicament delivery device which comprises a sealed medicament reservoir containing a predetermined dosage of a medicament delivery passage and means for opening the sealed reservoir.

15. A medicament delivery device according to claim 14 characterised in that the medicament reservoir comprises a chamber, one wall of which comprises a thin material and the medicament delivery device is provided with means for peeling the thin film from the chamber to expose the medicament.

16. A medicament delivery device according to claim 15 characterised in that the medicament reservoir preferably is a cartridge comprising a plurality of medicament chambers.

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

18. A medicament delivery device according to claim 17 characterised in that the inhaler is a dry powder inhaler. /

19. A medicament delivery device according to claim 14 characterised in that the inhaler is a prefilled inhaler.

20. A medicament delivery device according to claim 19 characterised in that the prefilled inhaler is a prefilled DPI.

21. A medicament delivery device according to claim 20 characterised in that the DPI is prefilled with a bronchially provocative agent.

22. A medicament delivery device according to claim 21 characterised in that the bronchially provocative agent is methacholine, or a salt thereof.

23. A medicament delivery device according to claim 18 characterised in that the DPI comprises a mouthpiece, a conduit adapted to receive a medicament cartridge, the conduit being provided with a lip positioned at the open end of a closed passage and which partially protrudes into the conduit, adjacent the lip, the inhaler is provided with a thin film collection drum, which drum is provided with an operating handle and is mounted on a rotatable axis, beyond the lip, the conduit being divided into a closed cavity and an inhalation passage.

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 18.

25. A Challenge test kit comprising at least one prefilled DPI according to claim 20.

26. A PC₂o test kit according to claim 25 characterised in that the prefilled DPI is sealed in a dosage coded package.

27. A method or a medicament delivery device substantially as described with reference to the accompanying drawings.