Oral cannabinoid formulations

Abstract

The present invention relates to an oral formulation containing one or more cannabinoids. Preferably one or more cannabinoids dissolved in a solvent system consisting essentially of: a non-ionic surfactant and water together with other components which ensure the cannabinoids stability and the formulations palatability. Furthermore, the cannabinoid may be selected from one or more 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).

Claims

1. An oral formulation comprising: (i) a plurality of micelles, wherein each micelle comprises a non-ionic surfactant and one or more cannabinoids, wherein the one or more cannabinoids are incorporated within the micelle; and (ii) an aqueous solvent comprising water and an antioxidant that is soluble in the aqueous solvent; wherein the micelles are miscible in the aqueous solvent.

2. The oral formulation of claim 1, wherein the one or more cannabinoids, non-ionic surfactant and water comprise at least 80% by weight of the oral formulation.

3. The oral formulation of claim 1, further comprising one or more of: a sweetener, a taste masking agent, a flavor, and a preservative.

4. The oral formulation of claim 1, wherein the non-ionic surfactant is present in an amount sufficient to ensure dissolution of the one or more cannabinoids in the formulation.

5. The oral formulation of claim 1, wherein the diameter of the micelles is in the nanometer range.

6. The oral formulation of claim 1, wherein the one or more cannabinoids, non-ionic surfactant and water comprise, at least 85% by weight of the oral formulation.

7. The oral formulation of claim 1, wherein the non-ionic surfactant is Polyoxyethylene (20) sorbitan monooleate, Polysorbate 80, macrogolglycerol hydroxystearate, or Polyoxamers.

8. The oral formulation of claim 7, wherein the non-ionic surfactant is macrogolglycerol hydroxystearate.

9. The oral formulation of claim 8, wherein the macrogolglycerol hydroxystearate is present in an amount of from 10 to 500 mg/mL.

10. The oral formulation of claim 1, wherein the one or more cannabinoids comprise 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) or tetrahydrocannabivarinic acid (THCVA).

11. The oral formulation of claim 1, wherein the one or more cannabinoids comprise CBD or CBDV.

12. The oral formulation of claim 10, wherein the one or more cannabinoids is present in an amount of 0.5 to 50 mg/mL.

13. The oral formulation of claim 1, wherein 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.

14. The oral formulation of claim 1, wherein the ratio of the one or more cannabinoids to the non-ionic surfactant ranges from 1:5 to 1:20.

15. The oral formulation of claim 14, wherein the ratio of the one or more cannabinoids to the non-ionic surfactant ranges from 1:8 to 1:20.

16. The oral formulation of claim 14, wherein the ratio of the one or more cannabinoids to the non-ionic surfactant ranges from 1:12 to 1:20.

17. The oral formulation of claim 1, further comprising a taste masking agent.

18. The oral formulation of claim 1, further comprising a flavoring.

19. The oral formulation of claim 1, further comprising one or more preservatives.

20. The oral formulation of claim 1, further comprising a sweetener.

21. The oral formulation of claim 1, comprising one or more cannabinoids, macrogolglycerol hydroxystearate, glycerol, peppermint flavoring, methyl parahydroxybenzoate, propyl parahydroxybenzoate, ascorbic acid, and sucralose, wherein the one or more cannabinoids is CBD, CBDV, or both.

22. The oral formulation of claim 1, which is stable in Climatic Zones I and II for up to 12 months at 30° C.

23. The oral formulation of claim 1, wherein the aqueous solvent comprises a taste masking agent, a sweetener, or a combination thereof.

24. The oral formulation of claim 19, wherein the preservative is methyl parahydroxybenzoate, propyl parahydroxybenzoate, or a combination thereof.

25. The oral formulation of claim 20, wherein the sweetener is sucralose.

26. The oral formulation of claim 1, wherein the antioxidant is ascorbic acid.

27. The oral formulation of claim 18, wherein the flavoring is blackcurrant, orange, or peppermint oil.

28. The oral formulation of claim 27, wherein the flavoring is peppermint oil.

29. The oral formulation of claim 23, wherein the taste masking agent is glycerol.

30. The oral formulation of claim 1, wherein the antioxidant is present in an amount ranging from 0.1 mg/mL to 15 mg/mL.

31. The oral formulation of claim 1, wherein the antioxidant is present in an amount ranging from 1 mg/mL to 10 mg/mL.

32. A method of treating a condition requiring the administration of a neuroprotectant or anti-convulsive medication comprising administering the oral formulation of claim 1.

33. A method of treating seizures comprising administering the oral formulation of claim 1.

34. The method of claim 32, wherein the condition is selected from the group consisting 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 tumors, neuropathic pain, cannabis use disorder, post-traumatic stress disorder, anxiety, early psychosis, Alzheimer's disease, and autism.

35. A method of preparing the oral formulation of claim 1, comprising: 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 comprising water and an antioxidant, optionally containing one or more excipients that dissolve in the aqueous phase; and iii) mixing the surfactant phase and the aqueous phase to form the oral formulation.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Active Pharmaceutical Ingredients.

(2) An object of the invention is to provide improved cannabinoid containing formulations.

(3) 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.

(4) 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.

(5) 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).

(6) 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).

(7) 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).

(8) 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.

(9) Excipients

(10) 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.

(11) Kolliphor RH40

(12) 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 (IID) limit: Oral Solution: maximum potency: 450 mg/mL.

(13) Glycerol

(14) 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.

(15) Sucralose

(16) 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.

(17) Ascorbic Acid

(18) 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.

(19) Peppermint Oil

(20) Peppermint (Mentha x 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 IID limits of 100 mg/mL in oral suspensions.

(21) Methyl Paraben

(22) 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.

(23) Propyl Paraben

(24) 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.

(25) Preferred Formulations

(26) 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).

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

(28) TABLE-US-00002 TABLE 2 Preferred formulation Broad Intermediate Amount range range Quantity per unit Component Use (mg/mL) (mg/mL) (mg/mL) (% w/v) Cannabinoid Active 0.5-50 1-20 10 1 ingredient Macrogolglycerol Non-ionic .sup. 10-500 50-300 120 12 hydroxystearate Ph. Eur. Surfactant (Kolliphor RH40) Glycerol Ph Eur Co-solvent/ .sup. 5-50 10-30  20 2 taste masking/ 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 Peppermint Oil Ph Eur Flavour/ 0.1-15 1-10 3 0.3 taste masking agent Methyl Preservative 0.1-15 1-10 1.8 0.18 Parahydroxybenzoate Ph. Eur Propyl Preservative 0.1-15 1-10 0.2 0.02 Parahydroxybenzoate Ph. Eur Water Ph Eur Solvent Q.S to Q.S to Q.S. to Q.S to 100% 100% 100% 100%

(29) 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.

(30) Method of Manufacture

(31) 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.

(32) 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.

(33) Method of Administration

(34) 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).

(35) 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 30 mL of solution that is administered to the patient before swallowing.

(36) 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

(37) 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.

(38) 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.

(39) Seven naïve and five non-naïve 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.

(40) 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.

(41) 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 11-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.

(42) The human equivalent dose (HED) can be estimated using the following formula:

(43) $\mathrm{HED}=\mathrm{Animal}\mathrm{dose}\left(\mathrm{mg}\text{/}\mathrm{kg}\right)\mathrm{multiplied}\mathrm{by}\frac{\mathrm{Animal}{K}_m}{\mathrm{Human}{K}_m}$
The Km for a dog is 20 and the Km for a human is 37.

(44) Thus, for a human a 2 mg/kg dose in a dog equates to a human dose of about 1.1 mg/kg.

(45) 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).

(46) TABLE-US-00003 TABLE 3 Estimation of bioavailability (using AUC(0-t) data) of CBD in plasma of male beagle dogs following a single oral administration (15 mg/kg) Subject number Formulation 47 48 49 50 57 58 59 60 Mean (%) SD Type I (oil-based) (100 mg/mL) 4.43 2.84 — — — 2.10 1.58 2.43 2.68 1.09 Low Ethanol (100 mg/mL) 5.47 2.64 — — — 12.4 1.44 12.2 6.85 5.22 Low Ethanol (200 mg/mL) 2.74 2.96 — — — 10.1 3.73 4.89 4.88 3.02 Oral aqueous (50 mg/mL) 15.4 7.64 — — — 6.32 17.9 7.13 10.9 5.38 Oral aqueous (20 mg/mL) 20.0 19.4 7.57 22.8 22.8 — — — 18.5 6.32

(47) The results demonstrate a significant improvement in the bioavailability when an oral aqueous formulation is used.

(48) A mean bioavailability of 18.5% was achieved with the 20 mg/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%.

(49) 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.

(50) 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 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h, and 48 h.

(51) Data were used to determine the Cmax, Tmax and AUC for both the CBD and the 7-OH CBD metabolite.

(52) TABLE-US-00004 TABLE 4 Mean bioavailability of CBD and 7-OH CBD in healthy male volunteers following a single oral administration Analyte CBD 7-OH CBD AUC AUC Cmax Tmax 0-INF Cmax Tmax 0-INF Formulation (ng/mL) (h) (ng/mL/h) (ng/mL) (h) (ng/mL/h) Oil-based 168 4 1060 91.2 3.03 884 (10 mg/kg) Oral Aqueous 136 2 512 102 2 532 (4 mg/kg) Oral Aqueous 340 N/A 1280 255 N/A 1330 (dose normalized) Fold 2.02 N/A 1.21 2.80 N/A 1.50 improvement

(53) 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.

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

(55) Similar increases in these parameters were observed with the 7-OH CBD metabolite.

(56) 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

(57) 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.

(58) 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.

(59) 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.

(60) 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.

(61) 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.

(62) 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.

(63) TABLE-US-00005 TABLE 5 Results of taste masking flavours Taste when diluted 100 mg in Taste when 1:1 in orange Flavour 10 mL water formulated squash (10 mg/mL) Blackcurrant Only Very bad sickly Unpalatable aftertaste of taste blackcurrant Orange liquid Tangy sharp Sight after taste Better than original refreshing of bitterness formulation taste Orange powder Sweet taste Sweet followed Sweetness enhanced by bitterness followed by sweet aftertaste Peppermint oil Minty menthol Minty no Not tested as passed bitterness as formulated

(64) Results from the taste test of the initial flavours in water were as expected.

(65) 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.

(66) 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.

(67) 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.

(68) 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.

(69) 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

(70) 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).

(71) 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.

(72) Common literature and the FDA inactive ingredient database list parabens as being acceptable excipients.

(73) 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.

(74) The antimicrobial activity of propyl paraben is reduced considerably in the presence of non-ionic surfactants as a result of micellization.

(75) It was found that the combination of methyl paraben with propyl paraben resulted in an effective preservative action.

Example 4: Antioxidants

(76) 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.

(77) Both water-soluble and water-insoluble antioxidants are commercially available, the choice of these being performed according to the nature of the formulation.

(78) 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.

(79) 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.

(80) 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.

(81) 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.

(82) The addition of a chelating agent such as EDTA might also be useful in providing enhanced stability to the oral solution.

Example 5: Stability

(83) 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.

(84) Table 6 below demonstrates the data obtained from the stability study.

(85) TABLE-US-00006 TABLE 6 Accelerated stability data with increasing CBD drug loading Initial Day 28 (25° C. ± 60% RH) Day 28 (40° C. ± 75% RH) Test 10 15 20 10 15 20 10 15 20 Description mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL mg/mL Appearance Clear Clear Turbid Clear, Clear, Yellow turbid Clear, Clear, Yellow colourless colourless emulsion slight slight emulsion not yellow slight turbid 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 No change OHCBD- OHCBD- OHCBD- (mg/mL) change change change change change 0.03 0.03 0.03

(86) 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.

(87) 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.

(88) 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;

(89) leading to an increase in micelle size as the surfactant has to incorporate higher drug concentrations within the micelles.

(90) 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.

(91) 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.

(92) 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.

(93) 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.

(94) 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.

(95) 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.

(96) 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.

(97) 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.

(98) 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.

(99) TABLE-US-00007 TABLE 7 3 month stability data Comments Test Acceptance criteria Initial 25° C. (3 months) 30° C. (3 months) 40° C. (3 months) Appearance of Solution Clear to yellow solution free Complies Complies Complies Complies from particulates Appearance of Amber glass bottle with white Complies Complies Complies Complies packaging child resistant cap. No evidence of leakage Assay (CBD Content) (%) Within ±10% of Label claim 99.1 97.3 97.3 96.6 Degradants (% of CBD content) CBE I 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 (mg/mL) For information only 3.87 3.59 3.39 2.82 pH For Information only 3.38 3.49 3.48 3.47 Microbial quality testing TAMC - NMT 10.sup.2 CFU/mL Complies Complies Complies Complies TYMC - NMT 10.sup.1 CFU/mL E. Coli - Absent in 1 mL

Example 6: Particle Size

(100) The preferred formulation was tested on a Malvern Zetasizer in order to measure the particle size of the micelles produced by the formulation.

(101) 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.

(102) TABLE-US-00008 TABLE 8 Particle size of micelles in oral aqueous formulation Z-Average Sample Details Date of Testing (d .Math. nm) 10 mg/mL CBD Oral Aqueous Sorbic acid and EDTA 19 Apr. 2017 15.66 10 mg/mL CBD Oral Aqueous - Nova Clinical Batch 19 Apr. 2017 15.76 10 mg/mL CBD Oral Aqueous with 0.1 mg/mL EDTA 15 Feb. 2017 16.33 10 mg/mL CBD Oral Aqueous with 0.2 mg/mL EDTA, 0.1 mg/mL Sorbic Acid 15 Feb. 2017 16.9 10 mg/mL CBD Oral Aqueous with 0.2 mg/mL EDTA, 0.1 mg/mL Sorbic Acid 15 Feb. 2017 16.71 10 mg/mL CBD Oral Aqueous with 0.2 mg/mL Ascorbic Acid, 31 Jan. 2017 16.9 0.2 mg/mL Sodium Metabisulphite, 0.2 mg/mL EDTA 10 mg/mL CBD Oral Aqueous - After temperature cycling bottle 2 9 Dec. 2016 16.75 10 mg/mL CBD Oral Aqueous - After temperature cycling bottle 1 9 Dec. 2016 15.92 10 mg/mL CBD Oral Aqueous Solution 30 Nov. 2016 15.89 10 mg/mL CBD Oral Aqueous Solution 3 May 2017 16.51 10 mg/mL CBD Oral Aqueous Solution 3 May 2017 17.18 10 mg/mL CBD Oral Aqueous Solution 3 May 2017 19.39