Novel liquid oral formulations of cannabidiol

Abstract

The present invention relates to stable liquid oral pharmaceutical formulations of cannabidiol (CBD), and also discloses methods for producing stabilized formulations of cannabidiol using cannabidiol from synthetic sources. The stable formulations of the present invention comprise synthetic CBD and one or more pharmaceutically acceptable excipients selected from solvents, oils, organoleptic modifiers, buffers, surfactants, and the like.

Description

[Technical Field]

[0001] The present invention relates to stable liquid oral pharmaceutical formulations of cannabidiol (CBD). The present invention further discloses methods for producing stabilized formulations of cannabidiol using cannabidiol from synthetic sources. [Background technology]

[0002] Natural cannabis used for medical purposes does not refer to a single entity but encompasses a variety of products. Cannabis contains approximately 500 molecules, including approximately 100 plant-derived cannabis compounds (phytocannabinoids), terpenes, and flavonoids. The best-characterized phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is responsible for the intoxicating effects of cannabis, whereas CBD does not.

[0003] Cannabidiol can be obtained from natural sources or synthetically produced. There are many drawbacks to using CBD from natural sources. One major drawback is that CBD is co-extracted with many other components. Furthermore, the qualitative and quantitative composition of natural CBD depends on the source, plant species, and purification procedure. This often results in a product with variable properties.

[0004] Additionally, purification processes are often complex and time-consuming. Undesirable constituents are removed from natural CBD through a process known as "winterization." Winterization is a time-consuming and expensive process in which the extract is placed in a freezer at temperatures between -20°C and -80°C for 24-48 hours, precipitating high-melting-point components such as waxes, triglycerides, and chlorophyll.

[0005] Even after these expensive purification steps, natural CBD contains many major impurities, such as cannabidivarin (CBDV), tetrahydrocannabinol (THC), the butyl analog of CBD (CBD-C4), cannabidiolic acid (CBDA), and terpenes.

[0006] In contrast, synthetic CBD has consistent quality attributes and can be manufactured under controlled conditions. It also offers an economical alternative to natural CBD. However, synthetic CBD is also prone to degradation, especially when exposed to air, light, and high temperatures.

[0007] FDA-approved CBD is available as Epidiolex™, an oral liquid (100 mg / mL) for treating seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. The CBD used in this product is extracted from the inflorescence of the cannabis plant.

[0008] Patent Document 1 to GW Pharma Ltd et al. discloses a method for treating treatment-resistant epilepsy using CBD in combination with one or more antiepileptic drugs (AEDs). Potential impurities detected were CBDA (up to 0.15 w / w%), CBDV (up to 1.0 w / w%), CBD-C4 (up to 0.5 w / w%), and THC (up to 0.15 w / w%).

[0009] Patent Document 2 to GW Pharma Ltd et al. discloses the use of a highly purified cannabis extract containing at least about 95% (w / w) cannabidiol (CBD), less than 0.15% THC, and up to 1% CBDV.

[0010] Patent Document 3 to GW Pharma Ltd et al. discloses a method for treating absence seizures using CBD of a specific purity.

[0011] Kiran Kumar et al., U.S. Patent No. 5,629,999 and Blagoja et al., U.S. Patent No. 5,629,999, disclose stable oral cannabinoid formulations of synthetic CBD containing antioxidants. These patents teach that stable formulations are only possible with the use of antioxidants. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] U.S. Patent No. 9,474,726 [Patent Document 2] U.S. Patent No. 10,709,673 [Patent Document 3] US Patent Application Publication No. 2022 / 0202738 [Patent Document 4] U.S. Patent No. 1,133,1279 [Patent Document 5] International Publication No. 2021 / 046628 Summary of the Invention [Problem to be solved by the invention]

[0013] There is no literature in the art that suggests how to make or stabilize formulations containing synthetic CBD without the use of antioxidants. [Means for solving the problem]

[0014] One aspect of the present invention is to provide a liquid oral formulation of CBD, wherein the CBD is obtained from a synthetic source.

[0015] Another aspect of the present invention is to provide a liquid oral formulation of CBD, wherein the CBD is from a synthetic source and the formulation is completely THC-free.

[0016] Yet another aspect of the present invention is to provide a liquid oral formulation of CBD, wherein the CBD is obtained from a synthetic source, and the formulation is completely free of THC and CBDV.

[0017] Yet another aspect of the present invention is to provide a solution formulation of CBD, wherein the CBD is obtained from a synthetic source, and the formulation is completely free of THC, CBDV, and terpenes.

[0018] Another aspect of the present invention is to provide a solution formulation of CBD, wherein the CBD is obtained from a synthetic source and the formulation does not contain any antioxidants.

[0019] Yet another aspect of the present invention is to provide a solution formulation of CBD, wherein the CBD is obtained from a synthetic source, and the formulation is free of THC and CBDV and antioxidants. DETAILED DESCRIPTION OF THE INVENTION

[0020] In the present invention, CBD refers to synthetic cannabidiol. Cannabidiol is present in the range of 2% to 60% w / v, preferably 5% to 20% w / v, of the total formulation. The chemical name of CBD is 2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol and has the following structure:

[0021] [ka]

[0022] The term "completely free" in the present invention relates to a preparation that is free of certain impurities, such as delta9-tetrahydrocannabinol (THC) and CBDV, or contains zero amounts or below the limit of quantification.

[0023] The term "substantially free" in the present invention relates to a value of less than 0.3%. For example, the term "substantially free of impurity A" means that the impurity A is less than 0.3%.

[0024] Natural CBD is a mixture of several different components. In addition to THC and CBDV, natural CBD may contain several other coexisting compounds. These compounds help stabilize natural CBD, but come with their own undesirable pharmacological effects. Some of the impurities reported in cannabidiol preparations are:

[0025] Impurity A: Cannabidiolic Acid (CBDA) 2,4-Dihydroxy-3-[(1R,6R)-6-isopropenyl-3-methyl-2-cyclohexen-1-yl]-6-pentylbenzoic acid structure:

[0026] [ka]

[0027] Impurity B: Cannabidibutol, cannabidiol-C4, CBD-C4, CBDB Chemical Name:(1R-trans)-5-Butyl-2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-1,3-benzenediol structure:

[0028] [ka]

[0029] Impurity C: Cannabielsoin (CBE) Chemical name: (5aS,6S,9R,9aR)-9-Isopropenyl-6-methyl-3-pentyl-5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furan-1,6-diol structure:

[0030] [ka]

[0031] Impurity D: Cannabichromene (CBC) 2-Methyl-2-(4-methyl-3-penten-1-yl)-7-pentyl-2H-chromen-5-ol structure:

[0032] [ka]

[0033] Impurity E: Cannabigerol (CBG) Chemical Name:2-[(2E)-3,7-dimethyl-2,6-octadien-1-yl]-5-pentyl-1,3-benzenediol structure:

[0034] [ka]

[0035] Impurity F: Cannabinol (CBN) 6,6,9-Trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol structure:

[0036] [ka]

[0037] Impurity G: 7-hydroxycannabidiol (OH CBD) 2-[(1R,6R)-3-(Hydroxymethyl)-6-isopropenyl-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol structure:

[0038] [ka]

[0039] Impurity H: Tetrahydrocannabidavarin (THCV) 6,6,9-Trimethyl-3-propyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol structure:

[0040] [ka]

[0041] Impurity I: δ9-Tetrahydrocannabinolic acid (THCA) (6aR,10aR)-1-Hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxylic acid structure:

[0042] [ka]

[0043] Impurity J: Cannabinol (CBN) 6,6,9-Trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol structure:

[0044] [ka]

[0045] Commercially available preparations of CBD in the United States use CBD from natural sources and contain less than 0.1% THC, approximately 0.5% CBDV, and approximately 1.5% total impurities. Actual specifications may be much higher, for example, around 1% CBDV.

[0046] Unlike formulations known in the prior art, the cannabidiol formulations of the present invention are substantially free of the impurities listed above, namely, impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H, impurity I, and impurity J. More particularly, the formulations are completely free of CBDV and THC. The total impurities in the formulations of the present invention are less than 0.5%.

[0047] THC and CBDV have the following structures: Cannabidivarin (CBDV) 2-[(1R,6R)-6-Isopropenyl-3-methyl-2-cyclohexen-1-yl]-5-propyl-1,3-benzenediol structure:

[0048] [ka]

[0049] Tetrahydrocannabinol (THC) Chemical Name: (6aR,10aR)-Delta-9-tetrahydrocannabinol; (-)-trans-Δ9-tetrahydrocannabinol structure:

[0050] [ka]

[0051] Impurity analysis was performed using standard analytical methods disclosed herein.

[0052] A formulation for oral administration in the context of the present invention means a formulation that is administered orally, such as a solution or suspension in aqueous or non-aqueous liquid form, an oil-in-water or water-in-oil liquid emulsion, an elixir or syrup, a linctus, drops, a tincture, or a slurry or spray, for example.

[0053] The present inventors have successfully formulated oral CBD compositions using synthetic CBD that is completely free of THC and CBDV. These formulations are substantially free of any of the impurities listed above, i.e., Impurity A, Impurity B, Impurity C, Impurity D, Impurity E, Impurity F, Impurity G, Impurity H, Impurity I, and Impurity J.

[0054] Unlike prior art formulations which are stabilized only by the use of antioxidants, these formulations have surprisingly been found to be stable in the absence of antioxidants.

[0055] The present invention may include solvents and / or co-solvents, oils, organoleptic modifiers, surfactants, preservatives, chelating agents and buffers.

[0056] The oil in the present invention may range up to 90 w / v% and is selected from soybean oil, MCT oil, sesame oil, olive oil, corn oil, vitamin E, grape seed oil, walnut oil, avocado oil, flaxseed oil, coconut oil, olive oil, hemp seed oil, ginger oil.

[0057] The solvent or co-solvent in the present invention may range up to 90% w / v and is selected from, but is not limited to, ethanol, N-methyl-2-pyrrolidone (NMP), tertiary butyl alcohol (TBA), glycerol, propylene glycol, polyethylene glycol, and combinations thereof.

[0058] The surfactant in the present invention may be selected from, but is not limited to, amphiphilic surfactants, lipophilic surfactants, polysorbates, Span-20, Span-60 and Span-80, cremophor EL, anionic bile salts such as sodium cholate, sodium glycocholate, sodium taurocholate, sodium taurodeoxycholate, sodium lauryl sulfate, and docusate sodium.

[0059] The chelating agent in the present invention may be selected from, but is not limited to, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and disodium EDTA, and the preservative may be selected from methylparaben, propylparaben, and chlorobutanol.

[0060] The buffer in the present invention is selected from, but not limited to, L-histidine, L-arginine, Tris base, meglumine, glycine, sodium succinate, diethanolamine, aspartic acid, glutamic acid, alanine, sodium acetate, sodium ascorbate, sodium citrate, citric acid, succinic acid, triethanolamine, boric acid, sodium hydroxide, sodium bicarbonate, and the like.

[0061] The present invention may further include flavoring agents, coloring agents and sweeteners. If a sweetener is used, it is typically present in the range of 0-10 w / v %.

[0062] The formulations of the present invention do not contain any antioxidants.

[0063] When provided as per the above dosage forms, the formulations may be dispensed into bottles, optionally equipped with syringes, sachets, ampoules, vials, droppers, pre-filled syringes made of glass, rubber, or plastics such as polyvinyl chloride, polypropylene, polystyrene, and polyethylene, as well as metals such as steel, aluminum, and various alloys. These containers may be further sealed, closed, or packaged using stoppers, stoppers, lids, seals, and caps made of a variety of materials.

[0064] A preferred embodiment of the present invention comprises: (i) synthetic cannabidiol; (ii) one or more solvents selected from the group consisting of ethanol, N-methyl-2-pyrrolidone (NMP), tertiary butyl alcohol (TBA), glycerol, propylene glycol, and polyethylene glycol; Including, (a) Contains no antioxidants; (b) contains no THC; (c) contains no CBDV; It may also be in the form of a liquid oral preparation.

[0065] Another embodiment of the present invention is (i) synthetic cannabidiol; (ii) one or more solvents selected from the group consisting of ethanol, N-methyl-2-pyrrolidone (NMP), tertiary butyl alcohol (TBA), glycerol, propylene glycol, and polyethylene glycol; Including, (a) Contains no antioxidants; (b) contains no THC; (c) completely free of CBDV; (d) is substantially free of impurities, such as impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H, impurity I, and impurity J; It may also be in the form of a liquid oral preparation.

[0066] The formulations of the present invention can be used to treat epilepsy, anxiety, depression, inflammation, and pain. Compared to solid oral formulations, the formulations of the present invention have the advantage of being in liquid form and therefore easily administered.

[0067] The following are examples intended to illustrate the invention, but should not be construed as limiting the scope of the invention.

[0068] [Example 1] [Table 1]

[0069] manufacturing process 1. A weighed amount of sesame oil was received into a manufacturing vessel. 2. In a separate steel vessel fitted with a propeller mixer, absolute ethanol was added followed by sucralose with continuous mixing. 3. Under stirring, the absolute ethanol and sucralose mixture was added to the above manufacturing vessel, followed by the cannabidiol, with continuous mixing. 4. Strawberry flavor was added to the above manufacturing tank and stirred continuously for 5 minutes. 5. The above liquid formulation was collected and filtered through a 50 micron filter and the required amount was filled into bottles, followed by capping and sealing the filled bottles using PP28mm Medi-Loc Tamper Evident Two-Piece CRC Closure.

[0070] Analytical procedure: The formulations of the present invention were analyzed using a specific HPLC standardized method using a Zobrax Eclipse XDB C8, (250 x 4.6 mm), 5 μm or equivalent column, a solvent system containing acetonitrile:water, and an elution time of 70 minutes.

[0071] [Table 2]

[0072] [Table 3]

[0073] [Table 4]

[0074] [Example 2] [Table 5]

[0075] manufacturing process 1. A weighed amount of MCT oil was received into a manufacturing vessel. 2. In a separate steel vessel fitted with a propeller mixer, the required amount of absolute ethanol was added followed by sucralose with continuous mixing. 3. Under stirring, the absolute ethanol and sucralose mixture was added to the above manufacturing vessel, followed by the cannabidiol, with continuous mixing. 4. Strawberry flavor was added to the above manufacturing tank and stirred continuously for 5 minutes, and then the final volume was adjusted using ethanol. 5. The above liquid formulation was collected and filtered through a 50 micron filter and the required amount was filled into bottles, followed by capping and sealing the filled bottles using PP28mm Medi-Loc Tamper Evident Two-Piece CRC Closure.

[0076] [Example 3] [Table 6]

[0077] manufacturing process 1. A weighed amount of cremophor® was received into a manufacturing vessel. 2. In a separate steel vessel fitted with a propeller mixer, absolute ethanol was added followed by sucralose with continuous mixing. 3. Under stirring, a mixture of the required amount of absolute ethanol and a weighed amount of sucralose was added to the above manufacturing tank, followed by the cannabidiol, with continuous mixing. 4. Vanilla flavor was added to the above manufacturing tank and stirred continuously for 5 minutes, and then the final volume was adjusted with ethanol. 5. The above liquid formulation was collected and filtered through a 50 micron filter and the required amount was filled into bottles, followed by capping and sealing the filled bottles using PP28mm Medi-Loc Tamper Evident Two-Piece CRC Closure.

[0078] [Example 4] [Table 7]

[0079] manufacturing process 1. A weighed amount of N-methylpyrrolidone was received into a manufacturing vessel. 2. In a separate steel vessel fitted with a propeller mixer, absolute ethanol was added followed by sucralose with continuous mixing. 3. Under stirring, the absolute ethanol and sucralose mixture was added to the above manufacturing vessel, followed by the cannabidiol, with continuous mixing. 4. Vanilla flavor was added to the above manufacturing tank and stirred continuously for 5 minutes, and then the final volume was adjusted with ethanol. 5. The above liquid formulation was collected and filtered through a 50 micron filter and the required amount was filled into bottles, followed by capping and sealing the filled bottles using PP28mm Medi-Loc Tamper Evident Two-Piece CRC Closure.

[0080] [Example 5] [Table 8]

[0081] manufacturing process 1. A weighed amount of N-methylpyrrolidone was received into a manufacturing vessel. 2. In a separate steel vessel fitted with a propeller mixer, the required amount of absolute ethanol was added followed by sucralose with continuous mixing. 3. Under stirring, the absolute ethanol and sucralose mixture was added to the above manufacturing vessel along with a weighed amount of propylene glycol, followed by the cannabidiol with continuous mixing. 4. Vanilla flavor was added to the above manufacturing tank and stirred continuously for 5 minutes, and then the final volume was adjusted with ethanol. 5. The above liquid formulation was collected and filtered through a 50 micron filter and the required amount was filled into bottles, followed by capping and sealing the filled bottles using PP28mm Medi-Loc Tamper Evident Two-Piece CRC Closure.

Claims

1. 1. A liquid oral formulation of cannabidiol comprising: (i) synthetic cannabidiol; (ii) one or more solvents selected from the group consisting of ethanol, N-methyl-2-pyrrolidone (NMP), tertiary butyl alcohol (TBA), glycerol, propylene glycol, and polyethylene glycol; Including, (a) does not contain any antioxidants; (b) does not contain any THC; (c) contains no CBDV; formulation.

2. 2. The formulation of claim 1, which is substantially free of impurities A, B, C, D, E, F, G, H, I and J.

3. The formulation of claim 1, which is a liquid formulation.

4. 10. The formulation of claim 1, which is a suspension.

5. 10. The formulation of claim 1, which is an oral spray.

6. The formulation of claim 1 which is an emulsion.

7. 10. The formulation of claim 1, further comprising a buffer.

8. 10. The formulation of claim 1, further comprising an oil selected from the group of soybean oil, olive oil, corn oil, vitamin E, grape seed oil, walnut oil, avocado oil, flaxseed oil, coconut oil, olive oil, hemp seed oil, and ginger oil.

9. 2. The formulation of claim 1, wherein the proportion of cannabidiol is between 2% w / v and 50% w / v.

10. (i) synthetic cannabidiol; (ii) one or more solvents selected from the group comprising ethanol, N-methyl-2-pyrrolidone (NMP), tertiary butyl alcohol (TBA), glycerol, propylene glycol, polyethylene glycol; (iii) an oil selected from the group consisting of soybean oil, olive oil, corn oil, vitamin E, grape seed oil, walnut oil, avocado oil, flaxseed oil, coconut oil, olive oil, hemp seed oil, and ginger oil; Including, (a) does not contain any antioxidants; (b) does not contain any THC; (c) contains no CBDV; A liquid oral formulation of cannabidiol.

11. (i) synthetic cannabidiol; (ii) one or more solvents selected from the group consisting of ethanol, N-methyl-2-pyrrolidone (NMP), tertiary butyl alcohol (TBA), glycerol, propylene glycol, and polyethylene glycol; Including, (a) does not contain any antioxidants; (b) does not contain any THC; (c) does not contain any CBDV; and Packaged in a container suitable for effective delivery of the spray, An oral spray formulation of cannabidiol.

12. (i) synthetic cannabidiol; (ii) one or more solvents selected from the group comprising ethanol, N-methyl-2-pyrrolidone (NMP), tertiary butyl alcohol (TBA), glycerol, propylene glycol, polyethylene glycol; (iii) an oil selected from the group consisting of soybean oil, olive oil, corn oil, vitamin E, grape seed oil, walnut oil, avocado oil, flaxseed oil, coconut oil, olive oil, hemp seed oil, and ginger oil; Including, (a) does not contain any antioxidants; (b) does not contain any THC; (c) does not contain any CBDV; and Packaged in a container suitable for effective delivery of the spray, An oral spray formulation of cannabidiol.

13. (i) synthetic cannabidiol; (ii) one or more solvents selected from the group consisting of ethanol, N-methyl-2-pyrrolidone (NMP), tertiary butyl alcohol (TBA), glycerol, propylene glycol, and polyethylene glycol; Including, (a) does not contain any antioxidants; (b) does not contain any THC; (c) is completely free of CBDV; (d) substantially free of impurities A, B, C, D, E, F, G, H, I, and J; An oral solution formulation of cannabidiol.

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