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Title:
PHARMACEUTICAL COMPOSITIONS COMPRISING 1,1-DIFLUOROETHANE AND A CANNABINOID
Document Type and Number:
WIPO Patent Application WO/2021/032990
Kind Code:
A1
Abstract:
A method of improving the stability of a pharmaceutical composition comprising (i) a propellant component and (ii) a drug component comprising at least one cannabinoid which is dissolved or suspended in the propellant is described. The method comprises using a propellant component comprising 1,1-difluoroethane (R- 152a).

Inventors:
CORR STUART (GB)
Application Number:
PCT/GB2020/052006
Publication Date:
February 25, 2021
Filing Date:
August 20, 2020
Export Citation:
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Assignee:
MEXICHEM FLUOR SA DE CV (MX)
MEXICHEM UK LTD (GB)
International Classes:
A61K9/00; A61K47/06
Domestic Patent References:
WO2018051130A12018-03-22
WO2019021005A12019-01-31
Attorney, Agent or Firm:
DEE, Ian Mark (GB)
Download PDF:
Claims:
Claims:

1. A method of improving the stability of a pharmaceutical composition comprising (i) a propellant component and (ii) a drug component comprising at least one cannabinoid which is dissolved or suspended in the propellant, said method comprising using a propellant component comprising 1 ,1-difluoroethane (R-152a).

2. The method of claim 1 further comprising selecting the components and conditions for the preparation of the pharmaceutical composition to maintain the water content of the pharmaceutical composition below 500 ppm, preferably below 200 ppm, more preferably below 150 ppm, still more preferably below 50 ppm and especially below 20 ppm based on the total weight of the pharmaceutical composition.

3. The method of claim 1 or claim 2, wherein the oxygen content of the resulting pharmaceutical composition is below 1000 ppm, preferably below 500 ppm, more preferably below 100 ppm and particularly below 50 ppm based on the total weight of the pharmaceutical composition.

4. The method of any one of the preceding claims, wherein the drug component comprises at least one cannabinoid.

5. The method of claim 4, wherein the drug component comprises at least one cannabinoid selected from the tetrahydrocannabinols (THC), preferably delta-9- tetrahydrocannabinol and delta-8-tetrahydrocannabinol.

6. The method of claim 5, wherein the drug component consists essentially of at least one cannabinoid selected from the tetrahydrocannabinols (THC), preferably delta-9-tetrahydrocannabinol and delta-8-tetrahydrocannabinol.

7. The method of any one of claims 1 to 5, wherein the drug component additionally contains at least one non-cannabinoid drug compound.

8. The method 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.

9. The method of any one of the preceding claims, wherein the propellant 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.

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

11. The method of claim 10, wherein the propellant component contains from 0.5 to 10 ppm, e.g. from 1 to 5 ppm, of unsaturated impurities.

12. The method of any one of the preceding claims, wherein the pharmaceutical composition further comprises a surfactant component comprising one or more surfactant compounds.

13. The method of any one of the preceding claims, wherein the pharmaceutical composition further comprises a co-solvent.

14. The method of claim 13, wherein the co-solvent comprises ethanol.

15. The method of claim 13, wherein the co-solvent is ethanol.

16. The method of any one of claims 1 to 11, wherein the pharmaceutical composition consists entirely of the two components (i) and (ii).

17. The method of any one of the preceding claims, wherein the pharmaceutical composition is in the form of a suspension, a solution or a partial solution.

18. The method of any one of the preceding claims, wherein the pharmaceutical composition is stabilised compared to a pharmaceutical composition that uses 1 ,1 ,1,2-tetrafluoroethane (HFA-134a) and/or 1 ,1 ,1,2,3,3,3-heptafluoropropane (HFA-227ea) as the predominant or sole propellant but which is otherwise identical.

19. The method of any one of the preceding claims, wherein the resulting pharmaceutical composition immediately after preparation contains no detectable impurities from the degradation of the at least one cannabinoid.

20. The method of claim 14 or 15, wherein the resulting pharmaceutical composition immediately after preparation contains no detectable impurities from the degradation of the at least one cannabinoid for amounts of ethanol up to 5 % by weight based on the total weight of the pharmaceutical composition.

21. The method of claim 14 or 15, wherein the resulting pharmaceutical composition immediately after preparation contains less than 0.5 % of impurities from the degradation of the at least one cannabinoid based on the total weight of the at least one cannabinoid and the impurities for amounts of ethanol up to 10 % by weight based on the total weight of the pharmaceutical composition.

Description:
PHARMACEUTICAL COMPOSITIONS COMPRISING 1,1-DIFLUOROETHANE

AND A CANNABINOID

The present invention relates to pharmaceutical formulations comprising one or more cannabinoids. More particularly, the present invention relates to a method of stabilising pharmaceutical formulations comprising one or more cannabinoids and a propellant and to inhalable pharmaceutical formulations comprising the one or more cannabinoids and the propellant.

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 cannabinoid/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 that 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.

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 elastomeric 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 liquid propellant is desirably similar to that of the solid drug in order to avoid rapid sinking or floating of the drug particles in the liquid. 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 propellant for R-12. 1,1 ,1 ,2,3,3,3-heptafluoropropane (HFA-227ea) was also introduced as a replacement propellant for dichlorotetrafluoroethane (R-114) in the MDI sector and is sometimes used alone or blended with HFA-134a for this application.

Although FIFA-134a and FIFA-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 FIFA-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 FIFA- 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 tetrafluoropropenes, such as 2,3,3,3-tetrafluoropropene (FIFO-1234yf) and 1 ,3,3,3- tetrafluoropropene (FIFO-1234ze).

Although the proposed alternatives to FIFA-134a have a low GWP, the toxicological 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 all.

There is a need for an inhalable pharmaceutical composition comprising a cannabinoid which has improved stability.

It has been found that the use of propellants comprising 1 ,1-difluoroethane (FIFA- 152a) in pharmaceutical compositions containing a cannabinoid compound, such as a tetrahydrocannabinol (THC), can unexpectedly improve the chemical stability of the cannabinoid compound compared to the stability it exhibits in formulations containing the known hydrofluoroalkane propellants 1,1,1 ,2-tetrafluoroethane (FIFA-134a) and 1,1 ,1,2,3,3,3-heptafluoropropane (HFA-227ea) Accordingly, the present invention provides a method of improving the stability of a pharmaceutical composition comprising (i) a propellant component and (ii) a drug component comprising at least one cannabinoid which is dissolved or suspended in the propellant, said method comprising using a propellant component comprising 1,1-difluoroethane (R-152a).

By improving the stability, we mean that the pharmaceutical composition comprising the at least one cannabinoid compound and propellant component comprising 1,1-difluoroethane (R-152a) is stabilised compared to a pharmaceutical composition that uses 1,1 ,1 ,2-tetrafluoroethane (HFA-134a) and/or 1 , 1,1, 2, 3,3,3- heptafluoropropane (HFA-227ea) as the predominant or sole propellant but which is otherwise identical.

The pharmaceutical composition that is prepared in accordance with the method of the invention may be delivered sublingually, but is preferably adapted for delivery to the respiratory tract and especially to the lungs. Preferably, the pharmaceutical composition is suitable for delivery to the respiratory tract using an inhaler device, such as a metered dose inhaler (MDI).

In one preferred stabilisation method, the pharmaceutical composition immediately after preparation contains no detectable impurities from the degradation of the at least one cannabinoid.

In another preferred stabilisation method, the pharmaceutical composition contains ethanol and immediately after preparation contains no detectable impurities from the degradation of the at least one cannabinoid for amounts of ethanol up to 5 % by weight based on the total weight of the pharmaceutical composition.

In yet another preferred stabilisation method, the pharmaceutical composition contains ethanol and immediately after preparation contains less than 0.5 % of impurities from the degradation of the at least one cannabinoid based on the total weight of the at least one cannabinoid and the impurities for amounts of ethanol up to 10 % by weight based on the total weight of the pharmaceutical composition.

The improved chemical stability may result, in particular, when the pharmaceutical 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 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 prepared in accordance with the method of the invention 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, in a preferred embodiment the present invention provides a method of improving the stability of a pharmaceutical composition comprising (i) a propellant component and (ii) a drug component comprising at least one cannabinoid which is dissolved or suspended in the propellant, said method comprising using a propellant component comprising 1,1-difluoroethane (R-152a) and selecting the components and conditions for the preparation of the pharmaceutical composition to maintain the water content of the pharmaceutical composition below 500 ppm, preferably below 200 ppm, more preferably below 150 ppm, particularly below 50 ppm and especially below 20 ppm based on the total weight of the pharmaceutical composition.

In practice, preparing a pharmaceutical composition with the low water levels recited above involves using a propellant component with a suitably low water content, as it is usually the largest mass item in the finished device, and then preparing the pharmaceutical composition under suitably dry conditions, e.g. in a dry nitrogen atmosphere. Preparing pharmaceutical compositions under dry conditions is well known and the techniques involved are well understood by those skilled in the art. Other steps to obtain a low water content in the finished device include drying and storing the can and valve components in a moisture-controlled atmosphere, e.g. dry nitrogen or air, prior to and during device assembly. If the pharmaceutical composition contains a significant amount of ethanol, then it may also be important to control the water content of the ethanol as well as the propellant, e.g. by drying to reduce the water content to suitably low levels. Suitable drying techniques are well known to those skilled in the art and include the use of a molecular sieve or other inorganic desiccant and membrane drying processes.

In a preferred embodiment, the pharmaceutical composition that is prepared in accordance with the method 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 referring to the oxygen content of the pharmaceutical composition, we are referring to the content of free oxygen dissolved in the composition and not any oxygen that happens to be chemically bound in compounds that may be used in the pharmaceutical composition. In an especially preferred embodiment, the pharmaceutical composition is oxygen-free. Alternatively, the pharmaceutical composition that is prepared in accordance with the method of the invention 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, in a preferred embodiment the present invention provides a method of improving the stability of a pharmaceutical composition comprising (i) a propellant component and (ii) a drug component comprising at least one cannabinoid which is dissolved or suspended in the propellant, said method comprising using a propellant component comprising 1,1-difluoroethane (R-152a) and wherein the oxygen content of the final pharmaceutical composition is below 1000 ppm, preferably below 500 ppm, more preferably below 100 ppm and particularly below 50 ppm based on the total weight of the pharmaceutical composition.

It has been also found that the use of propellants comprising 1 ,1-difluoroethane (HFA-152a) in pharmaceutical compositions containing a cannabinoid compound, such as a tetrahydrocannabinol (THC), can unexpectedly improve the solubility of the cannabinoid compound in the propellant compared to the solubility it exhibits in formulations containing the known hydrofluoroalkane propellants 1 , 1,1,2- tetrafluoroethane (HFA-134a) and 1 ,1 ,1,2,3,3,3-heptafluoropropane (HFA-227ea). The improved solubility is also observed for pharmaceutical compositions that also contain ethanol in addition to the 1 ,1-difluoroethane (HFA-152a). 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, JWH-018, JWH-073 and HU-210.

In one preferred embodiment, the drug component that is used in the method of the invention 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.

In a particularly preferred embodiment, the drug component that is used in the method of the present invention comprises or consists essentially of at least one tetrahydrocannabinol (THC).

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 specified cannabinoid compound or compounds.

The most preferred tetrahydrocannabinols (THC) are delta-9-tetrahydrocannabinol and delta-8-tetrahydrocannabinol, especially the former. The pharmaceutical composition that is prepared using the method of the invention may be a solution, a suspension or a partial solution in which a proportion of the cannabinoid(s) is dissolved in the propellant, 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 that is prepared in accordance with the method of the invention will typically be in the range of from 0.01 to 15.0 weight % based on the total weight of the 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 that is used in the method of the invention may consist essentially of or consist entirely of the at least one cannabinoid compound. 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 umeclidinium, 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), such as formoterol, arformoterol, 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 propellant component that is used in the method of the invention comprises 1 ,1-difluoroethane (HFA-152a). Thus, we do not exclude the possibility that the propellant component may include other propellant 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 propellants are HFA-227ea and HFA-134a.

If an additional propellant compound is included, such as HFA-134a or HFA-227ea, 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 method of the invention utilises 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 vinyl fluoride, vinyl chloride, vinylidene fluoride and chloro-fluoro ethylene compounds.

The amount of propellant component in the pharmaceutical composition that is prepared in accordance with the method of the present invention will vary depending on the amounts of the drugs and other components in the pharmaceutical composition. Typically, the propellant component will comprise from 65.0 to 99.9 weight % of the total weight of the pharmaceutical composition. Preferably, the propellant component will 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 that is prepared in accordance with the method 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 (ii).

In another embodiment, the pharmaceutical composition that is prepared in accordance with the method 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. C 1-4 alkanols are preferred co-solvents, with ethanol being especially preferred. The inclusion of a co-solvent can serve to solubilise the drug in the propellant 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 propellant 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 that is prepared in accordance with the method 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. 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 that is prepared in accordance with the method of the present invention 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 that is prepared in accordance with the method of the present invention 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 composition that is prepared in accordance with the method of the present 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 composition, they are normally used in amounts that are conventional in the art.

The pharmaceutical composition that is prepared in accordance with the method of the present invention finds 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 composition is contained in the pressurised aerosol container and the HFA-152a propellant functions to deliver the drug component as a fine aerosol spray.

The pharmaceutical composition that is prepared in accordance with the method of the present invention is 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. Preferably, the pressurised container is designed for use in a metered dose inhaler (MDI). More preferably, the pressurised container is a coated aluminium can or an uncoated aluminium can, especially the latter.

The pharmaceutical compositions 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 propellant 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-containing propellant 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 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 propellant 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 propellant component. The whole mixture can then be treated to disperse the drugs in the propellant component, e.g. by vigorous shaking or sonication. 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.

The present invention is now illustrated but not limited by the following example. Example 1

A number of experiments were conducted to investigate the chemical stability and solubility of delta-9-tetrahydrocannabinol (hereinafter THC) in propellants HFA- 134a, HFA-227ea and HFA-152a (Mexichem UK) both with and without ethanol. The chemical stability was investigated in normal ambient light conditions and in the dark using a containment system with light protection aids. The solubility was only investigated in normal ambient light conditions. Where ethanol was included in the formulations, it was used in an amount of either 5 % or 10 % by weight based on the total weight of the propellant and the ethanol.

For the ethanol-free formulations, the THC was introduced directly into standard uncoated 14 ml aluminium canisters (C128, Presspart, Blackburn, UK). Where ethanol was included, the THC was first suspended in the required amount of ethanol and sonicated. 1g of the resultant slurry was then weighed into standard uncoated 14 ml aluminium canisters (C128, Presspart, Blackburn, UK).

After the cannisters were filled with the THC or THC/ethanol suspension, they were crimped with a 50 mΐ_ valve (Bespak, Kings Lynn, UK) following which the required amount of propellant was filled into the canisters through the valve using a manual Pamasol crimper/filler (Pamasol, Switzerland). Finally, the canisters were sonicated for 20 minutes to aid dispersion of the drug in the suspension.

The stability of the various THC formulations was then investigated immediately after charging the propellant to the cannister using high performance liquid chromatography (HPLC). The solubility was investigated using standard gravimetric analytical techniques.

The results of investigating the chemical stability and solubility of the THC in HFA- 152a, HFA-134a and HFA-227ea, with and without ethanol, in normal ambient light conditions are shown in Table 1. The amount of impurities recorded in Table 1 are based on the total weight of THC and impurities in the formulation. The solubilities recorded in Table 1 are based on the total weight of THC in the formulation. The results of investigating the chemical stability of the THC in HFA-152a, HFA- 134a and HFA-227ea, with and without ethanol, in the dark are shown in Table 2. The amount of impurities recorded in Table 2 are based on the total weight of THC and impurities in the formulation.

Table 1

Table 2 In can be seen from the results presented in Tables 1 and 2 that delta-9- tetrahydrocannabinol exhibits much greater stability when HFA-152a is used as the propellant rather than HFA-134a or HFA-227ea both with and without ethanol. Furthermore, the solubility of delta-9-tetrahydrocannabinol is much greater in HFA- 152a than in HFA-134a or HFA-227ea both with and without ethanol.