WO2019021005A1

WO2019021005A1 - Pharmaceutical composition comprising a cannabinoid

Info

Publication number: WO2019021005A1
Application number: PCT/GB2018/052109
Authority: WO
Inventors: Stuart Corr
Original assignee: Mexichem UK Ltd; Mexichem Fluor SA de CV
Current assignee: Mexichem UK Ltd; Mexichem Fluor SA de CV
Priority date: 2017-07-28
Filing date: 2018-07-26
Publication date: 2019-01-31
Anticipated expiration: 2020-01-28
Also published as: GB201712159D0

Abstract

A pharmaceutical composition is described. The composition comprises; (i) a drug component comprising at least one cannabiooid or a pharmaceutically acceptable derivative or salt thereof; and (li) a propeliani component comprising 1,1- difiuoroethana (HFA-152a).

Description

PHARMACEUTICAL COMPOSITION COMPRISING A CANNABINOID

The present invention relates to the administration of pharmaceutical formulations comprising one or more cannabinoids. More particularly, the present invention relates to inhalable pharmaceutical formulations comprising one or more cannabinoids and a propellant comprising 1,1-difluoroethane (HFA-152a) and lo the delivery of such formulations from a medication delivery device, such as an inhaler. Cannabinoids are psychoactive compounds and are the main psychoactive component of cannabis. The medicinal properties of cannabinoids have been known for many years including their use for treating or alleviating chronic pain, seizures, arthritis, nausea, neurodegenerative diseases, such as multiple sclerosis, cancer and HIV. They may also be effective as bronchodilators in the treatment of asthma and COPD. However, alongside their potential benefits are the less desirable effects, including the psychotropic effects and the risk of diseases such as cancer if the cannabinoids are inhaled by smoking. Cannabinoids may be derived from natural sources or be synthetic or semi-synthetic in origin. A typical source of cannabinoids is the plant cannabis sativa or hemp and extracts derived therefrom such as hemp oil. Two particular cannabinoids of interest are delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD). It Is understood that the ratio of THC to CBD in any particular composition may be varied to minimise the psychotropic effects and optimise the therapeutic efficacy of the composition. It is known to deliver cannabinoids to the lung by smoking cannabis, by vaporisation techniques involving heating the cannabis to vaporise the cannabinoids which can then be inhaled and by spraying. it is also known to deliver cannabinoids using inhaler devices, including metered dose inhalers {MDIs), in which the cannabinoids are delivered using a propellant. The cannabinoid is combined with the liquefied propellant and stored in a pressurised container. The container Is then coupled to a suitable delivery device that typically includes a mouthpiece, a nozzle and a valve assembly. Actuation of the valve assembly releases a dose of the cannablnoid/propellant mixture from the container which is then dispensed from the nozzle into the mouthpiece where it can be inhaled. MDIs are a particularly well known type of inhalation drug delivery system and are well known to those skilled in the art. They are designed to deliver, on demand, a discrete and accurate amount of a drug to the respiratory tract of a patient using a liquefied propellant in which the drug is dissolved, suspended or dispersed. The design and operation of MDIs is described in many standard textbooks and in the patent literature. They all comprise a pressurised container that holds the drug formulation, a nozzle and a valve assembly that is capable of dispensing a controlled quantity of the drug through the nozzle when it is activated. The nozzle and valve assembly are typically located in a housing that is equipped with a mouth piece.

If a propellant is to function satisfactorily in an inhaler device, it needs to have a number of properties. These include an appropriate boiling point and vapour pressure so that it can be liquefied in a closed container at room temperature but develop a high enough pressure when the inhaler is activated to deliver the drug as an atomised formulation even at low ambient temperatures. Further, the propellant should be of low acute and chronic toxicity and have a high cardiac sensitisation threshold. It should have a high degree of chemical stability in contact with the drug, the container and the metallic and non-metallic components of the inhaler device, and have a low propensity to extract low molecular weight substances from any etastomeric materials in the inhaler device. The propellant should also be capable of maintaining the drug in a homogeneous solution, in a stable suspension or in a stable dispersion for a sufficient time to permit reproducible delivery of the drug in use. When the drug is in suspension in the propellant, the density of the iiquid propellant is desirably similar to that of the solid drug In order to avoid rapid sinking or floating of the drug particles in the Iiquid. Finally, the propellant should not present a significant flammability risk to the patient in use. In particular, it should form a non-flammable or low flammability mixture when mixed with air in the respiratory tract.

Dichlorodifluoromethane (R-12) possesses a suitable combination of properties and was for many years the most widely used MDI propellant, often blended with trichlorofluoromethane (R-11 ). Due to international concern that fully and partially halogenated chlorofluorocarbons (CFCs), such as dichlorodifluoromethane and trichlorofluoromethane, were damaging the earth's protective ozone layer, many countries entered into an agreement, the Montreal Protocol, stipulating that their manufacture and use should be severely restricted and eventually phased out completely. Dichlorodifluoromethane and trichlorofluoromethane were phased out for refrigeration use in the 1990's, but are still used in small quantities in the MDI sector as a result of an essential use exemption in the Montreal Protocol.

1,1,1 ,2-tetrafluoroethane (HFA-134a) was Introduced as a replacement refrigerant and MDI propellent for R-12, 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) was also introduced as a replacement propellent for dfchlorotetrafluoroethane (R-114) in the MDI sector and is sometimes used alone or blended with HFA-134a for this application.

Although HFA-134a and HFA-227ea have low ozone depletion potentials (ODPs), they have global warming potentials (GWPs), 1430 and 3220 respectively, which are now considered to be too high by some regulatory bodies, especially for dispersive uses when they are released into the atmosphere.

One industrial area that has received particular attention recently has been the automotive air-conditioning sector where the use of HFA-134a has come under regulatory control as a result of the European Mobile Air Conditioning Directive (2006/40/EC). Industry is developing a number of possible alternatives to HFA- 134a in automotive air conditioning and other applications that have a low greenhouse warming potential (GWP) as well as a low ozone depletion potential (ODP). Many of these alternatives include hydrofluoropropenes, especially the tetrafiuoropropenes, such as 2,3,3,3-tetrafluoropropene (HFO-1234yf) and 1,3,3,3- tetrafluoropropene (HFO-1234ze).

Although the proposed alternatives to HFA-134a have a low GWP, the toxtcological status of many of the components, such as certain of the fluoropropenes, is unclear and they are unlikely to be acceptable for use in the medical sector for many years, if at ail.

There is a need for an inhalable pharmaceutical composition comprising a cannabinoid which can be delivered with an inhaler device such as MDI using a propeliant having a reduced GWP in comparison with HFA-134a and HFA-227ea. According to a first aspect of the present invention, there is provided a pharmaceutical composition, e.g. a pharmaceutical suspension or a pharmaceutical solution, said composition comprising:

(i) a drug component comprising at least one cannabinoid or a pharmaceutically acceptable derivative or salt thereof; and

(ii) a propellant component comprising 1 , 1 -difluoroethane (HFA-152a).

The pharmaceutical composition of the first aspect of the invention may be delivered sublingualis but is preferably adapted for delivery to the respiratory tract and especially to the lungs. In a preferred embodiment, the pharmaceutical composition is suitable for delivery to the respiratory tract using an inhaler device, such as a metered dose inhaler (MDI).

The pharmaceutical composition typically contains less than 500 ppm of water based on the total weight of the pharmaceutical composition. In a preferred embodiment, the pharmaceutical composition contains less than 200 ppm, preferably less than 150 ppm, more preferably less than 50 ppm and particularly less than 20 ppm of water based on the total weight of the pharmaceutical composition. In referring to the water content of the pharmaceutical composition, we are referring to the content of free water in the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component. In an especially preferred embodiment, the pharmaceutical composition is water-free. Alternatively, the pharmaceutical composition of the first aspect may contain greater than 0.5 ppm of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as it can in practice be difficult to remove all the water from the composition and then retain it in such a water-free state.

Accordingly, a preferred embodiment of the first aspect of the present invention provides a pharmaceutical composition, e.g. a pharmaceutical suspension or a pharmaceutical solution, said composition comprising:

(ii) a propellant component comprising 1 ,1 -difluoroethane (HFA-152a), wherein the composition contains less than 200 ppm, preferably less than 150 ppm, more preferably less than 50 ppm and especially less than 20 ppm of water based on the total weight of the pharmaceutical composition. In a preferred embodiment, the pharmaceutical composition of the first aspect of the invention contains less than 1000 ppm, preferably less than 500 ppm, more preferably less than 100 ppm and particularly less than 50 ppm of dissolved oxygen based on the total weight of the pharmaceutical composition, in an especially preferred embodiment, the pharmaceutical composition is oxygen-free. Alternatively, the pharmaceutical composition of the first aspect may contain greater than 0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amounts discussed above, as it can in practice be difficult to retain the composition In an oxygen-free state. Accordingly, a preferred embodiment of the first aspect of the present invention provides a pharmaceutical composition, e.g. a pharmaceutical suspension or a pharmaceutical solution, said composition comprising:

(ii) a propellent component comprising 1 ,1-difluoroethane (HFA-152a),

wherein the composition contains less than 1000 ppm, preferably less than 500 ppm, more preferably less than 100 ppm and especially less than 50 ppm of oxygen based on the total weight of the pharmaceutical composition. The term "cannabinoid" as used herein encompasses naturally occurring as well as synthetic and semi-synthetic cannabinoids. Suitable naturally occurring cannabinoids Include those found in cannabis, such as the phytocannabinoids, e.g. the tetrahydrocannabinols (THC), cannabidiol (CBD) and cannabinol (CBN). Suitable synthetic cannabinoids include cannabinoids structurally related to tetrahydrocannabinol (THC), cannabimimetics and eicosanoids. More particular examples of synthetic cannabinoids for use in the present invention include nabilone, rimonabant, cannabicyclohexanol, JWB-018, JWH-073 and HU-210.

In one preferred embodiment, the drug component comprises at least one cannabinoid selected from the tetrahydrocannabinols (THC), preferably delta-9- tetrahydrocannabinol and delta-8-tetrahydrocannabinol, and cannabidiol (CBD). Preferably, the drug component consists essentially of at least one cannabinoid selected from the tetrahydrocannabinols (THC), preferably delta-9- tetrahydrocannabinol and delta-8~tetrahydrocannabinol, and cannabidiol (CBD). In one preferred embodiment, the drug component comprises or consists essentially of at least one tetrahydrocannabinol (THC). In another preferred embodiment, the drug component comprises or consists essentially of cannabidiol (CBD). In another preferred embodiment, the drug component comprises or consists essentially of at least one tetrahydrocannabinol (THC) and cannabidiol (CBD) in a THC: CBD weight ratio of between 0.4:0.6 to 0.6:0.4. In a yet another preferred embodiment, the drug component comprises or consists essentially of CBD containing less than 1% by weight of THC.

By the term "consists essentially of, we mean that at least 98 weight %, more preferably at least Θ9 weight % and especially at least 99.9 weight % of the drug component consists of the specified cannabinoid compound or compounds.

The pharmaceutical composition may be a solution, a suspension or a partial solution in which a proportion of the cannabinoid(s) is dissolved in the propellent, perhaps with the help of a co-solvent, with the remainder being undissolved and in suspension or at least capable of being placed in suspension after suitable agitation.

The amount of the drug component in the pharmaceutical composition of the first aspect of the present invention will typically be in the range of from 0.01 to 15.0 weight % based on the total weight of trie pharmaceutical composition. Preferably, the drug component will comprise from 0.01 to 10.0 weight %, more preferably from 0.05 to 5.0 weight % and especially from 0.05 to 3.0 weight % of the total weight of the pharmaceutical composition. The drug component may consist essentially of or consist entirely of the at least one cannabinoid compound, derivative or salt. By the term "consists essentially of, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drug component consists of the at least one cannabinoid compound. Alternatively, the drug component may contain other drugs. Suitable drugs for combining with the cannabinoid include corticosteroids, such as budesonide, mometasone, beclomethasone, fluticasone and the pharmaceutically acceptable derivatives thereof, such as the pharmaceutically acceptable salts and esters thereof; long acting muscarinic antagonists (LAMA), such as umeclldinlum, ipratropium, tiotropium, aclidinium as well as their pharmaceutically acceptable derivatives, such as their pharmaceutically acceptable salts, and the pharmaceutically acceptable salts of glycopyrrolate; short acting muscarinic antagonists (SAMA); long acting beta-2-agonists (LABA), auch as formoterol, arformotero), bambuterol, clenbuterol, salmeterol, indacaterol, olodaterol, vilanterol and the pharmaceutically acceptable derivatives thereof, such as the pharmaceutically acceptable salts and esters thereof; and opioids, such as morphine or methadone.

The propellent component in the pharmaceutical composition of the first aspect of the present invention comprises 1,1-difluoroethane (HFA-152a). Thus, we do not exclude the possibility that the propellant component may include other propellent compounds in addition to the HFA-152a. For example, the propellant component' may additionally comprise one or more additional hydrofluorocarbon or hydrocarbon propellant compounds, e.g. selected from HFA-227ea, HFA-134a, difluoromethane (HFA-32), propane, butane, isobutane and dimethyl ether. The preferred additional propellents are HFA-227ea and HFA-134a. If an additional propellant compound is included, such as HFA-134a or HFA-227ea, at least 5 % by weight, preferably at least 10 % by weight and more preferably at least 50 % by weight of the propellant component should be HFA-152a. Typically, the HFA-152a will constitute at least 90 weight %, e.g. from 90 to 99 weight %, of the propellant component. Preferably, the HFA-152a will constitute at least 95 weight %, e.g. from 95 to 99 weight %, and more preferably at least 99 weight % of the propellant component. in an especially preferred embodiment, the propellant component consists entirely of HFA-152a so that the pharmaceutical composition of the invention comprises HFA-152a as the sole propellant. By the term "consists entirely of" we do not, of course, exclude the presence of minor amounts, e.g. up to a few hundred parts per million, of impurities that may be present following the process that is used to make the HFA-152a providing that they do not affect the suitability of the propellant in medical applications. Preferably the HFA-152a propellant will contain no more than 10 ppm, e.g. from 0.5 to 10 ppm, more preferably no more than 5 ppm, e,g. from 1 to 5 ppm, of unsaturated impurities, such as v!nyl fluoride, vinyl chloride, vinylidene fluoride and chloro-fluoro ethylene compounds.

The amount of propeilant component in the pharmaceutical composition of the Invention will vary depending on the amounts of the drugs and other components In the pharmaceutical composition. Typically, the propeilant component will comprise from 65.0 to 99.9 weight % of the total weight of the pharmaceutical composition. Preferably, the propeilant component wilt comprise from 75.0 to 99.9 weight %, more preferably from 85.0 to 99.9 weight % and especially from 95.0 to 99.9 weight % of the total weight of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition of the first aspect of the present invention consists essentially of the two components (i) and (ii) listed above. By the term "consists essentially of, we mean that at least. 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the pharmaceutical composition consists of the two listed components. In one embodiment, the pharmaceutical composition consists entirely of the two components (i) and (il). In another embodiment, the pharmaceutical composition of the first aspect of the present invention additionally includes a co-solvent or carrier solvent, such as a monohydric or polyhydric alcohol. Suitable polyhydric alcohols include the glycols, glycol ethers and glycerol. C1.4 alkanols are preferred co-solvents, with ethanoi being especially preferred. The inclusion of a co-solvent can serve to solubilise the drug in the propeilant and/or inhibit deposition of drug particles on the surfaces of the inhaler device that are contacted by the pharmaceutical composition as It passes from the container in which it is stored to the nozzle outlet. Co-solvents can also be used to solubilise a surfactant, in the propeilant where one is used. If a co-solvent is used, it will typically be present in an amount of from 0.5 to 30 % by weight, preferably in an amount of from 0.5 to 20 % by weight, and more preferably in an amount of from 1 to 10 % by weight based on the total weight of the pharmaceutical composition. Mixtures of co-solvents may also be used.

The pharmaceutical composition of the first aspect of the present invention may also include a surfactant component comprising at least one surfactant compound. Surfactant compounds of the type that have been in use hitherto in pharmaceutical formulations for MDIs may be used in the pharmaceutical compositions of the present invention. Preferred surfactants are selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid and lecithin. By the term oleic acid, we are not necessarily referring to pure (9Z)-octadec-9-enoic acid. When sold for surfactant use in medical applications, oleic acid is typically a mixture of several fatty acids, with (9Z)-octadec-9-enoic acid being the predominant fatty acid, e.g. present in an amount of at least 65 weight % based on the total weight of the surfactant. If a surfactant component is used, it will typically be present in an amount of from 0.1 to 2.5 % by weight, preferably in an amount of from 0.2 to 1.5 % by weight based on the total weight of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition further comprises a TAS2R taste receptor agonist, which may be naturally occurring or synthetic. The use of a TAS2R taste receptor agonist induces bronchodilation resulting in a reduction in the amount of coughing as the composition is administered. Accordingly, a composition with such an agonist can be more readily tolerated by the patient. If a TAS2R taste receptor agonist is included, it may be present in an amount of from 0.001 to 0.1 weight %, preferably in an amount of from 0.005 to 0.01 weight % based on the total weight of the pharmaceutical composition. A particularly suitable TAS2R taste receptor agonist is saccharin. Mixtures of TAS2R taste receptor agonists may be used if desired. In a further embodiment, the pharmaceutical composition further comprises a flavour component to mask the taste of the cannabinoid(s). Suitable flavour compounds may be selected from peppermint oil, aniseed, chocolate, coco, menthol and vanillin. The flavour component may be present in an amount of from 0.01 to 0.1 weight %, preferably in an amount of from 0.03 to 0.1 weight % based on the total weight of the pharmaceutical composition. The flavour component may comprise a mixture of flavour compounds if desired.

The pharmaceutical compositions of the invention may also comprise one or more other additives of the type that are conventionally used in drug formulations for medication delivery devices, such as valve lubricants. Where other additives are included in the pharmaceutical compositions, they are normally used in amounts that are conventional In the art.

The pharmaceutical compositions of the invention find particular utility in the delivery of the drug component from a pressurised aerosol container, e.g. using a metered dose inhaler (MDI). For this application, the pharmaceutical compositions are contained in the pressurised aerosol container and the HFA-152a propellant functions to deliver the drug component as a fine aerosol spray. The pharmaceutical compositions of the invention are normally stored in a pressurised container or canister which is to be used in association with a medication delivery device. When so stored, the propellant component is normally in a liquid state. In a preferred embodiment, the pressurised container is designed for use in a metered dose inhaler (MDI). In a particularly preferred embodiment, the pressurised container is a coated aluminium can or an uncoated aluminium can, especially the latter.

Accordingly, a second aspect of the present invention provides a pressurised container holding the pharmaceutical composition of the first aspect of the present invention. In a third aspect, the present invention provides a medication delivery device, especially a metered dose inhaler, having a pressurised container holding the pharmaceutical composition of the first aspect of the present invention.

The metered dose inhaler typically comprises a nozzle and valve assembly that is crimped to a container holding the pharmaceutical composition to be dispensed. An elastomeric gasket is used to provide a seal between the container and the nozzle/valve assembly. Preferred elastomeric gasket materials are EPDM, chlorobutyl, bromobutyl and cyclootefin copolymer rubbers as these can exhibit good compatibility with HFA-152a and also provide a good barrier to prevent or limit HFA-152a permeating from the container.

The pharmaceutical compositions of the present invention are for use in medicine for treating a patient suffering or likely to suffer from a medical condition. Accordingly, the present invention also provides a method for treating a patient suffering or likely to suffer from a medical disorder which comprises administering to the patient a therapeutically or prophyiactically effective amount of a pharmaceutical composition as discussed above. The pharmaceutical composition is preferably delivered to the patient using a MDI. The pharmaceutical compositions of the invention can be prepared and the MDI devices filled using techniques that are standard in the art, such as pressure filling and cold filling. For example, the pharmaceutical compositions can be prepared by a simple blending operation in which the at least one cannabinoid, the HFA-152a- containing propellent and any optional ingredients are mixed together in the required proportions in a suitable mixing vessel. Mixing can be promoted by stirring as is common in the art, Conveniently, the HFA-152a-contalning propellent is liquefied to aid mixing. If the pharmaceutical composition is made in a separate mixing vessel, it can then be transferred to pressurised containers for storage, such as pressurised containers that are used as part of medication delivery devices and especially MDIs.

The pharmaceutical compositions of the invention can also be prepared within the confines of a pressurised container, such as an aerosol canister or vial, from which the compositions are ultimately released as an aerosol spray using a medication delivery device, such as a MDI. In this method, a weighed amount of the at least one cannabinoid, optionally dissolved or suspended in a co-solvent, is introduced into the open container, A valve is then crimped onto the container and the HFA- 152a-containing propeliant component, in liquid form, introduced through the valve into the container under pressure, optionally after first evacuating the container through the valve. Other components, if included, can be mixed with the drug component, or, alternatively, introduced into the container after the valve has been fitted, either alone or as a premix with the propeliant component. The whole mixture can then be treated to disperse the drugs in the propeliant component, e.g. by vigorous shaking or using an ultrasonic bath. Suitable containers may be made of plastics, metal, e.g. aluminium, or glass. Preferred containers are made of metal, especially aluminium which may be coated or uncoated. Uncoated aluminium containers are especially preferred.

Claims

Claims:

1. A pharmaceutical composition comprising:

(ii) a propellant component comprising 1 , 1 -dlfluoroethane (HFA-152a),

2. The pharmaceutical composition of claim 1 , wherein the composition contains less than 500 ppm, preferably less than 200 ppm, more preferably less than 150 ppm, still more preferably less than 50 ppm and especially less than 20 ppm of water based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition of claim 2, wherein the composition contains greater than 0.5 ppm, e.g. greater than 1 ppm, of water based on the total weight of the pharmaceutical composition.

4. The pharmaceutical composition of any one of the preceding claims, wherein the composition contains less than 1000 ppm, preferably less than 500 ppm, more preferably less than 100 ppm arid particularly less than 50 ppm of oxygen based on the total weight of the pharmaceutical composition.

5. The pharmaceutical composition of claim 4, wherein the composition contains greater than 0.5 ppm, e.g. greater than 1 ppm, of oxygen based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition of any one of the preceding claims, wherein the drug component comprises at least one cannabinoid.

7. The pharmaceutical composition of any one of the preceding claims, wherein the at least one cannabinoid is selected from the tetrahydrocannabinols

(THC), preferably delta-9-tetrahydrocannabinol and delta-8-tetrahydrocannabinol, and cannabidiol (CBD).

8. The pharmaceutical composition of claim 7, wherein the drug component comprises or consists essentially of at least one tetrahydrocannabinol (THC).

9. The pharmaceutical composition of claim 7, wherein the drug component comprises or consists essentially of cannabldlol (CBD).

10. The pharmaceutical composition of claim 7, wherein the drug component comprises or consists essentially of at least one tetrahydrocannabinol (THC) and cannabidiol (CBD) in a THC:CBD weight ratio of between 0.4:0.6 to 0.6:0.4.

11. The pharmaceutical composition of claim 7, wherein the drug component comprises or consists essentially of cannabidiol (CBD) containing less than 1% by weight of tetrahydrocannabinols (THC),

12. The pharmaceutical composition of claim 7, wherein the drug component consists essentially of at least one cannabinoid selected from the tetrahydrocannabinols (THC), preferably delta-9-tetrahydrocannabinol and delta-8- tetrahydrocannabinol, and cannabidiol (CBD).

13. The pharmaceutical composition of any one of claims 1 to 11, wherein the drug component additionally contains at least one non-cannabinoid drug compound.

14. The pharmaceutical composition of claim 13, wherein the at least one non- cannabinoid drug compound comprises at least one corticosteroid, preferably at least, one corticosteroid selected from the group consisting of budesonide, mometasone, beclomethasone, fluticasone and the pharmaceutically acceptable derivatives thereof, such as the pharmaceutically acceptable salts and esters thereof.

15. The pharmaceutical composition of claim 13 or 14, wherein the at least one non-cannabinoid drug compound comprises at least one long acting muscarinic antagonist (LAMA), preferably at least one long acting muscarinic antagonist (LAMA) selected from the group consisting of umeclidinium, Ipratropium, tlotropium, aclidinium and the pharmaceutically acceptable derivatives thereof, such as the pharmaceutically acceptable salts thereof, and the pharmaceutically acceptable salts of glycopyrrotate.

16. The pharmaceutical composition of any one of claims 13 to 15, wherein the at least one non-cannabinoid drug compound comprises at least one short acting muscarinic antagonist (SAMA).

17. The pharmaceutical composition of any one of claims 13 to 16, wherein the at least one non-cannabinoid drug compound comprises at least one long acting beta-2-agoniet (LABA), preferably at least one long acting beta-2-agonist (LABA) selected from the group consisting of formoterol, arformoterol, bambuterol, clenbuterol, salmeterol, indacaterol, oiodaterol, vilanterol and the pharmaceutically acceptable derivatives thereof, such as the pharmaceutically acceptable salts and esters thereof.

18. The pharmaceutical composition of any one of claims 13 to 17, wherein the at least one non-cannabinoid drug compound comprises at least one opioid, such as morphine or methadone,

19. The pharmaceutical composition of any one of the preceding claims, wherein the drug component comprises from 0.01 to 15,0 weight %, preferably from 0.01 to 10.0 weight %, more preferably from 0.05 to 5.0 weight % and especially from 0.05 to 3.0 weight % of the total weight of the pharmaceutical composition.

20. The pharmaceutical composition of any one of the preceding claims, wherein the propellent component comprises from 65.0 to 99.9 weight %, preferably from 75.0 to 99.9 weight %, more preferably from 85,0 to 99.9 weight % and especially from 95.0 to 99.9 weight % of the total weight of the pharmaceutical composition.

21. The pharmaceutical composition of any one of the preceding claims, wherein at least 90 weight %, preferably at least 95 weight % and more preferably at (east 99 weight % of the propellant component is 1 , 1 -difluoroethane (HFA-152a).

22. The pharmaceutical composition of any one of claims 1 to 20, wherein the propellant component is entirely 1,1 -difluoroethane (HFA-152a).

23. The pharmaceutical composition of claim 21 or 22, wherein the propellent component contains from 0.5 to 10 ppm, e.g. from 1 to 5 ppm, of unsaturated impurities.

24. The pharmaceutical composition of any one of the preceding claims, wherein at least 95 weight %, preferably at least 98 weight % and more preferably at. least 99 weight % of the composition consists of the two components (i) and (ii).

25. The pharmaceutical composition of any one of the preceding claims further comprising a co-solvent.

26. The pharmaceutical composition of claim 25, wherein the co-solvent comprises ethanol and/or glycerol.

27. The pharmaceutical composition of any one of the preceding claims further comprising a surfactant component comprising one or more surfactant compounds.

28. The pharmaceutical composition of any one of the preceding claims further comprising at least one TAS2R taste receptor agonist.

29. The pharmaceutical composition of any one of the preceding claims further comprising a flavour component comprising at least one favour compound.

30. The pharmaceutical composition of any one of claims 1 to 23 which consists entirely of the two components (i) and (ii).

31. The pharmaceutical composition of any one of the preceding claims in the form of a suspension.

32. The pharmaceutical composition of any one of claims 1 to 30 in the form of a solution.

33. The pharmaceutical composition of any one of claims 1 to 30 in the form of a partial solution.

34. A. sealed container that contains a pharmaceutical composition as claimed in any one of claims 1 to 33.

35. The sealed container of claim 34 which Is an uncoated aluminium can.

36. The sealed container of claim 34 or claim 35 which Is a pressurized aerosol container for use with an inhaler, such as a metered dose inhaler (MDI).

37. An Inhaler fitted with a sealed container as claimed in claim 36.

38. A metered dose inhaler (MDI) fitted with a sealed container as claimed in claim 36.

39. The inhaler of claim 37 or metered dose inhaler of claim 38 which comprises a nozzle and valve assembly attached to the pressurized aerosol container and a gasket made from an elastomeric material selected from EPDM, chlorobutyl, bromobutyl and cycloolefin copolymer rubbers to provide a seal between the container and the nozzle/valve assembly.

40, A method for treating a patient suffering or likely to suffer from a medical disorder which comprises administering to the patient a therapeutically or prophylactically effective amount of a pharmaceutical composition as claimed in any one of claims 1 to 33.

41. The method of claim 40, wherein the pharmaceutical composition is delivered to the patient using an inhaler.

42. The method of claim 40, wherein the pharmaceutical composition is delivered to the patient using a metered dose inhaler.