GB2361869A

GB2361869A - Cannabis-containing compositions for sublingual aerosol delivery

Info

Publication number: GB2361869A
Application number: GB0005718A
Authority: GB
Inventors: Calvin Ross
Original assignee: GW Pharma Ltd; Pharmasol Ltd
Current assignee: GW Pharma Ltd; Pharmasol Ltd
Priority date: 2000-03-09
Filing date: 2000-03-09
Publication date: 2001-11-07
Anticipated expiration: 2020-03-09
Also published as: GB2361869B; HK1041446B; ZA200207161B; HK1041446A1; GB0005718D0

Abstract

Pharmaceutical compositions suitable for sublingual aerosol delivery comprising cannabis. The cannabis may be derived from the cannabis family of plants or may be a synthetic cannabis analogue, derivative, precursor or metabolite such as delta-9-tetrahydrocannabinol. The compositions may include a propellant such as butane, 1,1,1,2-tetrafluoroethane (HFC-134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) and may contain a carrier such as ethanol, propylene glycol or a fatty acid alkyl ester. Surfactants and flavouring oils may also be included. The compositions may be dispensed from a device having a metering valve. At least part of the device may be formed from a polyester to improve functioning of the device.

Description

Sublingual Delivery of Cannabis The present invention relates to an

improved mode of administration for cannabis and its natural and synthetic derivatives. The term cannabis is used herein to refer to all physiologically active substances derived from the cannabis family of plants and synthetic cannabis analogues and derivatives, precursors, metabolites etc., or related substances having cannabis-like physiological effects.

The medicinal and psychoactive properties of the cannabis plant have been known for centuries. At present, cannabis is not legally available. However, there is growing pressure on politicians to legalise its use, especially for medicinal purposes.

Evidence suggests that cannabis is a safe, versatile and potentially inexpensive drug. It has been reported as being beneficial to patients suffering from a wide range of symptoms experienced in connection with various, often very serious, medical conditions. For example, cannabis has been used to alleviate symptoms associated with cancer, anorexia, AIDS, chronic pain, spacicity, glaucoma, arthritis, migraine and many other illnesses.

Cannabis is recognised as having anti-emetic properties and has been successfully used to treat nausea and vomiting in cancer patients undergoing chemotherapy. Studies also report use of cannabis in treating the weight loss syndrome of AIDS and in reducing intraocular pressure for the treatment of glaucoma. Cannabis is also reported to have muscle relaxing effects and anti-convulsant effects.

However, it is also well documented that these medicinal effects of cannabis come at the cost of less desirable effects. It is alleged that the administration of cannabis causes changes in mood, perception and motivation. The common euphoric effects have led to the use of cannabis as a recreational, "soft" drug and its criminalisation.

The psychoactive effects are said to vary with dose, with the typical cannabis smoker experiencing a "high" which lasts about 2 hours, during which there is impairment of cognitive functions, perception, reaction time, learning and memory. These side effects clearly have implications, such as for the operation of machinery, -2 and in particular for driving. These effects also make cannabis less attractive for widespread, mainstream use, as it can reduce a patient5s ability to perform relatively simple tasks during treatment.

The euphoric effects of cannabis may also constitute an undesirable side effect for patients using the drug for medicinal purposes, especially for "naive" cannabis users. Furthermore, here have been reports of unpleasant reactions to cannabis, such as anxiety, panic or hallucinations. It is believed that these undesirable effects are most commonly associated with higher doses of cannabis.

Despite these effects, years of research have failed to show that cannabis is dangerous. In fact, the results appear to have proved the opposite. Cannabis has been shown to be safer, with fewer serious side effects than most prescription drugs currently used as anti-emetics, muscle relaxants, hypnotics and analgesics, etc..

The physiological and pharmacological effects of cannabis depend upon a number of factors, including the dosage level and the route of administration.

There are currently two main methods of cannabis delivery. Lung delivery is most commonly achieved by smoking cannabis. Unfortunately, there are concerns about the effect of this mode of administration on the lungs. Cannabis smoke carries even more tars and other particulate matter than tobacco, and so may be a cause of lung cancer. Furthermore, many patients find the act of smoking unappealing, as well as generally unhealthy. It is known that some of the chemicals produced by smoking cannabis are aggressive and smoking has been shown to cause the gradual dissolving of teeth. For these reasons, smoking is not an approved medical means of administration for any drug.

Attempts have been made to overcome some of the problems associated with smoking both cannabis and tobacco by providing various smokeless inhalable aerosol formulations for lung delivery. A self-propelled inhalable aerosol of delta-9tetrahydrocannabinol was developed as long ago as 1975 as a bronchodilator. Inhalable aerosol formulations were made comprising either only liquid components 3 and or including a solid particulate component carrying the active agent, such as the cannabis. The various formulations were found to be of varying effectiveness in delivering the active agent to the alveoli of the lungs in the same manner as smoke.

However, both methods of lung delivery discussed above have been found to cause a pronounced and involuntary cough, possibly from irritation of the trachea and lungs. This unpleasant side effect is not overcome by the smoke-free method of lung delivery.

An oral dosage form of cannabis is available in the United States as a Schedule II drug. The capsules contain a synthetic version of delta-9tetrahydrocannabinol (delta-9-THC), the main active substance in cannabis, and they have had limited success for a number of reasons. Firstly, in light of its anti-emetic properties, the capsules are commonly used to treat nausea and vomiting. Clearly, an oral administration is not ideal as the patient may well have difficulty keeping the capsule down long enough for it to take effect. It has also been found that orally administered THC is erratically and slowly absorbed into the bloodstream, making the dose and duration of action difficult to control. Furthermore, the oral dose is less effective than smoked cannabis and therefore larger doses are required in order to achieve a desired therapeutic effect.

The applicants have discovered that an alternative mode of administration allows the clinical or medicinal effects of cannabis to be maximised, whilst reducing the above discussed unpleasant and negative side effects. According to the present invention, the cannabis is formulated for sublingual delivery in aerosol form, which offers unexpected advantages over known modes of cannabis delivery. The invention also relates to a device for delivering such a composition as an aerosol.

Formulations according to the invention may include a propellant or may be dispensed using a pump spray device. Furthermore, the valve of the aerosol device may be adapted specifically for sublingual. delivery. For example, the valve (or mouthpiece) of the device may be adapted to direct the sprayed dose towards the sublingual mucosa. The device may also be adapted to dispense particles of a particluar size, thereby optirrUsing the sublingual uptake.

It is known that sublingual delivery of a pharmaceutically active agent results in fast uptake. The active agent is administered to the sublingual mucosa, from which it is rapidly absorbed into the bloodstream. Sublingual delivery also avoids first-pass metabolism of the active agent.

The fast onset of the therapeutic effects of sublingually administered cannabis has the advantage of providing fast relief from the symptoms to be treated. It also has the advantage of reducing the risk of excessive doses being administered in an attempt to get immediate relief from symptoms, which is observed in connection with slow-acting active agents and means of administration.

Sublingual delivery is clearly more attractive than injection, as alternative method of delivery offering fast uptake. Injection is painful, especially when regular administration is required. It can also be difficult for a patient to inject themselves, especially if weak or lacking co-ordination, often making it necessary for someone other than the patient to perform the administration.

Sublingual delivery also has advantages over oral delivery. It is well suited for administration of anti-emetics, it having rapid onset and delivery is not affected by nausea and vomiting. A sublingual dose is also absorbed at a predictable rate and so its administration can be accurately controlled. Devices with metered valves may be used to dispense the active agents sublingually, allowing accurate volumes, and therefore accurate doses, to be dispensed.

Sublingual delivery also avoids the negative effects associated with smoking. The risk of lung cancer due to the tar and impurities drawn into the lung by smoking will be avoided. Furthermore, the pronounced and involuntary cough associated with lung delivery cannabis is not experienced with sublingual delivery.

A further and unexpected advantage associated with sublingual delivery of cannabis is that it is significantly more effective than smoking (which in turn is known to be significantly more effective than oral delivery). This is surprising in light of the huge surface area of the lungs which would be expected to allow much greater uptake of the cannabis than sublingual delivery which exposes a much smaller surface area to the active agent.

This effectiveness allows some of the undesirable effects of cannabis administration to be avoided, these effects being mainly associated with larger doses. Indeed, the applicants have discovered that the sublingual delivery of cannabis allows the beneficial medicinal effects of cannabis to be enjoyed whilst minimising the negative effects, such as the euphoria and impairment of faculties. That said, the sublingual administration of doses of cannabis large enough to produce said euphoric effect is still possible, if desired.

In one of the preferred embodiments of the present invention, a pharmaceutical composition suitable for sublingual delivery is provided comprising a pharmaceutically active agent which is cannabis and a propellant. The propellant may be, for example, 1,1,1,2-tetrafluoroethane (EFC-134a), 1,1,1,2,3,3,3- heptafluoropropane (HFC-227) or butane. Most preferably, the propellant included in the composition is HFC-134a or HFC-227.

In the past, aerosol spray formulations frequently included one or more chlorofluorocarbon as a propellant, dichloro-difluoromethane being commonly used. It is well documented that chlorofluorocarbons are implicated in the depletion of the ozone layer and their production, therefore, is being phased out. 1,1,1,2-tetrafluoroethane (1-fFC-134a) and 1,1,1,2,3,3, 3-heptafluoropropane (HFC227) are significantly less harmful to the ozone layer and they are of low toxicity and of suitable vapour pressure for use as aerosol propellants, making then suitable for use in pharmaceutical aerosols. An additional benefit is that HFC-134a and HFC227 can be used in combination with many pharmaceutically active agents, without causing any degradation to them or reducing their physiological activity. They are also not flammable.

Preferably, the composition of the present invention includes a carrier. In a preferred embodiment of the invention, the carrier is a lower alkyl (C,-C,) alcohol, a polyol, or a (poly) alkoxy derivative. In embodiments, the carrier is a C,-C, aki alcohol or a lanolin alcohol and, preferably, is ethanol or isopropyl alcohol. The most preferred alcohol is ethanol.

The preferred polyols include propylene glycol and glycerol and the preferred (poly) alkoxy derivatives include polyalkoxy alcohols, in particular 2-(2-ethoxyethoxy) ethanol (available under the Trademark Transcutol 0).

Further preferred (poly)alkoxy derivatives include polyoxyalkyl ethers and esters, such as polyoxyethylene ethers or esters. The preferred polyoxyethylene ethers and esters are polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters and polyoxyethylene stearates.

The preferred fatty acid alkyl esters are ethyl oleate, isopropyl myristate and isopropyl palmitate. The preferred polyalkylene glycol is polyethylene glycol.

In preferred embodiments, the inventive composition can comprise up to 50% or, preferably, 25% w/w carrier. More preferred embodiments include between 3% and 15% w/w, or between 4 and 10% w/w carrier. The pharmaceutical compositions can comprise between 50% and 99% w/w, preferably between 75% and 99% w/w, and, more preferably, between 88% and 95% w/w HFC-134a or 25 HFC-227.

In further embodiments, compositions used in the present invention can comprise a plurality of different carriers.

Further exciplents can be included in the formulations employed in the present invention. For example, neutral oils as well as surfactants (the latter for aiding the smooth operation of the valve), as are well known to those skilled in the art, may be included.

Thus, in further preferred embodiments, compositions employed in the invention can comprise an organic surfactant. The preferred organic surfactant is oleyl alcohol, although others can be employed, including sorbitail trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan mono-oleate, natural lecithin, oleyl polyoxytheylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, oleic acid, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl mono-oleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetyl pyridiniurn chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil or sunflower seed oil.

It is preferable to include a flavouring oil in a formulation to be delivered sublingually. The preferred flavouring oil is peppermint oil, although it is clear that other flavour oils may be used, according to preference.

Some of the preferred compositions for the sublingual delivery according to the present invention are tetrahydrocannabinols (THCs), such as delta9- tetrahydrocannabinol, the major active constituent of cannabis.

Many of the readily available substances derived from the cannabis plant are extracted in liquid form which may itself be directly sprayed using a pump spray or which may be soluble directly in the propellant, whilst other cannabis forms need to be solubilised in a co-solvent, such as ethanol, thus causing or allowing all or a proportion of the active agent present in the composition to dissolve and/or remain in solution, even after it has been dispensed.

The pharmaceutical compositions can be partial solutions in which only a proportion of the pharmaceutically active agent present therein is dissolved in the propellant and co-solvent, with the remainder being in suspension or suspendible. The exact proportions of dissolved and suspended active agent will depend upon the active agent concerned, its concentration and the identity and quantity of the 8 - co-solvent(s) used. In preferred embodiments the compositions are in the form of liquid solutions when maintained under pressure in devices in accordance with the invention.

A particularly preferred embodiment of the invention comprises a device in accordance with the first aspect of the invention filled with a solution of delta-9tetrahydrocannabinol in ethanol as a co-solvent and HFC-134a as a propellant.

The compositions of the present invention may also comprise cannabis in combination with other pharmaceutically active agents. For example, a formulation particularly suitable for providing improved anti-emetic effect comprises cannabis as the primary agent, with corticosteroid as a supplemental agent. In order to decrease toxicity of the primary agent, cannabis may be formulated together with the supplemental agent phenothiazine. Concurrent use of cannabis with prochlorperazine in low doses can reduce incidence of dysphoria which can accompany the administration of cannabis.

According to a further aspect of the invention, devices for delivering the cannabis compositions of the first aspect of the invention are provided.

Devices for administering metered aerosol doses of pharmaceutical preparations are well known in the art. Such devices include those disclosed in WO 92/11190, USA-4819834 and US-A-4407481. Many of these devices include metering valves having components formed from plastic materials, such as the valves available from Bespak PLC of Bergen Way, Kings Lynn, Norfolk PE30 2jj, United Kingdom, in which the valve core, metering chamber and some other structural components are formed from plastic materials. The plastic materials currently used for forming these structural parts in valves employed with many chlorofluorocarbon containing formulations include certain acetal co- polymers.

Although the plastics employed to manufacture metering valves, including the aforementioned acetal co-polymers, have also been found to be stable in the presence of HFC-134a alone, the applicants, to their surprise, have determined that many of these plastics materials can be caused to swell in the presence of formulations which include certain carriers or active agent solubilising co-solvents with HFC-134a. When such swelling takes place in a valve, the fit of mutually slidable components, such as metering chambers and valve cores, is adversely effected and they can bind together or become loose, causing the valve to leak or cease functioning altogether.

This problem has now been solved by using a device for providing pharmaceutical doses comprising a container, filled with a pharmaceutical composition including a pharmaceutically active agent in a solution of liquefied HFC-134a, or HFC- 227, and a carrier selected from pharmaceutically acceptable alcohols, polyols, (poly) alkoxy derivatives, fatty acid alkyl esters, polyalkylene glycols, and dimethylsulphoxide, and valve means arranged for delivering aerosol doses of said pharmaceutical composition to the exterior of the container, wherein at least a portion of the device is formed from a polyester. Preferably, the valve means includes at least one component formed from a polyester, which component, more preferably, is a metering chamber and/or a valve core.

In further embodiments, the container comprises a polyester and, preferably, consists of metal lined with a polyester. The canister cap can also be so formed.

Apart from allowing the aforementioned swelling problem to be solved, an advantage of this aspect of the present invention is that use of expensive metal valve components can be avoided.

The preferred polyesters are polyalkylene benzene dicarboxylates, more preferably polyalkylene tereplithalates and, most preferably, a polybutylene terephthalate.

Such materials, preferably, have a density of about 1.3g/cm' and a water absorption of about 0.6% (23'C saturation). The polyesters, also, are preferably partially crystalline in nature and have a crystalline melting range of 220-2250C.

Examples of suitable polybutylene tereplithalates include those available under the Trademark Celanex 0 from Hoechst UK Limited, Walton Manner, Milton Keynes, Bucks MK7 7AJ, United Kingdom. Particularly preferred are Celanex 0 2500 and Celanex" X 500/2.

An example of a device for sublingual. delivery of cannabis will now be described, by way of example only, and -with reference to the following drawing. Figure 1 is a cross sectional view of an embodiment of a device in accordance with 10 the invention. The device 1 comprises a substantially cylindrical canister 2 sealed -with a cap 3. Both the canister 2 and the cap 3 may be manufactured from a variety of materials. Preferably, the canister and cap are formed from stainless steel or glass. This is 15 because some of the cannabis substances which may be used in the present invention are "aggressive" chemicals and can attack "weaker" container materials. The canister and cap may be lined with a polyester (such as CelanexO 2500) or a lacquer (not shown). 20 A valve body moulding 4 comprises a cylindrical portion 5, which defines a metering chamber 6 and a stepped flange portion 7, and is formed by injection moulding from CelanexO 2500. The stepped flange portion 7 defines a first and outwardly facing annular seat 8 and a second, inwardly facing annular seat 9. The first annular seat 8 accommodates an annular sealing ring 10 and the second annular 25 seat 9 accommodates a first sealing washer 11. The first sealing washer 11 is located so as to cooperate with the cylindrical portion 5 of the valve body moulding 4, in defining the metering chamber 6. A base 12 of the cylindrical portion 5 of the valve body moulding 4 completes the 30 boundary to the metering chamber 6 and provides a seat for a second sealing washer 13.

The scaling ring 10 and the first and second scaling washers 11 and 13 can be formed from a butyl rubber, neoprene or one of the clastomers disclosed for such purposes in WO 92/11190.

An elongate, substantially cylindrical and partially hollow valve core 14 is slidably located within the first and second sealing washers 11 and 13 and extends through an orifice 15, defined in the base 12. The valve core 14 is formed by injection moulding from CelanexO5 2500.

A stepped inlet passage 16 communicates between a first end 17 of the valve core 14 and an inlet orifice 18, formed through the side of the valve core 14. In a likewise manner, an outlet passage 19 communicates between the second end 20 of the valve core 14 and an outlet orifice 21 formed through the side of the valve core 14. An annular flange 22 extends radially outwardly from the valve core 14 between the inlet and outlet orifices 18 and 21 and adjacent to the outlet orifice 21.

A stainless steel compression coil spring 23 acts between the annular flange 22 and the second scaling washer 13, urging the annular flange 22 into contact with the first scaling washer 11, such that the outlet orifice 21 lies inside the first sealing washer 11 and is thereby isolated from the metering chamber 6. In this position, as shown in Figure 1, the inlet orifice 18 is located within the metering chamber 6. A flexible tube 24 is engaged within the stepped inlet passage 16 and extends from the valve core 14 to the base of the canister 2 (as shown in Figure 1). Thus, the inlet orifice 18 is in communication with a region within the canister 2 adjacent to its base 12.

The cap 3 is firmly attached to the canister 2 by crimping and, thus, holds the assembly of the valve body moulding 4, valve core 14, coil spring 23, sealing washers 11 and 13 and sealing ring 10 in place as shown in Figure 1, with the sealing ring 10 and first sealing washer 11 sufficiently compressed to seal the interior of the device 1 and prevent the egress of its contents.

Downward movement of the valve core, in the direction of arrow A, against the action of the spring 22 will bring the outlet orifice 21 into the metering chamber immediately after the first orifice 18 has been scaled from the metering chamber 6 by the second sealing washer 13.

When filled with a composition in accordance wich the present invention, as shown at 25, the device 1 will provide metered doses of the composition when used as follows. The device 1 should be held in the position shown in Figure 1, so that the composition 25, by virtue of its pressure, enters the metering chamber 6 via the tube 24, the inlet passage 16 and the inlet orifice 18. Subsequent depression of the valve core 14, in the direction of arrow A, seals the inlet orifice 18 and hence the remainder of the canister 2, from the metering chamber 6 and opens the outlet passage to the metering chamber 6, via the outlet orifice 21. Since the composition 25 in the metering chamber 6 is pressurised with the propellant, it will be expelled from the metering chamber 6 through the outlet orifice 21 and the outlet passage 19. If the valve core 14 is then allowed to return to the position shown in Figure 1, under the influence of the spring 22, the outlet orifice 21 is again scaled from the metering chamber 6 and the metering chamber 6 will be filled with pressurised composition 25 from the canister 2, via the tube 24, stepped inlet passage 16 and inlet orifice 18.

There now follow some examples of compositions according to the present invention.

Example 1 A composition comprising delta-9-tetrahydrocannabinol (delta-9THC) with HIC- 134a suitable for use in a device as described above can be formulated from the following ingredients:- Component percent w/w g/can Delta-9-THC 0.7 0.099 Ethanol 96% BP 13.2 1.866 Peppermint oil 1.4 0.205 HFCA34a 84.7 12.02 Total 100 14.19 The peppermint oil is added to the delta-9-THC/ethanol solution and mixed thoroughly. 2.17g of the resulting solution is then placed in the canister 2 and the valve assembly, comprising the valve body moulding 4, first sealing washer 11, second sealing washer 13, spring 22, tube 23, and annular seal 10 are then sealed onto the canister 2 as shown in Figure 1 by the cap 3. The propellant is then added to the canister by being forced through the valve core 14 at great pressure, and the complete device is then checked for leaks.

Exam.12le 2 A second composition comprising delta-9-THC with HFC-134a suitable for use in a device as described above can be formulated from the following ingredients:- Component percent w/w Z/can Delta-9-THC 0.164 0.010 Ethanol 96% BP 4.992 0.305 HFC-134a 94.844 5.795 Total 100 6.11 The delta-9-THC is dissolved in the ethanol in the proportions set out above and 0.315 g of the resulting solution is then placed in a canister 2 and a valve assembly, comprising a valve body moulding 4, first sealing washer 11, second sealing washer 13, spring 22, tube 23, and annular seal 10, is then sealed onto the canister 2 by crimping as shown in Figure 1 by the cap 3. The propellant (HFC- 1 34a) is then added to the canister, by being forced through the valve core 14 at great pressure, and the complete device is then checked for leaks. After the propellant entered the canister it dissolves the remaining portions of the composition.

Example 3

A third composition comprising deka-9-THC and suitable for use in a device as described above can be formulated from the following ingredients:Component percent w/w Z/can Delta-9-THC 0.164 0.010 Ethanol 96% BP 7.5 0.458 HFCA34a 92.336 5.641 Total 100 6.11 The delta-9-THC is dissolved in the ethanol in the proportions set out above and 0.315g of the resulting solution is then placed in a canister 2. A valve assembly (as described in Example 2) is then scaled onto the canister 2 by crimping and the H:FC-134a propellant is then added to the canister, by being forced through the valve core 14 at great pressure, and the complete device is then checked for leaks. After the propellant entered the canister it dissolves the remaining portions of the composition.

Example 4

Further compositions comprising delta-9-THC with HFCA34a, suitable for use in a device as described herein, can be formulated in accordance with the details set out in the following table, in which all figures are given on a percent by weight basis.

Formulation A B c D E delta-9-THC 0.164 0.164 0.164 0.164 0.164 Transcatol 9.984 4.992 Oleyl alcohol 2.496 Propylene glycol 4.992 Ethanol 4.992 7.488 4.992 20.51 p134a 89.852 89.852 89.852 89.852 79.326 Total 100 100 100 100 100 Formulations A-E are prepared using a similar technique to that set out in Example 2 above. Briefly, the delta-9-THC is dissolved with the other excipient or excipients (excepting the HFC-134a) and the resulting solution is then placed in a canister 2. A valve assembly is then sealed onto the canister 2 by crimping and the H[FC-134a propellant is then added to the canister 2, by being forced through the valve core 14 at great pressure. After the propellant enters the canister 2, it dissolves the remaining portions of each composition.

Although only delta-9-tetrahydrocannabinol is referred to in the above mentioned examples, other cannabis active agents previously discussed in this application may be substituted therefor in quantities which would dissolve at least partially in the prop ellant/co-solvent mixture.

Claims

1. A pharmaceutical composition for sublingual aerosol delivery comprising a pharmaceutically active agent which is cannabis.

2. A composition as claimed in claim 1, which further comprises a propellant.

3. A composition as claimed in claim 2, wherein the propellant is 1,1,1,2 tetrafluoroethane (HFC-134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFC 227).

4. A composition as claimed in claim 3, wherein the composition comprises HFC-134a as the propellant.

5. A composition as claimed in claim 3, wherein the composition comprises between 50 and 99% w/w and, preferably, between 75 and 95% w/w HFC 134a or HFC-227.

6. A composition as claimed in any of claims 3-5, wherein the pharmaceutically active agent is insoluble, or only sparingly soluble in liquefied HFC- 134a or HFC-227.

7. A composition as claimed in claim 6, wherein the solubility of the active agent in liquefied HFC-134a or HFC-227 is from 3-0.001% w/v, preferably from 1-0.01% w/v.

8. A composition as claimed in any of the preceding claims, further comprising a carrier selected from pharmaceutically acceptable alcohols, polyols, (poly) alkoxy derivatives, fatty acid alkyl esters, polyalkylene glycols, and dimethyl sulphoxide.

9. A composition as claimed in claim 8, wherein the carrier is a C1-C4 lower alkyl alcohol or a lanolin alcohol and is preferably ethanol or isopropyl alcohol.

10. A composition as claimed in claim 9, wherein the carrier is ethanol.

11. A composition as claimed in claim 8, wherein the carrier is propylene glycol or glycerol.

12. A composition as claimed in claim 8, wherein the carrier is a polyalkoxy alcohol and is preferably 2-(2-ethoxy ethoxy)ethanol (Transcutol).

13. A composition as claimed in claim 8, wherein the carrier is a polyoxyalkyl ether or ester, and is preferably a polyoxyethylene ether or ester.

14. A composition as claimed in claim 13, wherein the carrier is a polyoxyethylene alkyl ether, a polyoxyethylene caster oil derivative, a polyoxyethylene sorbitan fatty acid ester or a polyoxyethylene stearate.

15. A composition as claimed in claim 8, wherein the carrier is ethyl oleate, isopropyl myristate or isopropyl palmitate.

16. A composition as claimed in claim 8, wherein the carrier is polyethylene glycol.

17. A composition as claimed in any of claims 8-16 wherein the composition comprises up to 50% w/w, preferably up to 25% w/w carrier.

18. A composition as claimed in any of claims 8-17, wherein the composition comprises a plurality of carriers.

18 -

19. A composition as claimed in any of claims 8-18, including a solution of the pharmaceutically active agent in liquefied HFC-134a or HFC-227, with the carrier as a co-solvent.

20.A composition as claimed in claim 19 wherein the co-solvent solubilises the pharmaceutically active agent.

21. A composition as claimed in claim 19 or 20, wherein substantially all of the pharmaceutically active agent present in the pharmaceutical composition is dissolved in the propellant and co-solvent.

22. A composition as claimed in claim 19 or 20, wherein a proportion of the pharmaceutically active agent present in the pharmaceutical composition is dissolved in the propellant and co-solvent, with the remainder being in suspension.

23. A composition as claimed in any of the preceding claims, wherein the composition further comprises an organic surfactant.

24. A composition as claimed in claim 23, wherein the organic surfactant is oleyl alcohol, sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan mono-oleate, natural lecithin, oleyl polyoxytheylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, oleic acid, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl mono-oleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetyl pyridinium. chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil or sunflower seed oil.

25. A composition as claimed in claim 24, wherein the surfactant is oleyl alcohol.

26. A composition as claimed in any of the preceding claims, wherein the pharmaceutically active agent is deha-9-tetrahydrocannabinol or a pharmaceutically acceptable salt thereof.

27.A composition as claimed in claim 26, wherein the delta-9tetrahydrocannabinol is in an anhydrous, hydrated, or solvated state, preferably, in an anhydrous state.

28. A composition as claimed in any of the preceding claims substantially free of weak organic or strong inorganic acid.

29. A composition as claimed in any of the preceding claims, further comprising a flavouring oil, preferably peppermint oil.

30. A composition as claimed in claim 1, wherein the composition comprises FIFC-134a, delta-9-cannabinol and ethanol.

31. A composition as claimed in any of the preceding claims, comprising a further pharmaceutically active agent.

32. A device for providing pharmaceutical doses comprising a container filled with a pharmaceutical composition according to any of claims 1-31 and valve means arranged for delivering aerosol doses of said pharmaceutical composition to the exterior of the container.

33. A device as claimed in claim 32, wherein at least a portion of the device is formed from a polyester.

34. A device as claimed in claim 32 or 33, wherein the valve means includes at least one component formed from a polyester.

35. A device as claimed in claim 34, wherein two relatively moveable, preferably mutually slidable, valve components are formed from a polyester.

36. A device as claimed in any one of claims 33 to 35 in which the device comprises a canister or cap formed from stainless steel or glass.

37. A pharmaceutical composition substantially as 10 hereinbefore described.

38. A pump action spray device substantially as hereinbefore described.

2 0:324930: SCB: VAT: LONDOCS

36. A device as claimed in claim 34, wherein said component is a metering chamber.

37. A device as claimed in claim 34, wherein said component is a valve core.

38. A device as claimed in any of claims 32-37, wherein the container includes a canister body comprising a polyester.

39. A device as claimed in claim 38, wherein the canister body is formed from metal lined with the polyester.

40. A device as claimed in any of claims 32-39, wherein said portion is a canister cap or lining.

41. A device as claimed in any of claims 32-40, wherein the polyester is a polyaklene benzene dicarboxylate.

42. A device as claimed in claim 41, wherein the polyester is a polyalkylene terephthalate.

43. A device as claimed in claim 42, wherein the polyester is a polybutylene terephthalate.

44. Use of a polyester in contact with a composition as defined in any of claims 1-31.

45. A use as claimed in claim 44, wherein the polyester is as defined in any one of claims 41-43.

46. A pharmaceutical composition substantially as hereinbefore described.

Amendments to the claims have been filed as follows CLAIMS 1. A pharmaceutical composition formulated for sublingual aerosol delivery comprising a pharmaceutically active agent which is cannabis.

2. A composition as claimed in claim 1, which further comprises a propellant.

3. A composition as claimed in claim 1 or claim 2 wherein the cannabis is a liquid extract derived from the cannabis plant. 4. A composition as claimed in any of the preceding 15 claims, further comprising at least one carrier.

5. A composition as claimed in claim 4, wherein the at least one carrier is ethanol.

6. A composition as claimed in claim 4, wherein the at least one carrier is propylene glycol. 7. A composition as claimed in claim 4, wherein the at least one carrier is a polyoxyethylene caster oil 25 derivative.

8. A composition as claimed in any of claims 4 to 7, wherein the composition comprises a plurality of carriers. 30 9. A composition as claimed in claim 8 wherein the plurality of carriers comprise ethanol and propylene glycol.

10. A composition as claimed in any of the preceding claims, wherein the composition further comprises an organic surfactant.

11. A composition as claimed in claim 10, wherein the organic surfactant is oleyl alcohol, sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan mono-oleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, oleic acid, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetyl pyridinium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil or sunflower seed oil.

12. A composition as claimed in claim 11, wherein the surfactant is oleyl alcohol.

13. A composition as claimed in any of the preceding claims, wherein the pharmaceutically active agent is delta-9-tetrahydrocannabinol or a pharmaceutically acceptable salt thereof.

14. A composition as claimed in claim 13, wherein the delta-9tetrahydrocannabinol is in an anhydrous, hydrated, or solvated state, preferably, in any anhydrous state.

15. A composition as claimed in any of the preceding claims substantially free of weak organic or strong inorganic acid.

16. A composition..as claimed in any of the preceding claims, further comprising a flavouring oil, preferably peppermint oil.

-.23 - 17. A composition as claimed in any of the preceding claims, comprising a further pharmaceutically active agent.

18. Use of cannabis in the preparation of an aerosol pharmaceutical formulation for administration to a patient via the sub-lingual route.

19. The use as claimed in claim 18 wherein said pharmaceutical formulation has a composition as claimed in any one of claims 1 to 17.

20. A device for providing pharmaceutical doses comprising a container filled with a pharmaceutical composition according to any of claims 1 to 17 and valve means arranged for delivering aerosol doses of said pharmaceutical composition to the exterior of the container.

21. A pump spray device comprising a pharmaceutical composition formulated for sublingual aerosol delivery wherein the pharmaceutically active agent is cannabis.

22. A device as claimed in claim 21 wherein the cannabis is a liquid extract derived from the cannabis plant.

23. A device as claimed in claim 21 or 22 wherein the composition further comprises at least one carrier.

24. A device as claimed in claim 23 wherein the at least one carrier is ethanol.

25. A device as claimed.in claim 23 wherein the at least one carrier is polyethylene glycol.

26. A device as claimed in claim 23 wherein the at least one carrier is a polyoxyethylate caster oil derivative.

27. A device as claimed in any one of claims 21 to 26 wherein the composition comprises a plurality of different carriers.

28. A device aS claimed in claim 27 wherein the plurality of carriers comprise ethanol and propylene glycol.

29. A device as claimed in any one of claims 21 to 28 wherein a valve or mouthpiece is adapted to spray a dose towards a patient's sub-lingualmucosa.

30. A device as claimed in any one of claims 21 to 29 wherein the device is adapted to dispense particles of a particular size, thereby optimising the sub-lingual uptake.

31. A device as claimed in any one of claims 21 to 30 further comprising a metered valve.

32. A device as claimed in any of claims 21 to 31 in which the device comprises a canister or cap formed from stainless steel or glass.

33. A pump action spray device for delivery of a pharmaceutical composition having a. valve or mouthpiece adapted to spray a dose of said composition towards a patient's sub-lingual mucosa.

34. A device as.claimed in claim 33 which-is adapted to dispense particles of a particular size, thereby optimising the sub-lingual uptake.

35. A device as claimed in claim 33 or 34 further comprising a metered valve.