GB2525269A

GB2525269A - Cannabinoid compositions and uses

Info

Publication number: GB2525269A
Application number: GB1420943.1A
Authority: GB
Inventors: Alex Hearn; Ritika Gupta; Moira Bowdrey
Original assignee: Kind Consumer Ltd
Current assignee: Kind Consumer Ltd
Priority date: 2014-02-14
Filing date: 2014-11-25
Publication date: 2015-10-21
Also published as: MX2016010541A; AU2015216718A1; AU2015216718B2; CA3014697C; WO2015121673A1; US10413521B2; US10561634B2; JP6391701B2; CA3014697A1; IL247262A0; GB2524469A; CA2939242C; US20200147035A1; IL247262B; US20170056368A1; NZ723838A; US20200163932A1; EP3104837A1; NZ754337A; JP2017506639A

Abstract

An inhalable composition for use as a medicament in the treatment of a subject, wherein said composition comprises: (i) one or more cannabinoids or pharmaceutically acceptable derivative or salt thereof; (ii) a propellant; (iii) a monohydric or polyhydric alcohol and(iv) a glycol and/or glycol ether, characterised in that the ratio of monohydric or polyhydric alcohol to glycol or glycol ether by weight is from 6:1 to 1:1, wherein the composition is administered in the form of an aerosol having a fine particle fraction (FPF) of 60% or more. Also disclosed is a method of manufacturing the above composition, and a pressurised container therefor. The inhaler may comprise a housing, a reservoir within the housing containing the inhalable composition comprising a cannabinoid and an alcohol, a composition flow path from the reservoir and an outlet at an inhaling end of the housing, and a non-metered breath operated outlet valve for controlling the flow of inhalable composition through the flow path.

Description

CANNABINOID COMPOSITIONS AND USES

FIELD OF THE INVENTION

The present invention i-dates to cannahinoid compositions and uses therefor,

BACKGROUND

Cannabinoids have long been known for their therapeutic potential in pain relief, treatment of seizures, anneinesis et cetera, It is, however, a class of compounds whose usage has been associated with a gicat dear of debate ong u As p'ycflo i2ivc. lets it was not until the discovery of cannahinoid receptors (GBI and CB2. and the isolation of individual, cannabinoids such as i'HC (tetralhydrocannahinol), CBD (eannabidiol), CBI' (CannahinoD, and TEICY (Tetrahydrocannabivarin), [at the psychoactive effects could he attributed primarily to compounds (like TI-IC) with high affinities to the receptor GB I -Furthermore, it has been established that individual cannabinoids differ frcm one another in their affiniLies to receptors and certain eannabinoids, such as CBD, behave as GB i/CB2 antagonists, thereby blocking some actions of their agonists, such as TI IC.

With omgoing research, therapeutic applications of cannabinoids are becoming increau gly n dent, rc-ulting in tegaLsanon ot these cornçoundc tar rrwdicai puiposcs v-i a number of countries, The primary targets of research in this field are being associated with safe, rapid and/or effective delivery of eannabinoids, A number of ways of delivering cannahinoids are known in the art..

For example, U32012/0304990 teaches the use of heating to vaporise a cannabis deposit, Onc dra%\back ot this syeiri is that ócrc is only a small emperature di+fcrcnttal between the temperature at which the cannabis will vaporise (1 80°c to 200°c) and the temperature at which toxins are produced (230°c).

A number of documents (for exanipk W003/055549, US6509005 and W(i)2004/000290} disclose the use of a. metered dose inhaler, Such inhalers suffer from a number of drawbacks. Firstly, the metering chamber is r&atively small, generally less than I 00d resulting in delivery of fairly concentrated doses,Aiso, such devices require users to optimally coordinate actuation of the outlet valve and inhalation, failing which, dose delivery could he variable.

A thither common mechanism is the simple spray which is disclosed, for example, in W002/064109 and US2006/135599 which are designed to provide sublingual or buceal spray. Such a spray is currently being marketed by OW Pharmaceuticals under the Sativex (TM) brand. These sprays suffer from the possibility of nonunifbrrn drug dose delivery owing to the flushing action of saliva. Further, they have a slower onset of action when compared with pulmonary delivery.

SUMMARY OF THE fJVENTIO1c

The present invention provides compositions, devices, and methods thr delivering a cannahinoid composition for use as a medicament, In one embodiment the eannabinoid composition is deliwied to a sub'eet in the feirn of an in iaahle aerosol haung a fIne particle fraction of 60% or more, In one embodiment, the subject is a subject in need of prophyiaxis or treatment with a eannahinoid, In one embodiment, the suhjee:t suffers from a condition or disorder selected from the group consisting of neuropathie pain, cannabis addiction, nausea, motion sickness, arthritis, and neurodegenerative disease. In one embodiment, the neurodegenerative disease is selected from the group consisting of Aizheimner's. Parkinson's and multiple sclerosis. In one embodiment, the invention p&'ide, methoth of ieat1ng. subject sufthnng from a conduion or disorder selected from any of the foregoing. In one embodiment, the invention provides methods of ameliorating one or more symptoms associated with the condition or disorder.

In one embodiment, the cannabinoid composition is delivered to the subject through an wha1er In one enbodmneni, the inhaler cc mprises a housing a reservoir within the housing, said reservoir containing an inhatable cannahinoid composition; a composition flow path from the reservoir and out of a composition outlet at an inhaling end of the housing and a nonmetered breath operated outlet valve for controlling the flow of the cannabinoid composition through the composition flow path, the inhaiable composition comprising a caririabinoid or a pharmaceutically acceptable derivative or salt thereol and an alcohol. The alcohol can he a monohydric or a polyhydric alcohol. In one embodiment, the alcohol is a monohydric alcohol and the inhalable composition further coniprises one or more of a glycol and a glycol ether. In a thrther embodiment, the ratio of alcohol, which is preferably a monohydric alcohol, to glycol or glycol ether by weight is from 6:1 to 1:1. in one embodiment, the inhalable composition comprises or consists of one or more cannabinoids or pharmaceutically acceptable derivatives or salts thereof; a propellant; a monohydrie alcohol; and a glycol and/or gLycol ether in a weight ratio of monohydre alcohol to glycol/glycol ether of from 6:1 to 1:1.

in one embodiment, the inhaler further comprises an air flow path frotn an inlet spaced from the inhaling end of the inhaler to an air outlet at the inhaling end., the air flow path being configured such that suction on the inhaling end causes flow through the air flow path which causes the breath operated valve to open, the air outlet being positioned adjacent to the composition outlet, sach that an' from Ihe an' outlet impinges on the composition leaving the composition outlet. in a thrther embodiment, there is a respective air flow outlet on either side of the inhalahie composition outlet.

2 0 In a further embodiment, the outlet valve comprises a flexible diaphragm within the housing positioned so as to be influenced by the air flowing through the air flow path; and a valve element movable with the diaphragm and biased by a biasing force into a position in which it closes the composition flow path, such that suction on the inhaling end causes a flow through the air flow path providing a pressure differential across the diaphragm thereby lifting the valve element against the biasing force to open the composition flow path; and wherein the biasing force is arranged to close the composition flow path once the suction ceases.

In a further embodiment, the inhaler comprises a first air flow path partly defined by one side of the diaphragm., a second air flow path partly defined by the opposite side of the diaphragm, each flow path having an opening at the outlet end, wherein the air flow paths are arranged such that suction at the outlet end results in a pressure differential across the diaphragm that moves the diaphragm and hence moves time, valve element against the biasing three to open the composition flow path.

lii a further embodiment, at least a portion of the flow path is a deformable tube, and the outlet valve is provided by a damning member which pinches the defbrmable tube closed wtien no suctton force is applied to the inhaling end to close the composition flow path and releases the tube to open the composition flow path when suction is applied at the inhaling end.

in a further embodiment, the inhaler fllrther comprises a refill valve in communication with the reservoir via which the reservoir may be refilled. In one embodiment, the reservoir is pressurised. in a further embodiment, the inhalable composition further comprises a propellant, in one embodiment, the propellant is a hydrofluoroearhon. In one embodiment, the propellant is present in an amount from at least 60 94 w'w, based on the total weight of the composition. In a fttrther embodiment, the size of the reservoir, the pressure within the reservoir, and the size of the composition flow path at its narrowest point are arranged so that, when the outlet valve is fully opened, the reservojr will discharge in less than 30 seconds.

In one embodiment, the inhaler is configured to eject the inhalable composition therefrom in the form of droplets, at least 99 94 vol of the droplets having a diameter of less than 10 microns, The invention also provides an inhalahie composition comprising one or more camiabinoiu' cm ph-'rmsee acaLv aecepahh derivative, o salts l2ereo. propellant monohydrie or polyhydric alcohol; and a glycol and/or glycol ether, present in a weight ratio of monohydric or polyhydric alcohol to glycol/glycol ether of from 6:1 to 1:1, In a preferred embodiment the alcohol is a nionohydric alcohol. In one embodiment, the one 3 0 or more eannahinoids is selected from tetrahydrocannahinol (TI-IC). in particular (-)-tran&-Atetrahydrocannabinoi (also known as dronabinol), eannabidiol (CBD), eannahmo (CBN), tetranydroc*annabtvann (1 HCV), cannabigerol (CI3U), cannabidivarm cBDV), eannahichromene (CBC), and the synthetic cannabinoid nabilone. In one embodiment, the one or more caiinabinoids or pharmaceutically acceptable derivatives or salts thereof is present in an amount of from 0.01 to 15 % w/w based on the total weight of the composition. [none embodimeni, the ratio of monohydric alcohol to glycol or glycol ether by weight is from 5:1 to 1.2:1. In one embodiment, the glyvol and/or glycol ether is selected from the group consisting of propylene glycol, polypropylene glycol, polyethylene giyeol (PEG), and combinations of two or more thereof in one embodiment the glyco ancL'or giyco ether is propylene glycol aid the composition comprises from 0.01 to S % w/w or from 0.1 to 2 % w propylene glycol, based on the total weight of the composition. In one embodiment, the monohydric alcohol is ethanol, In ore e nhodimenr, the ethanol is present in an amount from 0 5 to 4 % w/w, based on the total weight of the composition, In one embodiment, the composition frirther comprises a human IAS2R bitter taste recepoi agoitist, piefetaNy khs'rem 0e l'utran 1 cS2R bitter taste receptor agon t is saccharin. In one embodiment, the composition further comprises saccharin in an amount h eight from 0 001 % w'w to (11 % w/w Ia one emboduicuit the compos t on huruer comprises a flavour component, preferably selected from peppermint oil, aniseed, chocolate, coeo, menthol arid/or vanillin, In one embodiment, the composition comprises up to 0.1 % w/w menthol, based on the total weight of the composition.

The invention also provides a pressurised container containing a carmabinoid composition for use according to the invention, in one embodiment, the container is pressurised to a pressure of from 3 x io Pa to 1.5 x it? Pa, The invention also provides a method of manufacturing a eannabinoid composition tbr accoidng to the in cntion, hc method comp"ising preparing a premrnxture comprising a rnonohydric or polyhydric alcohol and a glyeol or glycol ether, and opliotrdly a IA S2R taste rece thou agonist and/or avour ng component, herein the i.atio of monohyduc or poyhydric akohil to glycol or gycol ether bi' weight us flonu 6 1 to 1:1; adding one or more cannabmoids or pharmaceutically acceptable derivatives or salts thereot, to the pre-rnixture to obtain a cannahinoidcontaining mixture; anti adding a 2ioptlicn to the canria'mo d-conlainmg miduic h a pretc red ernkx nneit the alcohol rnonohvCri alcoho' In one tmbodiment, the composition wmpriscs a TAS2R taste receptor agonist andlor flavouring component, and wherein the fnonohydric or polyhydric aicoho and glycol or glycol ether are combined betbre the IAS2R taste receptor agonist and/or flavouring component arc added.

The invention also provides an inhaler comprising a eannahinoid composition for use o according to the mvention.

ERIEF DESCRIPTION OlE THE DRAWINGS

Fig. I is an exploded perspective view of an inhaler; Fig 2 is a schematic axial cross-section through the outlet end of the inhaler itt the plane is containing an air flow path mid with the vane removed for clarity; Fig. 3 is a perspective view of the outlet end of the inhaler with the cover, vane and diaphragm removed to show the air fiow paths; Fig. 4 is a perspective view of the outlet end of the inhalcr; Fig. 5 is a plan view of the inhaler; Fig. 6 is a ±1111 cross-section of the inhae.r; Fig. 6A is a cross-section through line 6A-6A in Fig 6; and Figs. 7-9 are eross-sectici a! views of an inhaler of a second example in various orientations.

DETAILED DESCRIPTION

The present'nenon is particularly concerned with an aerosol composition for cannabinoids. The invention provides inhalable cannabinoid compositions, devices for their administration, and methods of use, in accordance with the methods and 33 coniposnot s of I he irvention, the cannabu oids are deLi ed l re iiy to the kngs h.ore they are efficiently absorbed into the systemic circulation, resulting in a rapid onset of therapeutic action.. The ranid onset of therapeutic action achievable through 11w compositions ano methods of the invention offers an advantage over prior cannabinoid acInery nthods sun as oral suit gL1l or suppcsiory delivcy, which gencially involve slower systemic absorntion. The compositions and methods of the invention also S oiler the ability to deliver cannahinoids via inhalation at lower temperatures than is possible via the inhalation of cannabinoids vaporised from a cannabis plant surface. In addition, the compositions of the invention adrrnrnstered according to the methods described herein are expected to provide a more uniform and reliable drug absorption profile compared to oral, suppository or sublingual delivery methods, The compositions of the invention may also be administered in a convenient and hygienic manner compared

to prior art compositions and delivery methods.

The tenn "cannabinoid" as used herein may encompass a chemica compound that activates any mammalian cannahinoid receptor, for example human C81 receptor or human CB2 receptor. As used herein a chemical compound that activates a mammalian tannali oid teceptor id ude' ctgoruh of d The skilled peison may rcathly deterrn'ie wheth i a c otnpnund is a ca&uabmoid receptor aon&st o at i or using assa s known in the art, for example using a suitable {3S]Gil'PyS binding assay (see, for example Griffin ei a!, Journal of Pharmacology and Experhrenmai Therapeutics, 285(2), pp. 33 1-560, 1998). The cannabinoids may be naturally occurring (such as, for example, endocaimahinoids or phytocannabinoids or they may be synthetic, Synthetic cannab1oids may include br cxamjle, the classical carrab noids strucurads relatec to FIR?, tne rin-cla,sical canrabinoids can abtinimeLc) ncludtng the ainnos Iky i nd o es I,5-diaryipyrazoies, quinolines and arylsulphonoamides, and eieosanouis related to the 2.5 endoeannabinoids. When a cannabinold saDt is used, it may he employed in the fbrrn of a solution. The one or more canriahinoids is preferably selected from the classicaL cannahinmds, note preferably selected horn hAt ahydrocannamnols (TI IC) preferably dtha94eLiahydrocannahmol ax. do ta-8--tctrahydrocannabinol, note prefcrabty (-H -) fransA9-tetrahydrocannabinoi and trans-A8-tctrahydrocamabinol, cairnabidiol (CBD), 3 0 caimabinol (CBN), tctrahydroeannabivarin (l'I-ICV), eannabigerol (CT3G, carmabidivarin (CBDV) and cannabichronicne (CBC), eannahicyclol (CBL), cannahichrornevarin (C]3C\'), cannahgerovarn (C1MJ' and cairnabignol monorrethyl et it (CBCM) UBI) and lift, are particularly preferred cannahinoids in the proscnt mvenfloru In a particularly preferred embodiment, the composition comprises both CBD and THC. CBD typically exhibits only a minimal psychoactive effect, CR11) may also act as a potent antagonist to the CA I receptor, thereby counteracting the psychoactive effect of THC without altering its advantageous clinical effects. The compound "tetrahydrocannahinol" as referred to herein may encompass (-)-(6aR, I OaR>-6,6,9-trimethyI-3pentyl-6a,7,8,10a-tefrahydro- 6H-bcnzo[clchromen-hoh The compound "cannahidiol" as referred to herein may encompass 24(1 R,6R)6-isopropenyi-3.methyleyelohex--2en yI]-5-pentyibenzcne-1,3-dioL Other cannabiroids suitable for use in the present invention are endocannabinoids, sabstances that iauially occm in the uaminahan body ad vhich activale one or more cannahinoid receptor, Preferably endocaimabinoid.s are selected from arachidonoylethanolaminc (AEA), 2-arachidonoyigiyceroi (2-AG), 2-arachidonyl gyceryi ether (noladin ether), N-arachidonoyi dopaniine NADA), virodhainine (OAE) and lysophosphatidylinositol (121).

Synthetic cannabinoids suitable for use in the present invention include nabi lone, rimonahant, JWH-O13, JWH-073. CP-55940, dimethylheptyipyran, HU-210, HU-33[, SR144528, WIN 55,212-2, JWU-133, levonantradol, and AM-2201.

Cannábinoid inhaler device According to the piesent Invention a caiinaoinolc ml aler comprises a nousing, a reseivu within the housing of inhalable composition comprising a cannabinoid or a pharmaceutically acceptable derivative r salt thereof, and an alcohol; a composition flow path from the reservoir and out of a composition outlet at an inhaling end of the housing; and a non-metered breath operated outlet valve for controlling the flow of inhalahie compositIon through the composition flow path.

The use of a non-metered and breath. operated valve provides a n.t.an her of advantages over the prior art dispensers. As the valve, is breath operated, it can oniy be opened wflen a ue' is Mhalrn sach bat, at the moment tk vak puns to K brase Fe coniposition there is an existing flow of air into the lungs thereby facilitating the entrainment of the composition into the lungs. Further, as the administration of fbrmulation is unmeterea. the user can self-titrate and can obtain a dose (i.e. one fill of the device) over a number of inhalations (or puffs) at a desired, comfortable pace. This can be done in a few inhaiatons and potentially in a single inhalation if desired.

Thus, the present invention provides a cannabmoid inhaler which is easy to use and provides a way of obtaining a relatively consistent dose with minimal wastage fir deep lung administration and rapid onset of clinical actions as compared to a metered (lose inhaler or spray.

The breath-operated valve may have a number of configurations. It may, for examp].e, comprise an electronjc flow sensor which detects suction on the inhaling end and activates a solenoid. to open the outlet valve. Alternatively, the valve may be a. heater which selectively vaporises a proportion of a viscous composition, with the reservoir being configured to replenish the viscous composition in the vicinity of the heater. As a 2 0 further example, the valve may take the form of a Venturi nozzle which generates a suction force when a user inhales. The suction force may directly remove the composition from the housing, or the valve may further comprise a closure element which is opened by the suction force.

The important consideration for the outlet valve is that it is able t.o selectively allow the dispensing of composition in response to a user inhaling from the inhaler.

However, preferably, the inhaler further comprises an air flow path from an inlet spaced from the inhaling end to an air outlet at the inhaling end, the air flow path being configured such. that suction on the inhahn.g end causes flow through. the air flow path which causes the breath onerated valve to open, the air outlet being positioned adjacent to -10 -the compositton outlet, such that air from the air outlet impinges on the composition caving the composition outlet.

The provision of an air flow path which both operates the breath operated valve and also impinges on the composition outlet provides a dna! benefit in opening the valve and having a beneficial effect on the particle size, as the impinging air breaks up larger droplets of the composition thereby significantly decreasing the ine-an particle size. If air flow outlet is provided on either side of the irihaEabie coiripositioi outlet, this effect is enhanced and any deflection of the composition plume caused by a single air outlet is avoided.

The breath-operated valve is preferably provided hv a flexible ciiaphmagm within the housing and being positioned so as to be influenced by the air flowing through the air flow path; a valve element movable with the diaphragm and biased by a biasing force into a position in which it closes the composition flow path; wherein suction on the inhaling end udusOs a flow th ough the an I1ow path pr udmg a r re ire dilcrentia d( ross the diiptragiri tlwehy ucing the vc.he elemtnt agai 1st the biai;g lowe to open the composition flow path; and wherein the biasing force is arranged to close the composition flow path once the suction ceases.

The use of a flexible diaphragm is beneficial, as it can provide a relatively large surthee area so that it is able to open the valve even with a relatively low flow rate. This allows the inhaler to open at a relatively low flow rate as compared to a standard metered dose inhaler which is useffli for patients who find it difficult to inhale deeply.

Preferably, the inhaler further comprises a first air flow path partly defined by one side of the diaphragm, a second air flow path partly defined by the opposite side of the a apniagm each flocs pah Invng an c'penn at the outlet end, w ie e n tie air flow pths are arranged such that suction at the outlet end results in a pressure differential across the diaphragm that moves the diaphragm arid hence moves the valve element against the :ii biasing force to open the composrUon flow path. The presence of the first and second air flow paths immmlses further the suction required to open the valve, P eferaoly a Icast a porLon of inc flow pati is a deformable tube, and he outki vave is provided by a clamping member which pinches the defonnable tube dosed when no suction force is applied to the inhaling end to close the composition flow path and releases the tube to open the composition flow path when suction is applied at the inhaling end. The defonrabic tube provides a simple mechanism for the breathoperated a1ve whih operates paruculailv well with the flex le diaphragm to prov do a smpic reliable and easy to operate hreathoperated valve, The inhaler may he designed for a single use. However, preferably, the inhaler has a refill valve in communication with El-ic reservoir via which the reservoir may be refilled.

The reservoir may he at atmospheric pressure. However, it is referahiy pressursed as this pit suie can pioide the snot n 1're to e\pel the cernpc'skcn from the rescrvo'l I he rescn'osr my be pressurised y.smg a c:rnpressed gas I loevei, prete'ahh. tht fonnuation further compnes a ptopeliart a I us aiiow the picasure in the icsevo-ir to be substantially maintained as the composition is dispensed.

Preferably, the pressure within the reservoir and the size of the composition flow path at its narrowest point are arranged so that, when the outlet valve is fully opened, the reservoir will discharge in less than 30 seconds.

Such a reservoir is an optimai size for cannubinuid delivery as it allows a user to obtain a dose over 8 to 1 0 puffs, on average. However, the inhaler is not so large that it contains a dose which is likely to be harmful to either the authorised patient or some third party. In view of this, it is not necessar to provide a lockout mechanism on the inhaler itself

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Preferably, the inhaler is configured to eject inhalable composition therefrom in the form of droplets, at least some o which have a diameter of 10 pm or less, and prererabry at least 99 %vol of the droplets have a diameter of iess than 10 m.

This relatively small particle size is ideal for pulmonary delivery, and co-operates particularly well with a breath-operated valve to ensure that there is a flow of reladvely small particle size delivered into the pre-existing suction air stream ensuring even more reliable and repealable delivery deep into the lungs.

The inhaler as described herein may comprise the inhalable composiflon as described herein.

An example of an inhaler in accordance with the presert invention will now he described with reference to the accornpanymg drawings IS Fig. 1 is an exploded perspective view of an inhaler; Fig. 2 is a schematic axial. cross-sectior through the outlet end of the inhaler in the plane containing an air flow path and with the vane removed for clarity; Fig. 3 is a perspective VIeW of the outlet end of the inhaler with the cover, vane and diaphragm removed to show the air flow paths; Fig. 4 is a perspective view of the outlet end of the inhaler; Fig. S is a plan view or the inhaler; Fig. 6 is a thu cross-section of the inhaler; Fig. 6A is a cross-section through line 6A-6A in Fig. 6; and Figs. 7-9 are cross-sectional views of an inhaler of a second example in various orientations.

The inhaler described below is based on that disclosed in WO 2010/073018. For further details of the device and its refill mechanism, reference is made to WO 2009/001078 and 13 --As shown in Fig. 1. the inhaler eornpnses a housing 1 winch is broadly divided trite Iwo parts. The distal part is a reservoir 2 and the proximal part is the brcathactivated valve mechanism 3. At the refill end 4 is a refill valve 5 allowing the reservoir to be filled. The reservoir may contain a wick 6 as shown in Fig. 5 and disclosed in WO 2011/107737, At S the opposite end is the outlet end 7 which will he described in more detail below, An elastomeric insert 10 (described in greater detail in GB 1305496.0) in the form of a tube open at both ends is inserted from the distal end, This insert 10 is normally pinched closed by a valve element 11 which is biased downwardly by a spring 12. This pinch closed valve mcehanisrn is described in greater detail in WO 2011/01 525.

The valve element 11 is part of a vane 13 which extends along most of the outlet end of the inhaler. The vane 13 is surrounded by a diaphragm 14 which extends across the entire lo\u kt. ol th van 3 with tie LXCC o; of the orifice thmugh whtch the ia se a. 5 element 11 projects. This vaive elemeni is sealed around its periphery to the surrot.inding housing. At the distal end of the diaphragm 14 is a kink 15 which provides some degree of freedom for the vane 13 to move up and down. The opposite end of the vane 13 is integral with a surrounding frame that is hued into the housing such that there is a direct connection between the frame and vane to provide a hinge about which the vane pivots.

A mechanism [hr opening the valve elemem 11 against the action of the spring 12 will now be described.

This is achieved by first 16 and second 17 air flow paths as best shown in Fig. 2. The flis flow'azh Ut s above ve diaphrag i 14 4it thc top ot 1h os oari bmg 2rntd by housing part 18 which is fixed to the housing I once the valve elements are in place, The first air flow path is essentially provided by a first air flow path outlet orifice 19 which leads into the space occupied by the vane 13 above the diaphragm 14, This flow iath -i no o hu &ificcs :14 -ftc second r I ow path 17 is x']ov the i a,ihiagr ii and N de{imd b'c a pair ol second air flow path inlet orifices 20 (only one of which is shown in Fig. 2). In the present example, the second air flow path is actually defined by two separate paths which extend from the inlet orifices 20 along passages 17 which are defined by the housing 1 on the lower surfhce and the diaphragm 11 at its upper surface and which extends alongside the second portion 9 of thee reservoir to the outlet end lenmuating at a pair of second air flow path outlet orifices 21 which are smaller than the corresponding inlet orifices 20 and are duected tosards u to brcak up the partide size ol toe.omposthou p1 uric as desriheJ n greater cetail m OrB 121 5282 3 ftc ov throagh the second air flow pa h..s dcpcted by airo\s £fl the lower)art of Fi 2 and in Fig 3 Baffles 22 are provided along the second air flow pat 17 to incicase the flow res s,ance r this path As user sacks on the outlet e d /, air is sucked out of the first flow ci h out'et c' iEee 19 thereby lowering the pressure in the first air flow path 16, At the same time, air is drawn in through the second flow path air iniet orifices 20. As these are larger than the second flow parh oatlc onces 21, 1 okirig cif, et aided by the laros 22 et1ectr ely causes pressure to increase in the second. air flow path. A eombinaton of a reduced pressure above the vane and a raised pressure below the vane 13 causes the vane to be moved upwardly defonning the diaphragm 14 and raising the valve element against the action of the spring 12. When a user stops. sucking on the outi& end 7, the pressure above and below the diaphragm 14 equahses and the spring 12 returns the valve element ii to a position in wmch it pinches the insert 10 closed.

A second example of an inhaler is shown in Figs. 7 to 9. This is described in greater detail in (iB 1305494.5. En place of the wick 6, this example is provided with a tube 30 having an internal bore. 31 leading to the insert 10 at the opposite end of tube 31 At the inlet end 32 of the tube 30, the bore 31 has an inlet 33 which is supported by a support 34 so that the inlet erd 32, and preferably the inlet3.3 of the bore 31 is on the main axis X of the housing I as shown in Figure 7.

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it will be appreciated from the drawings that the shape of the reservoir is complex. The igLt I portion h* a &ncraIiv cyhiducal configuration ocupymL' the malorlcv of the diameter of the device while the left hand portion ofthe reservoir may just be the internal bore 31 of the tube, or there. may be a portion of the reservoir on either side of this tube.

Further, in the right band portion, the volume of the reservoir is reduced by the inlet end portion of the tube 30, the support 34. and the refill valve assembly 5. Thus, while the volume of the reservoir 4 can be detennined by measuring these components, it may be simpler to determine this experimentally.

The operation of the device will now be described with reference to Figs. 7 to 9.

When a user sucks on the outlet end 7, the outlet valve 3 opens as previously described, Provided that the inlet 33 of the bore 31 is below the level L of the liquid in the reservoir, the liquid svili travel along the bore 31 and will be atomised downstream of the outlet valve element 11 to create a plume for inhalatIon. Figs. 7 to 9 show the centroid C of a body of liquid filling the reservoir 4, The inlet 33 of the bore Si is in the vicinity of the enttoid In tis spcJlc can:,le sho\k in Pig 1, t s displaced by 1nn rom the centroid C towards the refill end 4. In the horizontal orientation shown in Fig. I, all of the liquid above the level L which represents approximately 50% of the total liquid in the 2 0 reservoir can lje inhaled from the inhaler. When the inhaler is in the tip-down configuration shown in Fig. 2, as the inlet 33 is displaced tm the centroid C as described above, slightly more liquid is available than it is in Fig. 1. Conversely, in the tip-up configuration, slightly iess liquid is avaiiahie for inhalation. un a different arrangement, the inlet 33 is at the eentroid. so that there is essentially no variation in d spensing becwcen the thrce positiors 1 lie cuirent prefuenec is foi a shlit WsplacLrnent of the inlet 33 towards the refill end from the centroid C as shown as this causes slightly more liquid to be dispensed in the more common tipdown orientation.

Once the cigarette reaches the liquid level position L shown in Figs. 7 to 9 with the 3 0 reservoir approximately half full, no further liquid can he inhaled and the inhaler then needs to be refilled via the refill valveS.

Pressurized container In a further aspect, the present invention provides a pressurised container containing the composition as described herein, The pressurised container may he used to release a gaseous flow of the composition to a user. For example, the pressurised container may be provided with means for deiivenin the contents of the container to the lungs of a user, Such means may take the form of a button, irigger or hreathactivated mechanism. The pressurised container may he used to deliver an unnietereci dose of cannabinoid to the user. 11th may be advantageous over prior art methods of cannabis replacement therapy, such as conventional inhalers, nasal sprays, lozenges and patches currently on the market, because it can allow autonomy in cannabinoid replacement regulation, where the user can regulate the amount of compositional cannahinoid he or she wishes to inhale.

The pressuriscd container of the present invention may he used to release the composition to a uor without the neeC for a sepaJatc souicc ot cnergy or exampk the composition may he released withc at requiring the heating of substrates, combustion of material or a battery powered electnc current, As discussed above, this can result in a reduction in the levels of harmful by-products delivered to a user, The pressurised container of the present invention may take the form of a pressurised canister, for example, a pressurised aluminium canister, The canister may be fully recyclable and/or reusable, The canister may be refilled as required by a vending machine or a larger container containing the desired composition under a high pressure gradient. In one embodiment, the canister is an A\V5052 aluminium canister.

The pressurised container maybe capable of dispensing the composition as a mixture of acoso iced roples The mixture may hake the appeararn of a apoui ci smoke ftc piessunsed oiramei may he ptessuiise to a uesure of from 3 i0 Pa to J 5 x Pa, preferably from 5 x i0 Pa to 2 x 106 Pa, more preferably from 5.5 x i0 Pa to I x 10 Pa, even ira it preferably at about 6 x i05 Pa.

lnhakbe cannabmoid corpposiuni The compositions of the invention comprise one or more cannabinoids or pharnaceutically acceptable Jerivairses ci salts thereoi, a propellant, an alcohol, anc' a glycol and/or glycol ether, The alcohol may he a monohydric alcohol or a polyhydric alcohol, and is preferably a nionohydric alcohol, Monohydrie alcohol has a]ower viscosity than a glycol or glycol ethor kccodmgls, the (omp3sh'on b able to fcrm dioplets of a smalki diarrte.er a compar son to compositions in wh ch the monoh3dric alcohol is not present. The present inventors have surprisingly found that a specific ratio of monohydric alcohol to giyco or glycol ether results in a composition with a desired combination of both long tenn stability (for example the composition remains as a single phase for at least a week at a temperature of 240 °C) and small droplet size. in a prefened embodiment, the ratio of monohydric alcohol:glycol or glycol ether by weight is from 6:1 to Li.

The composition preferably comprises from 0.0 i to 15 % wfw of the one or more cannabinoids or pharmaceutically acceptable derivatives or salts thereof based on the total weight of the composition, more preferably from 0.01 to 10 9/ w/w, even more ureferably from 0.1 to 8 % w/w. still even more preferably from I to 5 % w/w, En one embodiment, the invention provides an inhalable composition comprising: one or more carmahinoids or pharmaceutically acceptable derivatives or salts thereof; a propellant; an alcohol; and a glycol anct'or glvcol ether, chara4erised in that the ratio of alcohol: glycol or glycol ether by weight is from 6:1 to 1:1. 18 --

In one embodiment, the alcohol is a monohydric alcohol, Preferably the monohydric alcohol is ethanol. Ethanol has a pwticulariy Low viscosity in comparison to a glycol or glycol ether, and is therefore particularly effective at enabling the composition to form S droplets of small diameter, In addition, ethanol is cheap, relatively non-harmful and readily available. Preferably the composition comprises from 0.5 to 4 %w/w ethanol, preferably from 0.75 to 3.5 %w/w, more preferably from ito 3 %w/w based on the total weight of the composition.

in one embodiment, the present invention provides a composition comprising; ene or moi.e caimabaoiis or nhairnaecttieslly aLeeptable dcrnanvcs ci salts thereof; a nionohydne alcohol; and a glycol and/or glycol ether, characterised in that the ratio of monohyaric alcohol gtycol or glycol ether by weigtu is from 6:1 to 11.

in accordance with the methods and compositions of the invention, the glycol and/or glycol ether may aid the dissolution of the one or more cannahinoids or pharmaceutically acceptable derivatives, or salts thereof in the composition. This avoids the presence of precipitates of cannabinoids (or other additives such as saccharin, if present) in the composition, wheh could cause irritation when delivered to a user. In addition, the presence of glycol or glyeol ether reduces the degradation of the cannabinoids that may occur over time, thereby increasing the long-term stability or "shelf life" of the composition.

The glycol and/or glycol ether may be selected from propylene glycoL polypropylene glycol and polyethylene glycol (PEG), or combinations of two or more thereof Suitably polyethylene glcois may hae a molecuku r usc ot les thin 2U,00) d/mol An exan'ple of a suikbie polyet'yci e g yco is PFG 400 Picletrhly.he g yt.ol oi ycol ether is propylene glycol. Propylene glycol provides the composition with a. particularly desirable droplet size profile and provides enhanced solvation of excipients and reduces egradaton of excipients, Preferably the composition comprises from (LU I to 5 %w/w propylene glycol, more preferably from 0.1 to 3 %w/w, even more preferably from 0,3 to 2 %wfw, the composition thrther comprises a human TAS2R bluer taste receptor agonist. The use of a human 1AS2R hitter taste receptor agonist induces bronchodilation.

resulting in a reduction in the eveis of dehveryrelated coughing. Accordingly, a user is more able to tolerate the composition since it causes very little irritation.

The human TAS2R bluer taste receptor agonist may be a naturally occurring compound or synthetic co npohnd Fxarnples of su table natuia ty-oucutnng comnpounth neiue Absinthn, Aloin, Amarogentn, Arnirographolide, Arborescin, Argiahin, Artemorin, Camphor, Casearillin, Cnicin, Crispolide, Ethylpyrazine, Falcarindiol, Fielicin, [Iutrnulone isomci s 1 unonn, Noscapme Papa'c'crine, Par henolide Quassrn Si ng'in, and 1 lhi nine Fxantnles ol suitable synthetic toniound mdutk Acc',uUame K, B&n,oin, Carisoprodol, Chioroquine, Croniolyn, Dapsone, Denatonium ben'zoate, Dimerhyl tkotormarnick, lliphcnhvdranii:c, Dn'tiy sulfoxide larotid' ic, Sacehaim, Sodium hcnzoate, and Sodiam cyclamate.

Preferably the human TAS2R bitter taste receptor agonist is saccharin. Saccharin is particularly effective as a human TAS2R bitter taste receptor agonist, may he readily dissolved in thc eomposrten, t readily aailable asic provides the cernpos4ton vitn a desirable taste profile. Preferably the formulation comprises 0.001 %w/w to 0.1 %wiw, more preferably 0,003%w/w to 0.01 %w!w and even more preferably 0,005%w/w to 0.008%w/w saccharin. Lower levels of saccharin result in a composition with an unacceptable tolerability. Higher levels of saccharin result in an acceptable tolerability but are disfavoured since saccharin they may lead to precipitates of saccharin tbrrning in the composition. which may cairse irritation when the composition is administered to a user or blockage when the composition is incorporated into art inhaler. Such weight r° . ntage also provide the composition with an op'mised taste profik

--

The pronellant may he a nydrotluorocarbon, preferably a hydmfluoroaiicwie, even more ieferably il,2,2-tetrafIuotoethane (HFA-134a) or i,I,l,23,3hcptafiuoropropane HFC- 227). Such coinpourvJs are particularly effective as propeilants and have no adverse efièct on the body. c

The composition may comprise at least 60 %w/w propellant, more preferably at least 66 %w/w. even more preterahly from 90 to 99.5 %w/w, even more preferably from 92 to 99 %w/w, and even more preferably from 96 to 99 %iw, based on the total weight of the composition. The propellant is preferably liquefied. Preferably the composition is a liquid. More preferably the composition is a pressurized liquid.

the composition may further comprise a flavour componenL The use of' a flavour component may mask the taste of the cannahinoids or derivatives or salis thereof Suitable naoiu coTnpononh ricluth the la\oJr componcnts typicc ly aLdtG to inlkLaIe :1.5 products. Examples include carotenoid products, aJkenols, aldehydea, esters and deita lactone flavour constjtuents. Suitable carotenoid products include beta ionone, alpha ionone, beta-damascone, beta-darnascenone, oxo-edulan I, oxo-edulan Ii, theaspirone, 4-oxo-bcta-ionone, 3-oxo-alpha-ionone. dihydroactinodiolide, 4-oxoisophorone, safranal, beta-cyciocitral. Suitable aikenols include C4 lo C10 ailcenois, preferably C3 to C alkenols. Specific examples include: cis-2-Penten-l-oi, cis-2-l-lexen-1-ol, trans-2-Hexen- I -ol, trans-2-Jlexcn-l-ol, cis-3--Hexen lol, trans-3-Hexen 1-ol, trans-2-Mepten-1 -ol, cis- 34lepten-hoi, trans..3$Iepten-l oi, cis_44:lepten_lol, trans2cten-l -ol, eis-3-Octen-i-ol, cis-5-Octen-l-ol, l-Octen-3-oi and 3-Octen-2-oL Suitable aldehydes include benzaldchyde, glucose and cinnarnadehyde, Suitable esters include allyl hexanoate, bniyl c+cta, boniyi cttate. butyl bjviae, ethl but) rate, ethyl hxenoie, cthyi cinnamate, ethyl fbrmate, ethyl heptanoate, ethyl isovalerate, ethyl lactate, ethyl nonanoate, ethyl valerate, gerariyi acetate, geranyl hutyrate, isohutyl acetate. isohutyl formaL, iso'ni a1⁄4 ette, isopi opyl autate linaivi acetfl, In ly huty'ate, inn > formate, methyl acetate, methy anthranilatc, methyl henzoate, methyl beuzyl acetate, methyl hutyrate, methyl cinnarnate, methyl pentanoate, methyl phenyl acetate, methyl salicylate (oil of wintergreeri). nonyl caprylate. octyl acetate, octsd butyiate, amyl acetate 21 -- (pent)'! acetate), pentyl hexanoate, pentyl pentanoate, propyl ethanoate, propyl isohutyrate, terpenyl butyrate, ethyl fonnate, ethyl acetate, ethyl propionate, ethyl butyrate, ethyl valerate, ethyl hexanoate, ethyl heptanoate, ethyl octanoate, ethy nonanoate, ethyl clecanoate. ethyl dodecanoate, ethyl myristal.e, ethyl alinitate. Suitable S deita4actone flavour constituents include delta.4-iexalactorie. clelta-Octalactone, delta Nonalactone, deItaDeea1aetone, delia4indeealaclone, delta-Dodecalactone, Massoin iactone, Jasmine lactone and 6-Pentyi-aphapyrone. Flavour components may serve to mask the taste olcannabinoids.

The flavour component is preferably menthol and/or vanillir. The presence of menthol, together with the saccharin, reduces the irritation experienced by a user. Preferably the composition eonipnses up to 0.1 %w/w menthol, preferably from 0.01 %w/w to 0.08 more preferably from 0.02 %w/w to 0,06 %w/w, even more preferably from 0.03 %w/w to 0.05 %wtw., still even more preferably about 0.04 %w/w, based on the total a. 5 weight of the composition.

In a particularly preferred embodiment, the invention provides an inhalable composition comprising; One or more eannabinoids, A propellant comprising nF434a.

Ethanol, and Pro3vlene glyeo, enatacteuzed in ti-at tqe rato of ethano to propylene glyco] oy weight is from 6:1 to I:], Even more preferably the one or more cannabinoids are selected from TIIC and CBD. or a mixture thereof, Preferably each component of the inhalable composition is present in the preiCnxtdprcportions disclosed herein. Even more preferably the one or more cannabinoids are present from 0.0! to 15 %w/w, the propellant is present in at least 56 %w/w, ethanol is present from 0.5 to 5 %w/w and the propylene glvco.. is preseLt horn 0 01 to S %w/w The (Mnulahfl proportloth o2aL con porents present in the cornposton must add up to 100 %w"w. 22 -

!n a further embodiment of the invention, the inhalabie composition consists essentially of the components described heiin.

in a iurther embodiment of the invention, the inhalable composition consists of the S components described herein.

ethodspfdevcy The present invention provides methods of delivering a eannabinoid composition to a subject by inhalation with an inhaler device. In contrast to compositions of the poor art, the compositions of the present Invention form small diameter droplets without the use of organic acids, resulting in less irritation to the airways. Accordingly, the methods of the invention comprise methods for reducing discomfort and local irritation due to administering a cannabinoid composition by inhalation, the methods comprising administering a cannabinoid composition lacking organic acids.

The composition for use according 10 the present invention may he delivered to a user vi.a oral inhalation, specifically via pulmonary administration. Accordingly, it is effective for use in cannabis replacement therapy or as an alternative to recreational smoking of cannabis plant material, since it mimics some of the habitual aspects of cannabis smoking.

In. accordance with the methods of the invention, the cannahinoid composition comprises a nionohyonc alcohol and glycol or giyco.E ether in a ratio ot from 6:1 to 1:1.As discussed above, the ratio of monohydric alcohol to glycol ether by weight resuirs in a combi ia on ci both Lihili at Cd uen ccl clto'Jot sue pnv'ik Ptcterah y hc ntio o monohydrie alcohol: giycoi or glyco! ether b weight is fmrn 5:1 to 1.2:1.

In one embodiment, the cannahinoid composition is delivered via a conventional pressurised metered-dose inhaler pMDl). According to the present invendon the composition is delivered in the fbrm of aerosol droplets, some of wnich such as, ibr -23 example, at La.t I U %o) I av a thameter ol lC',a thar 0 am tynhally ess thai> 5 pm (The term "diameter" as used herein is taken to mean the Largest dimension ma droplet, and is measured using a Malvern Spraytee equipment, if necessary using a flow adaptor to ensure a total flow rate of at least 15 L!min through the equipment.) Typically, the macnty (such as, for example, at least 50 %vol) of the aerosol droplets have a diameter if less than 5 m, typically substantially all sueh as, for exannle, at least 90 %el, or even at least 95 %vol) of the drop'ets have a diameter of less than 5 tm, Advantageously, when administered to a user, droplets with a size of less than 10 urn tend to be deposited in the lungs, rac>,e. tiar foi exan pie tie orop iarynx ALcordmgh, 4 least some (sach as, for exampe, at least 10 %wiw), typically substantially all (such as, for example, at least 90 %w/wh of the catmahinoid enters the bloodstream via the pulmonary route, which results in rapid absorption of the composition.

The composition may he delivered to the subject as an aerosol, wherein the droplets have a size distribution wherein the fine particle fraction (FPF) is greater than 30%, preferably greate. than 40%, more preeiablv gi atc i than 50% In pa.liuLi cntnodi'ncns ethe invention, the fine particle fraction is 60% or more, preferably 61% or more, 62% or more, 63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71% or more, 72% or more, 73% or mtre, 74% or more, 7»= or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more, 81 % or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or n ore, 93% or mor.3 94% or more, 95% 01 more 96% or m're, 97(7 or note 98!4 or more, or 99% or more. FPF is the percentage, by weight of aerosol particles that have a / diameter less Far 5 nitrons, whee the term diarnetef' as aed herein i' taken to ncGn th. Lu gest c.unension of a droplet, ane ic measuroc. umn& a Maivem Spraytec equipment if necessary using a flow adaptor to ensure a total flow rate of at least 15 L/min through the equipment.

typically at east some (such as, for example, at least 10 %vol) of the droplets have a diameter oifrom 0.5 to 3 pm. Such droplets maybe deposited in the deep lung, and are 24 --therefore particularly able to enter the blood stream via the pulmonary route. Typically at least some (such as, for example, at least 10 %voi) of the droplets have a diameter of from 0,4 to 0.5 im, In another embodiment, the cannabinoid composition is delivered via an inhaler device described herein. In accordance with this embodiment> the droplets may exhibit the following droplet diameter distribution: Dv 50 of iess than 20 pm, typically less than 10 xni, more typically iess than 8, even more typically less than 6 pm, and/or Dv 50 of less than 6 pm, typically less than 4 pm, more typically less than 3 pm, even more typically tess than 1 pm, andtor Dv IC) of less than 4 pm, typically less than 2 pm, more typically less than 1 pm, even more typically less than 0.5 pm.

The term "DviO" as used herein refers to a droplet diameter that 10 %vol of the droplets in a composition have a smaller diameter than. The term "Dv50" as used herein refers to a droplet diameter that 50 %vol of the droplets in a composition have a smaller diameter than. The term "Dv90" as used herein refers to a droplet diameter that 90 %vol of the 2 0 droplets in a composition have a smaller diameter than. Dv 10, Dv50 and Dv90 values may he determined using a Malvern Spraytec device.

Methods of manufacture in a further aspect the present invention provides a method of manufacturing the composition described herein, the method comprising; preparing a pre-ndxture comprising a monohydrie or polyhydric alcohol and a glyeol or glycol ether, and optionally a I'AS2R taste receptor agonist and/or flavouring com1onent, whemem the ratio of mnonohvthlL or po]yhydric.thehol g-col or gy ol ether hyweight is from 6:1 to 1:1; addmg one or ir ore earsabmoids or pharmaceutlialy aecepable denvathcs i salts thereof, to the premixture to obtain a cannahinoid-containing mixture; and adding a -n -propellant to the cannabinoid-coit&ning mixture, In a preferred embodiment the alcohol is a monohydric alcohol, If the cannabinoid is added before the alcohol and glycol or glycol ether arc combined, thtn piecip 4itiori of arnahmoid ma3 o.cr ikewise, if he corrpoition ornpriscs other components, such as a flavouring component or a TAS2R taste receptor agonist, then these components should be ftilly mixed into the pre-mixture heibre the cannabinoids are acd&d in orier o avoid piecipitation of cannabinids In particular, it has been found that when the composition comprises menthol, the menthol should be fully dissolved into the premixture before the eannabinoids is added in order to avoid nrecipiwuon of thL cannabinoids When the composition is to include a TAS2R taste receptor agonist andior a flavouring component. preferably the monohydrie or polyhydric alcohol and glyco]. or glycol ether are combined before the TAS2R taste receptor agonist andtor a flavouring component arc at d& This aoi's proc ptatun of tie flavounng component or I \S'R taste eceptor agonist.

Mftiod ot tnatmei t In a further aspect, the present invention provides a method of treating a condition selected lion neuropthie pain, cannabis adduAion, nause5, mot.on slccnes, arthritis rd neurodegenerative diseases such as Aizheimers, Parkinsons and multiple sclerosis using the composition as described herein, The inhalabie compositions described herein will now be frirther described with reference to the following nonJimiting examples.

Example 1

0.8 g of the following composition was prepared: CUD: 9.185 ing A9(-)-trans-THC; 0.415 rug Ethanol: 18 m.g Propylene glycol: 15 mg Menthol: 0.32 mg Saccharin: 005 rig HFA434a: 0.77 g THC and CBD were present in a ratio of 23:1 and account for 1.25 %w1w of the composition. This composition is considered to he particuiariy effective for the treatment of neuropathc pain.

Example 2

0.8 g of the following composition was prepared: A°)4umi HC lb rng CBD:8Orng Ethanol: 24 mg Propylene (ilycol: 16 mg Menthol: 0.4 rig Saccharin: 0.0504 mg HFA-134a:0.664 g The cannabinoids account for 12% of the formulation weight. This composition is considered to be particularly effective for the treatment of nausea. motion sickness or other similar conditions.

Examnle 3 -. 27 OS g of the following composition ws prepared: 9(-frans-THC: 0.25mg CBD:Smg Ethanol; 16mg Propy]en.e (iiycoL 12mg MenthdL: 0.32mg Saccharin: 0.0504mg HFAA34a: 0.766g The eannabinoids are in a ratio of 20:1. This composition is considered to be particularly effective for the relief of the symptoms of arthritis, Examnle 4 OS g of the thilowing composition was prepareth CBD: 9 mg A9(±iransJiHC: I rug Ethanol: 15 mg Propylene glyeol: 14$ mg Menthol: O35 mg Saccharin: 0.05 ing RF'A434a: 0,76 g The carmabinoids CBI) and ILK) account for 1,25% of the formulation weight. This LompUsltrnn is considejed to he parneutarly eftectie to reducing the symptoms of Alzheimefs disease, 30'

Example 5

I he fbuiowing composition was prepared: setran& I HC:i 11. rug Ethanol: 196 mg S Propylene glycol: 70 mg Menthol: 8 mg Saccharin: 07 rug HFAI34a: 20168 The formulation was inserted mb a pinch valve sirnuhited cigarette as described herein.

Five doses were emitted from the device and the droplet size profile of each was measured using a Malvem Spraytec device as described herein. The fine particle fraction meiisured for the composition was 77%

Claims

-29 -Cb lins I An inhalable composition for use as a medicament in the treatment of a subject wherein said composition comprises: one or more cammbinoids or a pharmaceutically acceptable derivative or salt thereofi a propellant; a nionohydric or polyhydric alcohol; and a glyco] and/or glycol ether, characterised in that the ratio of monohydric or polyhydric aleohoT to glycol or gTycol ether by weight is from 6:1 to 1:1, wherein the composition is administered in the form of an aerosol having a fine particle fraction of 60% or more.
2. The composition for use according to claim I wherein the fine particle fraction is 70% or more.
3. The composition for use according to claim 1 wherein the fine particle fraction is 75% or more.
4. The composition for use according to claims 1-3 wherein the alcohol is a monohydric alcohol.
5. The composition for use according to claim 14 wherein the one or more cannabinoids is selected from tetrahydrocannahinol (THC), preferably dronabjnol, eannahidiol (OW), cannabinol (CBN), tetrahydrocannabivarin (THCV), cannabigerol (CBG). cannabidivarin (CBDV) and cannabichromene (CBC).
6. fho composition for use according to claim 1-5 wherein the one or more Ladnablmild p, dronabir ol -30 -
7. The composition fbr use according to claims L6 comprising from 0,01 to 15 % w/w of the one or more cannahinoids or pharmaceutically acceptable derivatives or salts thereof based on the total weight of the compositIon.
8. The composition fur use according to claims 1-7 wherein the ratio of moriohydric alcohol to glycol or glycol ether by weight is from 5:1 to 1.2:1
9. The composition thr use according to claims I 8 wherein the glyc-oi and/or glycol ether is selected from the group consisting of propylene giycoi, polypropylene glycol, polyethylene glyeol (PEG), and combinations of two or more thcrcof
10. the composition for use according to claims 1-9 wherein the glycol and/or giycol ether is propylene glycol and the composition comprises from 0.01 to 5 % w'w propylene giycol. based on the total weight of the composition.
11. The composition fur use according to claims 1-10 wherein the glycol and/or glycol ether is propylene glycol and the composition comprises front 0.1 to 2 % viiw propylene glycol, based on the total weight of the composition.
12. The composition for use according to claims 1-11 wherein the nlonohydric alcohol is cthanol.
13. The composition for use according to claim 12 wherein the composition comprises front 0.5 to 4 % w/w ethanol, based on the total weight of the COtflpOsitlOii.
14. The composition for use according to claims 1-13 wherein the composition further comprises a human TAS2R hitter taste receptor agonist, preferably wherein the human TAS2R bitter taste receptor agonist is saccharin.
15. The composition fur use according to claims 1-14 wherein the composition further comprises saccharin in an amow.it by weight from 0.001 % w/w to 0.1 % w/w. 31 -16. The composition for use according to claims i-iS wherein the oropeilant is a hydrnfluorocarbori.17. The composition for use according to claims 116 comprising at least 60% w/w propellant, based on the total weight ot'the composition.18, The composition for use ceording to claims 1 to 17 further comprising a flavour component, preferably selected from peppermint oil, anisee.d chocolate, coco, menthol and/or vanillin, 19. The composition for use according to ciaiin 18 wherein the composition comprises up to (H % w/w menthol, based on the total weight of the composition.20. The composition for use according to any of claims 149 wherein the inhaler comprises: a housing; a reservoir within the housing containing an inhalati.e composition comprising a cannabinoid or a pharmaceutically acceptable derivative or salt thereof, and an alcohol; a composition how path from the reservoir and out of a composition outlet at an inhaling end of the housing; and a nonmetered breath operated outlet valve thr controlling the flow of inhalable composition through the composition flow path.21. The composition fbi' use according to claim 20, wherein the breath operated inhaler further comprises an air flow path from an inlet spaced from the inhaling end of the inhaler to an air outlet at the inhaling end, the air flow path being configured such that st&io i on the in ialmg end causes flow through the air flo\% path which causes:1 c breath oprated ahe to open, tl C 4!! oull&t be ig positioned adiacent to the omposition ouLet such th0 air frcrn the air o'ukt unpaucs on the ompthIlon leaving the composition outlet. 32 -22. The composition for use according to ciahu 21, wherein there is a respective air flow o dcl on cuber siec o tie tnha)cihc omnosiL'ii outlet s 23. The composition fin use according to claim 2.1 or 22, wherein the outlet valve comprises: a flexible diaphragm wiThin the housing and being positioned so as to be infi erLcd by the air flow ing through the air flow path, a valve element movable with the diaphragm and biased by a biasing force into a position in which it closes the composition flow path; wherein suction on the inhaling end causes a flow through the air flow path providing a pressure differential across the diaphragm thereby lifting the valve element against the biasing force to open the composition flow path; and wherein the biasing fbrce is arranged to close the composition flow path once the suctIon ceases..24. Tho composition for use according to claim 23, farther comprising a first air flow path partly dcfrncd.iy one side of U e dap1nagn', a 1ceond ai flow path pzr'iv cicfncd b the op osue side of the diapluag.n each ilow. p th hav1ng an opciu tg a the ottlet end, wherein the an flow pat i, are anangcd such that suction a the outle. end resu ts in a pressrre diffeicotial KiUSS the J ap i agir that moves the diaphiagm and hnce im.n es the \dlVL elonient against I e Masing iUrc.o opa th compo'itlon flow path the coirpositior tot use accoidmg to ckms -24 wheicir at cat a portion of di flow path is a deformabie tube, and the outlet valve is provided by a clamping member which pinches the deformable tube closed when no suction force is applied to the inhaling end to close the composition flow path and releases the tube to open the composition flow path when suction is applied at the inhaling end, 26. The composition for use according to claims 1-25 further comprising a refill valve in communication with the reservoir via which the reservoir may be refi lied.-33 - 27. The composition for use according to claims 1 --26, wherein the reservoir is pressurised.S28. The composition for use according to claim 27, wherein the size of the reservoir, the pressure within the reservoir, and the size of the composition flow path at its narrowest point are arranged SO that, when the outlet valve is Cully opened, the reservoir will discharge in less than 30 seconds.29. The composition for use according to claims 128 wherein the inhaler is configured to eject the inhalable composition therefrom in the form of droplets, at least 99 % vol of the droplets having a diameter of less than 10 microns.30. A pressurised con1ainr containing the composition for use according to any of fl,' clauns I to z. 31. The pressurised container of claim 30 prcssurised to a pressure of from 3 x 1.0 Pa to 1.5 x i0 Pa. n32. A method of manufacturing the composition for use according to any of claims I to 31, the method comprising: preparing a pre-mixture comprising a monohydrie or polyhydric alcohol and a glyc.ol or glycol ether, and optionally a TAS2R taste receptor agonist and/or flavouring component, wherein the ratio of monohydric or polyhydrie alcohol to glycol or glycol ether by weight is from 6:1 to 1:1; adding one or more cannabinoids or pharmaceutically acceptable derivatives or salts thereof, to the premixture to obtain a cairnabinoid-containing mixture; and adding a propellant to the camiahinoid-containing mixture.33. A method according to claim 32 wherein the alcohol is a monohydric alcohol.-34 - 34 A mcuoc1 according to cLam 32 o" 13 \%he'em tflc composition cot puses a I AS2R a,te icceptor agonist and. or flavouimg conpoten and ierel the akil ol rd glycol or glycol ether are combined before the TAS2R taste receptor agonist and/or flavouring component are added.35. The composition for use according to claims 1-29 wherein the subject is suffering Iron' a eoncition se ectec fr m neuropathe porn, cannabis addiction nausea, notioi sicimess, arthritis and neurodegenerative diseases such as Aizheimers, Parkinsons and multiple sclerosis.36, The composition for use according to any of claims 1-29 wherein the subject is a human. :i 5