FIELD OF THE INVENTION [0001] The present invention relates to an oral formulation containing one or more

cannabinoids.

BACKGROUND TO THE INVENTION [0002] Cannabinoids are lipophilic substances that are known to be poorly soluble in water

(less than 1 μg/mL). In contrast, and by way of example, cannabidiol (CBD) is soluble in ethanol at 36 mg/mL and the polar solvent dimethyl sulfoxide (DMSO) at 60 mg/mL.

[0003] Consequently, whilst it is desirable to have an aqueous cannabinoid containing formulation, developing such a formulation which comprises substantial amounts (greater than 30% v/v) of water is a major challenge.

[0004] The contemporary use of cannabinoids in medicine has necessitated finding more effective ways of delivering these poorly soluble compounds. In addition to poor aqueous solubility cannabinoids are also known to have limited bioavailability and poor stability in formulations.

[0005] If cannabinoids are required to be provided at relatively high doses (in daily amounts of up to 2000mg) and / or in challenging patient groups, e.g. young children, and / or for particular indications this can create further challenges.

[0006] There are currently three commercially available cannabinoid formulations on the market which due to the lack of aqueous solubility of cannabinoids utilise alcohol and / or oil based excipients. These are: dronabinol (Marinol®) which is a synthetic tetrahydrocannabinol (THC) which is delivered orally, in sesame oil as capsules; nabilone (Cesamet®) which is a synthetic cannabinoid and an analog of THC and is delivered orally in capsules with povidone and corn starch; and nabiximols (Sativex®) a natural extract of cannabinoids, dissolved in ethanol and propylene glycol, containing defined amounts of THC and Cannabidiol (CBD) delivered as a liquid, by way of an oromucosal spray.

[0007] The applicant also provides an oral solution containing CBD (Epidiolex®) on a named patient basis. The CBD is formulated in sesame oil and further comprises the sweetener sucralose, strawberry flavouring and up to 10% v/v ethanol.

[0008] Whilst there is no clear FDA guidance for maximum allowable ethanol concentration in prescription medicines, an article (Ethanol in Liquid Preparations Intended for Children,

Paediatrics: Official Journal of The American Academy of Paediatrics, 1984: 73:405), recommends that a Blood Alcohol Concentration (BAC) of 0.25 g/L (250 mg/L) should not be exceeded following a single dose of alcohol containing medications.

[0009] Furthermore, the use of oil-based formulations often causes gastrointestinal side effects such as diarrhoea which can be so severe it may cause the patient to discontinue use of the medication.

[0010] Alternative approaches to cannabinoid formulations have been suggested.

[0011] WO 2015/184127 (Insys) discloses a number of different oral formulations including: an alcohol-free formulation, in which the cannabinoid is formulated in a mix of polyethylene glycol and propylene glycol, optionally with water; a formulation containing alcohol; and a formulation containing lipids. In each of the formulations disclosed, the cannabinoid is a synthetically produced (as opposed to a naturally extracted) cannabidiol. The specification teaches the inclusion of a number of pharmaceutically acceptable excipients such as, anti-oxidants, sweeteners, enhancers, preservatives, flavouring agents and pH modifiers.

[0012] WO 2012/033478 (Murty), discloses Self Emulsifying Drug Delivery Systems (SEDDS) which are said to offer improved administration of cannabinoids. SEDDS generally consist of hard or soft capsules filled with a liquid or a gel that consists of lipophilic active pharmaceutical ingredient (API), oil (to dissolve the API) and a surfactant. Upon contact with gastric fluid, the SEDDS spontaneously emulsify due to the presence of surfactants. Many surfactants, however, are lipid based and interact with lipases in the GIT. This can lead to a reduced capability of the lipid based surfactants to emulsify the API as well as the oil carrier, both reducing

bioavailability.

[0013] Lipid based formulations are classified according to the Lipid Formulation Classification System (LFCS), Type I formulations are oils which require digestion, Type II formulations are water-insoluble self-emulsifying drug delivery systems (SEDDS), Type II I systems are SEDDS or self-micro emulsifying drug delivery systems (SMEDDS) or self-nano emulsifying drug delivery systems (SNEDDS) which contain some water-soluble surfactants and/or co- solvents (Type I IIA) or a greater proportion of water soluble components (Type N IB).

Category Type IV represents a recent trend towards formulations which contain

predominantly hydrophilic excipient surfactants and co-solvents.

[0014] Table 1 , below, is a tabular Lipid Formulation Classification System overview taken from US 2015/1 1 1939: Content of formulation (wt.-%)

Excipients in formulation Type Type Type Type Type

I II MA 1MB IV

Oil: triglycerides or mixed mono- and 100 40-80 40-80 <20

diglycerides

Water-insoluble surfactants (HLB < 12) 20-60 0-20

Water-soluble surfactants (HLB > 12) 20-40 20-50 30-80

Hydrophilic co-solvent 0-40 20-50 0-50

A further description of the Lipid Formulation Classification System can also be found in FABAD J. Pharm. Sci. , pages 55-64, 2013.

[0015] Drug Development and Industrial Pharmacy (2014), 40, 783-792 discloses the general principals of formulating drugs with poor water solubility. More specifically it discusses the formulation of phenobarbital, a drug with a solubility of 1 mg/ml which is still 1000 times more soluble than cannabidiol in water.

[0016] It states the presence of co solvents in the formulations are critical to the stability of the drug, and further states that the biggest limitation of co solvency is the toxicity of most water miscible co solvents that have a high potential for increasing drug solubility. It concludes the formulation of this poorly water-soluble drug represents a challenging task for formulation experts.

[0017] The microemulsions it teaches are colloidal dispersions, thermodynamically stable systems that are isotropic and have low viscosity. The structure consists in microdomains of lipids or water, stabilised by an interfacial film of surfactant and co-surfactant molecules. They are classified as oil in water or water in oil emulsions and the droplet size is less than 150nm.

[0018] It also discusses the increased interest in S(M)EDDS which are isotropic mixtures of oil, surfactant, co-surfactant and drug. The efficacy of oral formulations of these is stated to depend on many formulation related parameters including: surfactant concentration, oil/surfactant ratio, polarity of the emulsion, droplet size and charge. Additionally, taste is stated to have an important role in compliance.

[0019] The formulations developed all comprised surfactant (Cremophor or Labrasol, at 20% w/w), a separate oil phase, (a number of oils were tested which were proprietary forms of: glycerol monocaprylocaprate, caprylic/ capric triglyceride, propylene glycol caprylate and propylene glycol dicaprylate/ dicaprate were tested, typically at 4% w/w), and a co-surfactant (including Transcutol, PEG 400, glycerol, ethanol and propylene glycol, typically at

concentrations between 20 and 35% w/w).

[0020] The conclusion was that Phenobarbital could be dissolved easily in a number of ME's, but the selection of the oil phase was very important.

[0021] In contrast, the Applicant has been able to formulate a cannabinoid, which is 1000 times less soluble than phenobarbital, without the use of a separate oil phase, and at concentration of above 0.5% and up to 2%.

[0022] Additional cannabinoid formulations from the art include:

[0023] US2016/0213624, which describes formulations of a hemp oil, and not CBD per se, by emulsification with a surfactant / emulsifier, such as Polysorbate 80. The surfactant / emulsifier is used in an amount of less than 0.02% v/v.

[0024] US2016/0184258 which discloses SEDDS formulations, particularly type III formulations which comprise e.g. a cannabis extract, dissolved in ethanol, an oil base - typically about 35- 56%, a surfactant - typically about 28-52%, and a co-solvent - such as ethanol, typically about 7-9%.

[0025] International Journal of Pharmaceutics discloses non-ionic microemulsions of THC for parenteral administration using Solutol as a surfactant without the addition of lipids, co- surfactants or other modifiers. The resulting microemulsion contained 0.19% THC and 2.52% (by wt) Solutol.

[0026] Pharmacology, Biochemistry and Behaviour 2017, 153, p69-75 discloses Cremophor/ saline (10/90) solutions of THC at concentrations of up to 5mg/ml THC.

[0027] CN1031 10582 also discloses a cannabinoid containing micro-emulsion containing: the following components in percentage by weight: (a) 0.01wt% - 3Qwt% cannabinoid; (b) 0.01 wt% - 30wt% of oil phase; (c) 0.01wt% - 60wt% of surfactant; and; (d) 0.01wt% - 40wt% of cosurfactant.

[0028] Clearly there is a need to have oral formulations (as opposed to injectables which are not designed for, nor indeed suitable for, oral delivery) which are more bioavailable, and which can deliver sufficient amounts of cannabinoids (greater than 0.5%, more preferably still at least 1 % by wt) in a patient friendly formulation.

[0029] In addition to the problems with the use of ethanol, or an oil -based excipient, in cannabinoid containing oral formulations, the strong bitter taste of cannabinoids provides a further problem which needs to be overcome when producing an oral cannabinoid formulation.

[0030] For paediatric products aimed at younger children, it is desirable to have low or no ethanol formulations, preferably dispensed as a syrup, as younger children find it difficult to swallow capsules. They also favour sweet, flavoured products, such as syrups, particularly where the taste of cannabinoid requires masking. [0031] An object of the present invention was to develop alternative cannabinoid containing oral formulations which were aqueous based, rather than being a Type I to IV formulation as classified by the LFCS.

[0032] More particularly, an object was to develop a formulation with improved bioavailability compared to the lipid-based formulations favoured in commercial cannabinoid medicines.

[0033] A further object was to provide a stable formulation, and yet a further object was to address the requirements for use with young children, i.e. a predominantly water based oral formulation which was free from alcohol and which was palatable. It was important that the formulation could deliver an effective dose as an oral solution or syrup, in relatively small volumes, typically less than 10 mL. An effective dose meant that the cannabinoid should be present in an amount of at last 0.5% by volume, and more preferably still at 1 % or more by volume. Thus, a 10ml_ volume would contain at least 50mg of cannabinoid.

BRIEF SUM MARY OF THE DISCLOSURE

[0034] In accordance with a first aspect of the present invention there is provided an oral cannabinoid containing formulation comprising one or more cannabinoids dissolved in a solvent system consisting essentially of:

(i) a non-ionic surfactant; and

(ii) water

together with other components which ensure the cannabinoids stability and the formulations palatability.

[0035] Preferably the oral cannabinoid formulation excludes oil-based excipients separate of the non-ionic surfactant, and any additional solvent and/ or co solvent.

[0036] Preferably the cannabinoids dissolved in the solvent system comprise at least 80% by weight of the oral cannabinoid formulation.

[0037] Preferably the other components comprise one or more of: a sweetener, a taste masking agent, an antioxidant, a flavor, and a preservative.

[0038] Preferably the non-ionic surfactant is present in an amount sufficient to ensure dissolution of the one or more cannabinoids in the solvent system. Where the cannabinoid is cannabidiol (CBD) this results in a clear colourless or light-yellow solution.

[0039] Preferably the one or more cannabinoids are incorporated within micelles. More preferably the diameter of the micelles is in the nanometre range.

[0040] The one or more cannabinoids, non-ionic surfactant and water of the oral cannabinoid containing formulation of the invention preferably comprise, by weight, at least 65% of the formulation, more preferably at least 70% through 75%, 80% to most preferably still at least [0041] Preferably the non-ionic surfactant is selected from: Polyoxyethylene (20) sorbitan monooleate, Polysorbate 80; macrogolglycerol hydroxystearate and Polyoxamers. More preferably the non-ionic surfactant is macrogolglycerol hydroxystearate.

[0042] Preferably the non-ionic surfactant is present in an amount of from 10 to 500 mg/mL depending on the concentration of the cannabinoid. Where the cannabinoid is present in an amount of about 1 % (w/v) the amount of non-ionic surfactant is more preferably 50-150 mg/mL, and most preferably about 120mg/mL. Where the cannabinoid is present in higher amounts (to 5% w/v) the non-ionic surfactant may be present in amounts approaching the higher 500mg/ml levels, depending on the cannabinoid. The use of a non-ionic surfactant significantly improves the bioavailability of the one or more cannabinoids in the formulation.

[0043] Preferably the one or more cannabinoid is selected from: cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) and

tetrahydrocannabivarinic acid (THCV A). More preferably the one or more cannabinoid is CBD or CBDV.

[0044] Preferably the one or more cannabinoid is present in an amount of 0.5 to 50 mg/mL, more preferably 1 to 30 mg/mL and most preferably about 10 to 20 mg/mL.

[0045] Preferably the one or more cannabinoid is a natural or a synthetic cannabinoid.

[0046] In a preferred embodiment of the invention the non-ionic surfactant is present in an amount of from 10 to 500 mg/mL and the cannabinoid is present in an amount of from 0.5 to 50 mg/mL.

[0047] Furthermore, the one or more cannabinoid and non-ionic surfactant are preferably used in a ratio of from 1 :5 to 1 :20 (cannabinoid: non-ionic surfactant); more preferably in a ratio of from 1 :8 to 1 :20 (cannabinoid: non-ionic surfactant), more preferably still in a ratio of from 1 :12 to 1 : 20 (cannabinoid: non-ionic surfactant). Bioavailability is further improved by managing the ratio of cannabinoid to non-ionic surfactant.

[0048] In a further embodiment of the invention the oral cannabinoid containing formulation further comprises a taste masking agent. Palatability of the oral cannabinoid containing formulation is improved by the addition of a taste masking agent.

[0049] Preferably the taste masking agent is glycerol. More preferably the taste masking agent is present in an amount of 5 to 50 mg/mL, more preferably 10-30 mg/mL, and most preferably about 20 mg/mL.

[0050] In a further embodiment of the invention the oral cannabinoid containing formulation further comprises flavouring. Palatability of the oral cannabinoid containing formulation is improved by the addition of a flavouring. [0051] Preferably the flavouring is selected from: blackcurrant flavouring, orange flavouring and peppermint flavouring. More preferably the flavouring is peppermint flavouring.

[0052] Preferably the flavouring is present in an amount of from 0.1 to 15 mg/mL, more preferably 1-10 mg/mL, and most preferably about 3 mg/mL.

[0053] In a further embodiment of the invention the oral cannabinoid containing formulation further comprises one or more preservatives.

[0054] Preferably the one or more preservatives are selected from: methyl

parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate and butyl parahydroxybenzoate. More preferably the one or more preservatives are methyl

parahydroxybenzoate and propyl parahydroxybenzoate.

[0055] Preferably the one or more preservatives are present in an amount of from 0.1 to 15 mg/mL, more preferably 1-10 mg/mL, and most preferably about 0.2 mg/mL each.

[0056] In a further embodiment of the invention the oral cannabinoid containing formulation further comprises one or more antioxidants.

[0057] Preferably the one or more antioxidant is selected from an aqueous and / or an oil based antioxidant. More preferably the one or more antioxidant is selected from an aqueous based antioxidant, which include: sodium sulphite; sodium metabisulphite; ascorbic acid; and sodium formaldehyde sulphoxylate, and / or an oilbased antioxidant which include: ascorbyl palmitate, butylated hydroxytoluene (BHT); butylated hydroxyanisole (BHA); propyl gallate; and alpha-tocopherol.

[0058] Preferably the antioxidant is an aqueous based antioxidant. More preferably the antioxidant is ascorbic acid.

[0059] Preferably the antioxidant is present in an amount of from 0.1 to 15 mg/mL, more preferably 1 to 10 mg/mL, and most preferably about 4 mg/mL.

[0060] In a further embodiment of the invention the oral cannabinoid containing formulation further comprises a sweetener. Preferably the sweetener is sucralose. Palatability of the oral cannabinoid containing formulation is improved by the addition of a sweetener.

[0061] Preferably the sweetener is present in an amount of from 0.1 to 15 mg/mL, more preferably 1 to 10 mg/mL, and most preferably about 4 mg/mL.

[0062] In a further embodiment of the present invention the oral cannabinoid containing formulation comprises or consists essentially of one or more cannabinoids, a non-ionic surfactant, water, a taste masking agent, a flavouring, one or more preservatives, one or more antioxidants and a sweetener.

[0063] Preferably the oral cannabinoid containing formulation of the invention comprises or consists essentially of CBD and / or CBDV, macrogolglycerol hydroxystearate, glycerol, peppermint flavouring, methyl parahydroxybenzoate, propyl parahydroxybenzoate, ascorbic acid and sucralose. [0064] The oral cannabinoid formulations of the invention are stable in Climatic Zones I and II for up to 12 months at 30°C.

[0065] In a further aspect of the present invention the oral cannabinoid formulation is suitable for use in the treatment of conditions requiring the administration of a neuroprotectant or anti- convulsive medication.

[0066] Preferably the oral cannabinoid formulation is for use in the treatment of seizures.

[0067] Preferably the oral cannabinoid formulation is for use in the treatment of Dravet syndrome, Lennox Gastaut syndrome, myoclonic seizures, juvenile myoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms, West syndrome, infantile spasms, refractory infantile spasms, tuberous sclerosis complex, brain tumours, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's disease, and autism.

[0068] In accordance with a second aspect of the present invention there is provided a method of preparing an oral cannabinoid containing formulation according to the invention, comprising the steps of:

i) preparing a surfactant phase containing one or more cannabinoids and a non-ionic surfactant, optionally containing one or more excipients that dissolve in the surfactant phase; ii) preparing an aqueous phase, optionally containing one or more excipients that dissolve in the aqueous phase; and

iii) mixing the surfactant phase and the aqueous phase to form an oral cannabinoid containing formulation.

[0069] Preferably the non-ionic surfactant is macrogolglycerol hydroxystearate (Kolliphor RH40).

[0070] Optionally the one or more excipients that dissolve in the surfactant phase are taken from the group consisting of: one or more preservatives; and / or one or more antioxidants.

[0071] Optionally the one or more excipients that dissolve in the aqueous phase are taken from the group consisting of: one or more antioxidants; one or more taste masking agents; one or more sweeteners.

[0072] Optionally a flavouring is added after step (iii), preferably the flavouring is peppermint oil.

[0073] Preferably the formulation is aseptically filled into a bottle or other container. More preferably the process is performed under nitrogen.

[0074] In accordance with a third aspect of the present invention there is provided a method of treating a subject comprising administering an oral cannabinoid formulation of the invention to the subject. Preferably the subject is a human.

DEFINITIONS [0075] "Cannabinoids" are a group of compounds including the endocannabinoids, the phytocannabinoids and those which are neither endocannabinoids or phytocannabinoids, hereinafter "syntho-cannabinoids".

[0076] "Endocannabinoids" are endogenous cannabinoids, which are high affinity ligands of CB1 and CB2 receptors.

[0077] "Phytocannabinoids" are cannabinoids that originate in nature and can be found in the cannabis plant. The phytocannabinoids can be present in an extract including a botanical drug substance, isolated, or reproduced synthetically.

[0078] "Syntho-cannabinoids" are those compounds capable of interacting with the cannabinoid receptors (CB1 and/or CB2) but are not found endogenously or in the cannabis plant. Examples include WIN 55212 and rimonabant.

[0079] An "isolated phytocannabinoid" is one which has been extracted from the cannabis plant and purified to such an extent that all the additional components such as secondary and minor cannabinoids and the non-cannabinoid fraction have been removed.

[0080] A "synthetic cannabinoid" is one which has been produced by chemical synthesis. This term includes modifying an isolated phytocannabinoid, by, for example, forming a

pharmaceutically acceptable salt thereof.

[0081] A "substantially pure" cannabinoid is defined as a cannabinoid which is present at greater than 95% (w/w) pure. More preferably greater than 96% (w/w) through 97% (w/w) thorough 98% (w/w) to 99% % (w/w) and greater.

[0082] A "highly purified" cannabinoid is defined as a cannabinoid that has been extracted from the cannabis plant and purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been substantially removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.

[0083] A "botanical drug substance" or "BDS" is defined in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research as: "A drug derived from one or more plants, algae, or microscopic fungi. It is prepared from botanical raw materials by one or more of the following processes: pulverisation, decoction, expression, aqueous extraction, ethanolic extraction or other similar processes."

[0084] A botanical drug substance does not include a highly purified or chemically modified substance derived from natural sources. Thus, in the case of cannabis, BDS derived from cannabis plants do not include highly purified Pharmacopoeial grade cannabinoids.

[0085] The term "predominantly water based oral formulation" describes an oral formulation which comprises water as the major component by volume. In this regard the amount of water is preferably greater than 50% (v/v) of the oral formulation, more preferably greater than 60% (v/v), more preferably greater than 70% (v/v), more preferably greater than 80% (v/v), more preferably still around 85% (v/v) of the oral formulation.

[0086] The term "oral formulation" is defined as a solution suitable and intended for oral administration. The term can be used to describe liquid preparations of medicaments suitable for administration to children and other populations which require an oral medication such as elderly or disabled patients.

[0087] The term "nanometre" or "nm" refers to a unit of length which is one thousand-millionth of a metre. With respect to the present invention the term is used to describe the size of particles in the oral formulation. Such particle sizes are within the nanometre range, which is between 1 and 999 nanometres (nm).

DETAILED DESCRIPTION OF THE INVENTION

Active pharmaceutical ingredients.

[0088] An object of the invention is to provide improved cannabinoid containing formulations.

[0089] There are many known cannabinoids and the formulation according to the present invention comprises at least one cannabinoid selected from the group consisting of:

cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA). This list is not exhaustive and merely details the cannabinoids which are identified in the present application for reference. So far, over 100 different cannabinoids have been identified and these cannabinoids can be split into different groups as follows: Phytocannabinoids; Endocannabinoids; and Synthetic

cannabinoids.

[0090] The formulation according to the present invention may also comprise at least one cannabinoid selected from those disclosed in Handbook of Cannabis, Roger Pertwee, Chapter 1 , pages 3 to 15.

[0091] It is preferred that the formulation comprises one or more cannabinoids, which are preferably selected from the group consisting of, cannabidiol (CBD) or cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabigerol (CBG) and cannabidiolic acid (CBDA) or a combination thereof. It is preferred that the formulation comprises cannabidiol (CBD) and/or cannabidivarin (CBDV).

[0092] It is preferred that the one or more cannabinoid is present in an amount of from about 0.1 to 20 (% w/v), based on the total composition, preferably from about 5 to 15 (% w/v). [0093] Preferably, the one or more cannabinoid is synthetic or highly purified from its natural source (for example, plant derived recrystallized form). When a highly purified source is used, it is purified such that the one or more cannabinoid is present at greater than 95%, more preferably 98% of the total extract (w/w).

[0094] The unit dose of cannabinoid in the oral pharmaceutical formulation may be in the range of from 0.001 to 350 mg/mL, preferably 0.1 to 35 mg/mL, more preferably 1 to 20 mg/mL.

Excipients

[0095] In order to solubilize the one or more cannabinoids, the non-ionic surfactant

macrogolglycerol hydroxystearate (Kolliphor RH40) was used. In order to make the formulation both palatable and stable sweeteners, taste masking agents, antioxidants, flavour and preservatives were also used.

Kolliphor RH40

[0096] Derived from hydrogenated castor oil and ethylene oxide, Kolliphor® RH40 is the commercial name for macrogolglycerol hydroxystearate and is used as a non-ionic oil-in-water solubiliser. It is considered safe for the pediatric population with the Inactive Ingredients

Database (II D) limit: Oral Solution: maximum potency: 450 mg/mL. Glycerol

[0097] Glycerol, also known as glycerin or glycerine, is used in a wide variety of pharmaceutical formulations including oral, otic, ophthalmic, topical and parenteral preparations. In the context of the present formulations it is used primarily as a taste masker. Glycerol is an accepted pharmaceutical excipient for oral use at levels of the proposed IID limit: 500 mg/mL.

Sucralose

[0098] Sucralose is manufactured by the chlorination of sucrose in a multistep synthesis which substitutes three of the hydroxyl groups of sucrose with chlorine atoms. It is used as a no- calorie sweetener, is safe for diabetics and non-diabetics and does not affect insulin levels. It is considered safe for the pediatric population with an ADI limit of 5 mg/kg/day.

Ascorbic acid

[0099] Ascorbic acid is used as an antioxidant in pharmaceutical formulations at a

concentration of 0.01-0.1 %. It is also used to adjust as an adjunct for oral liquids. There is no upper limit for the use of ascorbic acid although the amount used should be kept to the minimum amount required, where possible. Peppermint Oil

[00100] Peppermint (Mentha ^χ piperita, also known as M. balsamea Willd.) is a hybrid mint, a cross between watermint and spearmint. The plant, indigenous to Europe and the Middle East, is now widespread in cultivation in many regions of the world. It is found wild occasionally with its parent species. It is commonly used as a flavoring in medications and dietary supplements with I ID limits of 100 mg/mL in oral suspensions.

Methyl Paraben

[00101] Methyl paraben is a preservative and methyl ester of p-hydroxybenzoic acid. It is an antifungal agent used in cosmetics and used as a food preservative. Methylparaben is readily absorbed from the gastrointestinal tract or through the skin. It is hydrolyzed to p- hydroxybenzoic acid and rapidly excreted in urine without accumulating in the body. Acute toxicity studies have shown that methylparaben is practically non-toxic by both oral and parenteral administration in animals.

Propyl Paraben

[00102] Propyl paraben is the n-propyl ester of p-hydroxybenzoic acid and occurs as a natural substance found in many plants and some insects. It is manufactured synthetically for use in cosmetics, pharmaceuticals and foods. It is a fine white crystalline powder which is odourless, tasteless and non-irritating. Acute toxicity studies in animals indicate that propyl paraben is relatively non-toxic by both oral and parenteral routes, although it is mildly irritating to the skin. A permitted daily exposure (PDE) value of 2 mg/kg/day for adults and pediatric patients is acceptable. Preferred Formulations

[00103] It is preferred that the oral aqueous cannabinoid formulation according to the invention is palatable and provides sufficient bioavailability such that a therapeutically effective dose of cannabinoid can be delivered in relatively small quantities. Such formulations comprise the components as listed in Table 2 below. All of the excipients listed are approved by the FDA in the Inactive Ingredients Database (IID).

[00104] Table 2 below illustrates the most preferred formulation where the cannabinoid is cannabidiol (CBD); clearly other cannabinoids can be utilized in this formulation.

Table 2. Preferred formulation

Inter¬

Broad Amount mediate Quantity

Component Use range per unit range (mg/mL)

(mg/mL) (% w/v)

(mg/mL) Active

Cannabinoid 0.5-50 1-20 10 1 ingredient

Macrogolglycerol

Non-ionic

hydroxystearate Ph. Eur. 10-500 50-300 120 12

Surfactant

(Kolliphor RH40)

Co-solvent /

taste

Glycerol Ph Eur masking / 5-50 10-30 20 2 stabilising

agent

Sucralose USP-NF Sweetener 0.1-15 1-10 4 0.4

Ascorbic acid Ph Eur Antioxidant 0.1-15 1-10 4 0.4

Flavour /

taste

Peppermint Oil Ph Eur 1-10 3

masking 0.1-15 0.3 agent

Methyl

Parahydroxybenzoate Preservative 0.1-15 1-10 1.8 0.18 Ph. Eur

Propyl

Parahydroxybenzoate Preservative 0.1-15 1-10 0.2 0.02 Ph. Eur

Q.S to Q.S to 100 Q. S. to Q.S to

Water Ph Eur Solvent

100 % % 100 % 100 %

[00105] As is described above, for a 1 % cannabinoid solution the amount of non-ionic surfactant required to form a clear stable formulation is around 120 mg/mL. However, where the percentage of cannabinoid in the formulation is higher, the concentration of non-ionic surfactant may need to be increased.

Method of Manufacture

[00106] The preferred formulation (Table 2 above) was prepared as per the steps indicated below:

1. Mix Kolliphor RH40, methyl paraben, propyl paraben and cannabinoid under heat

(Surfactant phase);

2. Separately mix glycerol, sucralose, ascorbic acid and water (Aqueous phase);

3. Add aqueous phase to surfactant phase;

4. Add peppermint oil;

5. Q.S. to volume;

6. Filtration;

7. Bottle filling; and

8. Nitrogen headspace blanket and capping.

[00107] The addition of the preservative(s) to the surfactant phase enables protection of the cannabinoids during the heating phase resulting in less degradants in the final product. Method of Administration

[00108] The preferred formulation as described above in Table 2 is suitable for administration as an oral solution. Preferably the oral solution will be dispensed in bottles optionally with syringes such that an accurate dose may be provided to the patient based on an amount of cannabinoid (in mg) per weight of patient (in kg).

[00109] In addition to an oral solution that is taken either via spoon or syringe and swallowed by the patient, the formulation of the invention may be prepared in alternative means such as a spray, a drink or in a small volume such as 30ml_ of solution that is administered to the patient before swallowing.

[00110] The Examples that follow describe the development of the claimed formulations which are aqueous formulations which are free from alcohol and the bitter taste of the cannabinoids is masked. The formulations also provide good stability and exceptional bioavailability compared with a Type I oil-based formulation.

Example 1 : Bioavailability

[00111] In order to determine whether the oral aqueous cannabinoid formulation detailed in Table 2 above was able to provide suitable bioavailability a PK study using dogs was undertaken.

[00112] The oral aqueous cannabinoid formulation was compared with a Type I oil-based formulation and a formulation that was low in ethanol. The design of the study was to measure the plasma pharmacokinetics of purified CBD, its metabolites and other components of the final formulation (6-OH CBD, THC, 11-OH THC, 7-COOH-CBD) following intravenous and oral administration to the dog.

[00113] Seven naive and five non-naive male pure-bred beagle dogs were used. Each animal received a single intravenous dose of a 3 mg/mL solution of cannabidiol (CBD; 2 mg/kg) to enable bioavailability of future oral doses to be estimated.

[00114] Each animal then received a series of oral administrations of CBD, presented as capsules, gels and suspensions, all at 15 mg/kg, in a series of Latin square crossover regimens. The volume of blood taken at each sampling time-point was 2 ml_ and were collected mostly from the jugular vein. On a few occasions, cephalic vein samples were collected.

[00115] The sampling times were: 0.5, 1 , 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 h post-dose.

The determination of CBD, 6-OH CBD, THC and 1 1-OH THC in dog plasma was performed by protein precipitation with reverse phase liquid chromatography with tandem mass spectrometric detection. The LLOQ of CBD was 1 ng/mL and all metabolites had an LLOQ of 0.5 ng/mL.

[00116] The human equivalent dose (HED) can be estimated using the following formula: HED = Animal dose (mg/kg) multiplied by Animal K _m

Human K _m

The Km for a dog is 20 and the Km for a human is 37.

[00117] Thus, for a human a 2 mg/kg dose in a dog equates to a human dose of about 1.1 mg/kg.

[00118] Table 3 details the bioavailability of the different formulations tested. The CBD oral aqueous was dosed in two different concentrations (20 and 50 mg/mL). Table 3. Estimation of bioavailability (using AUC(O-t) data) of CBD in plasma of male beagle dogs following a single oral administration (15 mg/kg)

[00119] The results demonstrate a significant improvement in the bioavailability when an oral aqueous formulation is used.

[00120] A mean bioavailability of 18.5% was achieved with the 20mg/mL oral aqueous solution. In comparison to the Type I oil-based formulation and the low ethanol formulations where the bioavailability of the CBD was only between 2.6 and 6.8%.

[00121] Surprisingly the bioavailability from the water-based formulation demonstrated a seven-fold increase over the standard Type I oil-based formulation suggesting that a smaller quantity of cannabinoid would be required in order to administer effective doses if an oral aqueous formulation was used. An advantage of this would be a reduction in costs associated with expensive active ingredients such as cannabinoids. [00122] In a further bioavailability study, the formulation as detailed in Table 2 was tested on 12 healthy male volunteers. Subjects were screened and tested with either the oral aqueous formulation at a dose of 4 mg/kg or CBD in a Type I (oil-based) formulation at 10 mg/kg. Blood samples were taken pre-dose and then at 0.25h, 0.5h, 1 h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, and 48h. [00123] Data were used to determine the Cmax, Tmax and AUC for both the CBD and the 7-OH CBD metabolite. Table 4. Mean bioavailability of CBD and 7-OH CBD in healthy male volunteers following a single oral administration

[00124] As can be seen from Table 4 above when studied in a human population the dose normalized oral aqueous provided a 2-fold increase in the peak serum concentration (Cmax) of CBD compared to the oil-based formulation. Furthermore, the time taken to achieve this maximum concentration (Tmax) was halved from 4 hours with the oil-based formulation to 2 hours with the oral aqueous formulation.

[00125] The total drug exposure over time (AUC 0-infinity) was also substantially increased with the oral aqueous formulation.

[00126] Similar increases in these parameters were observed with the 7-OH CBD metabolite.

[00127] Such data are significant as it has been shown for the first time in a human population that such water-based formulations are able to not only able to provide stable and palatable formulation they were also able to improve the bioavailability of the active CBD in comparison to lipid-based formulations favoured in commercial cannabinoid medicines. Example 2: Taste masking

[00128] Initial screenings of cannabinoids solubilized in a surfactant and hydrated with water have excessive palatability issues. Firstly, surfactants such as Kolliphor RH40 exhibit very bitter taste with an unpleasant lingering of the bitterness. In addition, cannabinoids produce a burning sensation within the mouth; this can cause patient compliance issues especially in a paediatric population. It is known that cannabinoids sensitise the capsicum receptors within the mouth and this results in throat catch commonly associated with nicotine and smokers.

[00129] Therefore, as the route of administration of the formulation is oral for a pediatric patient group, optimization of the taste of the formulation was of paramount importance.

[00130] Formulations based around the excipient Kolliphor RH40 which is a non-ionic surfactant was assessed with various flavours. These formulations contained glycerol and the antioxidant alpha tocopherol to study the effect on taste masking of a 10 mg/mL CBD solution.

[00131] Various initial flavours were added to placebo and tasted. These flavours included lime, cherry, orange, blackcurrant, strawberry, pineapple, tutti-frutti, peanut butter, banana and peppermint oil. Of these flavours the ones which demonstrated promise included blackcurrant, orange and peppermint oil.

[00132] These flavours were then tested by inclusion of the active ingredient to determine if the burning sensation of the active could be masked by these flavours.

[00133] The flavours were added to the final mixture once hydrated and then were q.s. to volume with water. The results are presented in Table 5 below.

Table 5. Results of taste masking flavours

[00134] Results from the taste test of the initial flavours in water were as expected. [00135] When formulated with the Kolliphor and the cannabinoid, the flavours in combination with the other excipients needed to mask the bitterness and the burning sensation that the surfactant and active produced.

[00136] When formulated the blackcurrant flavour produced an unpalatable sickly taste. The bitterness was still apparent in both orange flavoured solutions. The peppermint oil solution was minty and the burning sensation had been removed.

[00137] By diluting the formulation 1 : 1 into orange squash the associated bitterness was reduced in the orange formulations. The peppermint-based solution was diluted in plain water the taste was palatable with a refreshing mouthfeel. Peppermint oil was chosen as the best option to reduce bitterness and burning in an oral aqueous solution.

[00138] The final optimised formulation was prepared and the taste resulted in no bitterness or burning sensation both for CBD and CBDV at 10 mg/mL.

[00139] Other taste masking agents other than glycerol that are commonly used in the manufacture of food and beverage products are Tastegem® and isomalt.

Example 3: Preservatives

[00140] Oral liquids require an antimicrobial preservative in order maintain

microbiological quality of the product at all stages throughout its proposed usage and shelf-life. The lowest specified concentration of antimicrobial preservative should be demonstrated to be effective in controlling microorganisms by using a pharmacopoeia antimicrobial preservative effectiveness test (PET).

[00141] Most common preservatives are used in combination as they provide synergistic effects. For example, paediatric paracetamol brands such as Calpol® contain a mixture of methyl, ethyl and propyl parabens to boost the antimicrobial properties of the mixture.

[00142] Common literature and the FDA inactive ingredient database list parabens as being acceptable excipients.

[00143] Propyl paraben and methyl paraben exhibit antimicrobial activity between pH 4- 8. Preservative efficacy decreases with increasing pH owing to the formation of the phenolate anion. Parabens are more active against yeasts and moulds than against bacteria. They are also more active against Gram-positive than against Gram-negative bacteria. The activity of the parabens increases with increasing chain length of the alkyl moiety; however, solubility decreases. Activity may be improved by using combinations of parabens, as additive effects occur. Propyl paraben has been used with methyl paraben in parenteral preparations, and is used in combination with other parabens in topical and oral formulations.

[00144] The antimicrobial activity of propyl paraben is reduced considerably in the presence of non-ionic surfactants as a result of micellization. [00145] It was found that the combination of methyl paraben with propyl paraben resulted in an effective preservative action.

Example 4: Antioxidants

[00146] Antioxidants are included in pharmaceutical solutions to enhance the stability of therapeutic agents that are susceptible to chemical degradation by oxidation. Typically, antioxidants are molecules that are redox systems that exhibit higher oxidative potential than the therapeutic agent or, alternatively, are compounds that inhibit free radical-induced drug decomposition. Typically, in aqueous solution antioxidants are oxidised (and hence degraded) in preference to the therapeutic agent, thereby protecting the drug from decomposition

[00147] Both water-soluble and water-insoluble antioxidants are commercially available, the choice of these being performed according to the nature of the formulation.

[00148] Examples of aqueous based antioxidants include: sodium sulphite; sodium metabisulphite; ascorbic acid; and sodium formaldehyde sulphoxylate. Examples of oil-based antioxidants include: ascorbyl palmitate, butylated hydroxytoluene (BHT); butylated

hydroxyanisole (BHA); propyl gallate; and alpha-tocopherol.

[00149] Alpha tocopherol and ascorbic acid were screened for their effectiveness for use within the formulation. Ascorbic acid was used in the aqueous phase whereas the alpha tocopherol was used in the surfactant phase in terms of order of addition.

[00150] It was noticed that the alpha-tocopherol containing solutions all appeared hazy at a 0.5% concentration, demonstrating immiscibility when hydrated with the aqueous phase. The lead antioxidant, ascorbic acid, in all formulations resulted in clear colourless solutions and was further optimised to finalise the composition.

[00151] Furthermore, it is envisaged that more than one antioxidant may be used. In this regard a combination of an oil-based and an aqueous based antioxidant may be provided. Preferably ascorbic acid and ascorbyl palmitate are used in combination.

[00152] The addition of a chelating agent such as EDTA might also be useful in providing enhanced stability to the oral solution. Example 5: Stability

[00153] Based on the palatability and bioavailability studies a 1 month accelerated study at 25°C ± 60 % RH and 40°C ± 75 % RH was carried out. Different concentrations of CBD at 10, 15 and 20 mg/mL used with the Kolliphor RH40 and other excipient levels remaining constant.

[00154] Table 6 below demonstrates the data obtained from the stability study. Table 6. Accelerated stability data with increasing CBD drug loading

Initial Day 28 (25°C ± 60% RH) Day 28 (40°C ± 75% RH)

Test

Description 10 15 20 10 15 20 mg/mL 10 15 20 mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL

Clear Clear Turbid Clear, Clear, Yellow turbid Clear, Clear, Yellow colourless colourless emulsion slight slight emulsion not yellow slight turbid

Appearance solution solution yellow yellow homogenous solution yellow emulsion solution solution solution

CBD

content 9.93 14.70 19.58 9.96 14.78 19.59 9.91 14.68 18.99

(mg/mL)

Degradants No No No No No OHCBD- OHCBD- OHCBD-

No change

(mg/mL) change change change change change 0.03 0.03 0.03

[00155] Results presented in Table 6 demonstrate that over a period of 1 month at the accelerated conditions the major change was the appearance of the solution with all the solutions turning yellow.

[00156] Previously this has been attributed to the reduction in ascorbic acid and additional work has also demonstrated that over time peppermint oil in the light causes a yellowing of the solution. In terms of chemical stability, there was no change in the 10 or 15 mg/mL solutions either at long term or accelerated conditions.

[00157] The 20 mg/mL formulation initially started off as a turbid emulsion; the ratio of drug to surfactant has increased as the Kolliphor RH40 was set constant to 12% w/v. Thus; leading to an increase in micelle size as the surfactant has to incorporate higher drug concentrations within the micelles.

[00158] Generally, emulsions are thermodynamically unstable due to their interfacial tension between the oil and water phase and their large interfacial area. However, a micro emulsion containing colloidal mixtures of surfactants and water are thermodynamically stable.

[00159] The 20 mg/mL is more representative of a colloidal mixture as the levels of degradants and impurities are not enough to explain the 3% decrease in CBD content. This decrease in 3% CBD content is attributed to the heterogeneity of the mixture as there are now phases present within the vial. When mixing, the micelles disperse throughout the mixture and therefore the 3% decrease in CBD content could be due to the sampling and homogeneity of the solution as chemically the CBD is still stable and no increases in impurities were present. The 20 mg/mL formulation has been prepared with increased Kolliphor RH40 levels to 20% w/v which resulted in a clear homogenous solution. By increasing the relative percentage of surfactant as the cannabinoid concentration increases should ensure micelles remain in the nanometre as opposed to the micrometre range as indicated by the clear as opposed to turbid appearance.

[00160] In conclusion the CBD oral aqueous solution is not limited to a 10 mg/mL concentration. If an increased concentration solution is required then this can be achieved by increasing the surfactant: drug ratio resulting in a clear homogenous micellar solution.

[00161] A 3 month stability study was conducted on a batch comprising 10 mg/mL CBD. The batch used was manufactured according to the method of manufacture described above. The batch was sub-divided to provide sufficient samples for the different storage conditions and time-points. Data from this study is provided in Table 7.

[00162] Throughout the 3 month study period there was little change in CBD content or in the pH of the samples. The formation of OH-CBD over various temperature and humidity conditions can be considered as an increasing trend of temperature as the results demonstrate that the increase in temperature 25 - 40°C over 3 months is causing the increase in OH-CBD formation with the OH-CBD at 0.24% at the accelerated 3 month time point.

[00163] These results at 3 months for the 40°C ± 2°C / 75% RH ± 5% RH storage condition are within specification. All other individual unspecified degradants fall below the 0.2 % specification limit and any other peaks above 0.1 % are being reported and monitored and all other results are within specification.

[00164] At the intermediate storage condition 30°C 65% RH the 3 month data for the active batch complies with specification with no change over time.

[00165] At the accelerated storage condition 40°C 75% RH at the 3 month data for the active batch complies with specification with no change over time

[00166] In conclusion the shelf life based on the EMA guidance for evaluation of stability data (for clinical IMP) allows a shelf life of 12 month at 30°C in Climatic Zones I and II .

Table 7. 3 month stability data

Comments

Test Acceptance criteria

Initial 25°C (3 months) 30°C (3 months) 40°C (3 months)

Clear to yellow solution free

Appearance of Solution Complies Complies Complies Complies from particulates

Amber glass bottle with white

Appearance of

child resistant cap. No Complies Complies Complies Complies packaging

evidence of leakage

Assay (CBD Content)

Within ± 10 % of Label claim 99.1 97.3 97.3 96.6 (%)

Degradants {% of CBD content)

CBE 1 NMT 0.2 % ND ND ND ND

OH-CBD NMT 0.5 % <0.1 <0.1 <0.1 0.24

Individual unspecified

NMT 0.2 % <0.1 <0.1 <0.1 <0.1 degradants

Monitor increase in any

Greater than 0.1 % <0.1 <0.1 <0.1 <0.1 unspecified degradants

Antioxidant assay

For information only

(mg/mL) 3.87 3.59 3.39 2.82

PH For Information only 3.38 3.49 3.48 3.47

TAMC - NMT 10 ² CFU/mL

Microbial quality testing TYMC - NMT 10 ¹ CFU/mL Complies Complies Complies Complies

E.Coli - Absent in 1 ml_

Example 6: Particle size

[00167] The preferred formulation was tested on a Malvern Zetasizer in order to measure the particle size of the micelles produced by the formulation.

[00168] Table 8 below details the average size of the particles of twelve batches of the formulation. As can be seen the particle size of all formulations is very consistent. All batches were shown to produce average micelle size of less than 20 nanometres. Such particle size may be important to enable faster uptake of the active agent into cells. Table 8. Particle size of micelles in oral aqueous formulation

Sample Details Date of Testing Z-Average (d.nm)

10mg/mL CBD Oral Aqueous Sorbic acid and EDTA 19-Apr-17 15.66

10mg/mL CBD Oral Aqueous - Nova Clinical Batch 19-Apr-17 15.76

10mg/mL CBD Oral Aqueous with 0.1 mg/mL EDTA 15-Feb-17 16.33

10mg/mL CBD Oral Aqueous with 0.2mg/mL EDTA, 0.1 mg/mL Sorbic Acid 15-Feb-17 16.9

10mg/mL CBD Oral Aqueous with 0.2mg/mL EDTA, 0.1 mg/mL Sorbic Acid 15-Feb-17 16.71

10mg/mL CBD Oral Aqueous with 0.2mg/mL Ascorbic Acid, 31 -Jan-17 16.9

0.2mg/mL Sodium Metabisulphite, 0.2mg/mL EDTA

10mg/mL CBD Oral Aqueous - After temperature cycling bottle 2 09-Dec-16 16.75

10mg/mL CBD Oral Aqueous - After temperature cycling bottle 1 09-Dec-16 15.92

10mg/mL CBD Oral Aqueous Solution 30-NOV-16 15.89

10mg/mL CBD Oral Aqueous Solution 03-May-17 16.51

10mg/mL CBD Oral Aqueous Solution 03-May-17 17.18

10mg/mL CBD Oral Aqueous Solution 03-May-17 19.39