Composite composition of cannabinoids

Abstract

To provide a cannabinoid-containing composition having improved absorption.　The composite composition contains (a) an amorphous cannabinoid, (b) a hydrophilic polymer, and (c) an emulsifier.

Description

Complex cannabinoid composition

[0001] The present invention relates to a complex composition containing an amorphous cannabinoid.

[0002] Cannabinoids are a collective term for chemical compounds found in hemp, including cannabidiol, cannabinol, tetrahydrocannabinol, cannabichromene, cannabielsoin, cannabigerol, and cannabidivarin. Cannabidiol is used to treat intractable epilepsy, such as Dravet syndrome and Lennox-Gastaut syndrome, as well as tuberous sclerosis and schizophrenia. Cannabidiol is also used to treat a wide range of conditions, including glaucoma, AIDS wasting, neuropathic pain, multiple sclerosis-related spasticity, fibromyalgia, and chemotherapy-induced nausea. It has also been reported to exhibit therapeutic effects in the treatment of allergies, inflammation, infections, epilepsy, depression, migraines, bipolar disorder, anxiety disorders, and drug dependence and withdrawal symptoms. It is also particularly effective as an antiemetic, and is administered to suppress vomiting, side effects associated with the use of opioid analgesics and anesthetics, antiretroviral therapy, and cancer chemotherapy (Patent Document 1, etc.). It is also used in functional foods to relieve mental anxiety and relax the mind and body, and as an ingredient in cosmetics to improve skin problems.

[0003] However, cannabidiol has the drawback of being extremely poorly absorbable. Therefore, attempts have been made to formulate it into a dry powder formulation for inhalation (Patent Document 2) and a transdermal formulation (Patent Documents 3 and 4). For oral administration, liposome formulations using terpenes (Patent Document 1), microcapsules using terpenes (Patent Document 5), and self-emulsifying compositions using various oily media (Patent Document 6) have been reported. Furthermore, a technique for converting cannabidiols into amorphous forms using cyclodextrin, mesoporous silica, crospovidone, etc. has also been reported (Non-Patent Document 1).

[0004] Special table 2016-537412 publication Special table 2022-548377 publication Special table 2022-551730 publication Special table 2023-523155 publication Special table 2018-505912 publication Special table 2009-514890 publication

[0005] International Journal of Pharmaceutics, 589 (2020), 119812

[0006] However, a composition that sufficiently improves the absorbability of cannabinoids has not yet been developed. Therefore, an object of the present invention is to provide a cannabinoid-containing composition with improved absorbability.

[0007] The present inventors therefore prepared an emulsion composition using a cannabinoid, a hydrophilic polymer, and an emulsifier, and spray-dried or freeze-dried the emulsion composition, resulting in a composite composition containing the cannabinoid in an amorphous form. They discovered that use of this composite composition significantly improves the absorbability of the cannabinoid, and thus completed the present invention.

[0008] The present invention provides the following inventions [1] to [7]. [1] A composite composition containing (a) an amorphous cannabinoid, (b) a hydrophilic polymer, and (c) an emulsifier. [2] The composite composition of [1], wherein the hydrophilic polymer (b) is at least one polymer selected from a hydrophilic cellulose-based polymer, polyvinylpyrrolidone, copovidone, and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [3] The composite composition of [1] or [2], wherein the hydrophilic polymer (b) is at least one polymer selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose. [4] The composite composition of any of [1] to [3], wherein the emulsifier (c) has an HLB of 8 to 19. [5] The composite composition according to any one of [1] to [4], wherein the emulsifier (c) is at least one selected from glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, sucrose fatty acid esters, lecithin, and saponin. [6] A method for producing an amorphous cannabinoid-containing composite composition, comprising the steps of obtaining a fine emulsion containing (a) a cannabinoid, (b) a hydrophilic polymer, and (c) an emulsifier, and drying the fine emulsion. [7] A pharmaceutical composition, food composition, or cosmetic composition containing the composite composition according to any one of [1] to [5].

[0009] The composite composition of the present invention contains amorphous cannabinoids in a stable manner, significantly improving the absorbability of the cannabinoids. Therefore, pharmaceutical compositions, food compositions, and cosmetic compositions using the composite composition of the present invention stably exert the various pharmacological actions of cannabinoids.

[0010] FIG. 1 shows X-ray diffraction patterns of an amorphous cannabidiol-containing powder composition of the present invention (Example 1) and cannabidiol isolate raw material powder (Comparative Example 1).

[0011] Terms used in this specification are used in the sense commonly used in the art unless otherwise specified.

[0012] As used herein, the terms "contain" or "comprise" include "consist" of "consist essentially of" and "may further contain other components."

[0013] As used herein, "hydrophilic" refers to having an affinity for water, specifically the property of being easily soluble or miscible in water. Thus, a hydrophilic polymer is a polymer that is easily soluble or miscible in water. A hydrophilic emulsifier is an emulsifier that is easily soluble or miscible in water.

[0014] The term "composite composition" as used herein refers to a composition in which two or more substances form a complex. Here, the term "composite" includes both a case in which two or more substances are chemically bonded and a case in which two or more substances are physically bonded.

[0015] In this specification, the term "amorphous" refers to a state in which a substance does not have a crystalline structure, and specifically refers to a state in which a halo pattern is observed in X-ray diffraction.

[0016] One aspect of the present invention is a composite composition containing (a) an amorphous cannabinoid, (b) a hydrophilic polymer, and (c) an emulsifier.

[0017] Cannabinoids include cannabidiol, cannabinol, tetrahydrocannabinol, cannabichromene, cannabielsoin, cannabigerol, cannabidivarin, and the like. Cannabidiols include cannabidiol, cannabinol, and cannabigerol. Of these, cannabidiol is more preferred. Cannabidiol is the international nonproprietary name for the compound with the IUPAC name "2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol." Cannabidiol is a type of cannabinoid found in hemp, has various pharmacological effects, and is used not only as a medicine but also as a cosmetic and health food. Cannabidiols can be cannabinoids extracted from hemp or their purified products. (a) Amorphous cannabinoids are cannabinoids that do not have a crystalline structure, specifically cannabinoids that exhibit a halo pattern in X-ray diffraction.

[0018] The content of (a) amorphous cannabinoid in the composite composition is not particularly limited, but from the viewpoint of reducing the dosage as a composition, it is preferably 5% by mass or more in the composite composition, more preferably 10% by mass or more, even more preferably 15% by mass or more, and even more preferably 20% by mass or more. Furthermore, from the viewpoint of maintaining the cannabinoid in an amorphous form, the upper limit of the content is preferably 70% by mass or less, more preferably 65% ​​by mass or less, and even more preferably 60% by mass or less. Specifically, it is preferably 5% by mass or more and 70% by mass or less, more preferably 10% by mass or more and 70% by mass or less, more preferably 10% by mass or more and 65% by mass or less, even more preferably 15% by mass or more and 60% by mass or less, and even more preferably 20% by mass or more and 60% by mass or less.

[0019] The (b) hydrophilic polymer may be any polymer that is easily soluble or miscible with water, and is preferably at least one polymer selected from hydrophilic cellulose-based polymers, polyvinylpyrrolidone, copovidone (a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. Of these, at least one selected from hydrophilic cellulose-based polymers and polyvinylpyrrolidone is more preferred. The hydrophilic cellulose-based polymer may be any cellulose-based polymer that is easily soluble or miscible with water, and is more preferably at least one polymer selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and carboxymethylcellulose, and even more preferably at least one selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0020] The content of (b) hydrophilic polymer in the composite composition is preferably 20% by mass or more and 96% by mass or less, more preferably 30% by mass or more and 85% by mass or less, and even more preferably 35% by mass or more and 75% by mass or less, from the viewpoint of maintaining the cannabinoid in an amorphous state and improving the absorbability of the cannabinoid.

[0021] The (c) emulsifier is not particularly limited, but is preferably an emulsifier that is easily soluble or miscible with water (hydrophilic emulsifier), and more preferably an emulsifier with an HLB of 8 to 19. The (c) emulsifier is preferably a hydrophilic emulsifier, for example, at least one selected from glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, sucrose fatty acid esters, lecithin, and saponin, and more preferably at least one selected from glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, sucrose fatty acid esters, and lecithin. Here, the constituent fatty acids of the various fatty acid esters are preferably fatty acids having 8 to 20 carbon atoms. The HLB value is a value determined by the Griffin method.

[0022] The content of (c) emulsifier in the composite composition is preferably 1% by mass or more and 60% by mass or less, more preferably 5% by mass or more and 50% by mass or less, and even more preferably 5% by mass or more and 40% by mass or less, from the viewpoint of maintaining the cannabinoid in an amorphous state and improving the absorbability of the cannabinoid.

[0023] From the viewpoint of maintaining the cannabinoid in an amorphous state and improving the absorbability of the cannabinoid, the mass ratio (a / b) of the (a) amorphous cannabinoid to the (b) hydrophilic polymer in the composite composition is preferably 0.05 to 3, more preferably 0.1 to 2, and even more preferably 0.1 to 1. Furthermore, from the viewpoint of maintaining the cannabinoid in an amorphous state and improving the absorbability of the cannabinoid, the mass ratio (b / c) of the (b) hydrophilic polymer to the (c) emulsifier is preferably 0.1 to 20, more preferably 0.5 to 15, and even more preferably 1 to 10.

[0024] In addition to the components (a), (b), and (c), the composite composition of the present invention may also contain small amounts of crystalline cannabinoids, monosaccharides such as glucose, fructose, sucrose, lactose, maltose, and sorbitol, oligosaccharides, sugar alcohols, acids, colorants, flavorings, preservatives, and the like.

[0025] The composite composition of the present invention includes a form in which the components are chemically bound to each other to form a powder, and a form in which the components are physically bound to each other to form a powder. It is presumed that cannabidiol is stably maintained as an amorphous substance by forming a complex with the components (b) and (c).

[0026] The composite composition of the present invention can be produced by mixing a cannabinoid, a hydrophilic polymer, and an emulsifier to form a powder. However, another preferred embodiment of the present invention is a method for producing an amorphous cannabinoid-containing composite composition, which comprises the steps of obtaining a fine emulsion containing (a) a cannabinoid, (b) a hydrophilic polymer, and (c) an emulsifier (Step (1)), and drying the fine emulsion (Step (2)). By employing Steps (1) and (2), a composite composition can be obtained that stably contains amorphous cannabinoid and has good cannabinoid absorbability.

[0027] Step (1) is a process for obtaining a fine emulsion containing (a) a cannabinoid, (b) a hydrophilic polymer, and (c) an emulsifier. The cannabinoid may be extracted from hemp, a purified product thereof, or a chemically synthesized product. Commercially available cannabinoids are available in the form of crystalline powder. The cannabinoid, hydrophilic polymer, and emulsifier may be blended in the amounts described above. Since the cannabinoid is poorly soluble in water, it is preferably dissolved in ethanol or the like before use. The hydrophilic polymer and emulsifier are preferably dissolved in water before use. These solutions are mixed and finely emulsified. A wet grinding method is preferably used as a fine emulsification method. Specifically, grinders such as ball mills, bead mills, disc mills, high-pressure homogenizers, and ultra-high-pressure homogenizers, or grinders such as mass colloiders, may be used. Among these, ultra-high-pressure homogenizers are preferred because they are more likely to produce a uniform powder.

[0028] Step (2) is a step of drying the fine emulsion. Examples of drying methods include evaporation drying, vacuum drying, spray drying, freeze drying, hot air drying, cold air drying, and air drying. However, freeze drying and spray drying are preferred from the viewpoint of efficiently amorphizing the cannabinoids by rapid drying.

[0029] The resulting composite composition stably contains amorphous cannabinoids and exhibits good cannabinoid absorption. Therefore, the composite composition or various forms of compositions containing the same are useful as pharmaceutical compositions, food compositions, or cosmetic compositions. The pharmaceutical composition is used for the aforementioned purposes, i.e., for the treatment of intractable epilepsy such as Dravet syndrome and Lennox-Gastaut syndrome, for the treatment of tuberous sclerosis, for the treatment of schizophrenia, for glaucoma, for AIDS wasting, for neuropathic pain, for the treatment of multiple sclerosis-related convulsions, for fibromyalgia, and for the treatment of a wide range of conditions, including chemotherapy-induced nausea. It is also used to treat allergies, inflammation, infections, epilepsy, depression, migraine, bipolar disorder, anxiety disorders, and drug addiction and withdrawal symptoms. It is also particularly effective as an antiemetic, suppressing vomiting and side effects associated with the use of opioid analgesics and anesthetics, antiretroviral therapy, and cancer chemotherapy. Furthermore, as a food composition, it is used as a health food, functional food, or food for specified health uses for the purpose of preventing the above-mentioned diseases. Furthermore, as a cosmetic composition, it is used for the purpose of promoting the recovery and regeneration of damaged skin and improving and stabilizing skin function. Therefore, another aspect of the present invention is a pharmaceutical composition, food composition, or cosmetic composition containing the composite composition. Here, the pharmaceutical composition is preferably a pharmaceutical composition for oral administration.

[0030] Examples of the composition include solid compositions such as tablets, coated tablets, powders, granules, capsules, etc. To produce a pharmaceutical composition, food composition, or cosmetic composition, it can be formulated into various forms by blending with pharmaceutically acceptable carriers such as excipients, binders, disintegrants, lubricants, diluents, stabilizers, colorants, flavorings, odors, etc.

[0031] Examples of excipients include lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, gum arabic, and mixtures thereof. Examples of lubricants include purified talc, stearates, borax, polyethylene glycol, and mixtures thereof. Examples of binders include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, potassium phosphate, and mixtures thereof.

[0032] Disintegrants include, for example, dry starch, sodium alginate, powdered agar, powdered laminaran, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and mixtures thereof. Diluents include, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures thereof. Stabilizers include, for example, sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and mixtures thereof.

[0033] The amount of the composite composition in the pharmaceutical composition, food composition, or cosmetic composition of the present invention is preferably 1% by mass to 100% by mass. The intake amount of the pharmaceutical composition, food composition, or cosmetic composition of the present invention for adults is preferably 1 mg to 2000 mg per day in terms of the amount of cannabinoid.

[0034] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples in any way.

[0035] Example 1: 1.2 g of hydroxypropyl methylcellulose (HPMC: Methocel, manufactured by Dow Chemical Company) and 0.72 g of emulsifier (sucrose fatty acid ester: Ryoto Sugar Ester, manufactured by Mitsubishi Chemical Corporation) were dissolved in 78.08 g of purified water. Separately, 0.72 g of cannabidiol isolate raw material powder provided by CannaTech Co., Ltd. was dissolved in 7.28 g of ethanol to prepare a cannabidiol solution. Then, under stirring conditions, 5.33 g of the cannabidiol solution was added dropwise to the HPMC / emulsifier solution. The sample was treated with an ultra-high pressure homogenizer at 200 MPa x 1 pass and then freeze-dried at 10°C for approximately 16 hours to obtain a powder.

[0036] Example 2: 1.2 g of polyvinylpyrrolidone (PVP:PVP, manufactured by JH Nanhang Life Sciences) and 0.72 g of emulsifier (sucrose fatty acid ester: Ryoto Sugar Ester, manufactured by Mitsubishi Chemical Corporation) were dissolved in 78.08 g of purified water. Separately, 0.72 g of cannabidiol isolate raw material powder provided by CannaTech Co., Ltd. was dissolved in 7.28 g of ethanol to prepare a cannabidiol solution. Then, under stirring conditions, 5.33 g of the cannabidiol solution was added dropwise to the PVP / emulsifier solution. The sample was treated with an ultra-high pressure homogenizer at 200 MPa x 1 pass and then freeze-dried at 10°C for approximately 16 hours to obtain a powder.

[0037] Example 3: 0.3 g of hydroxypropyl methylcellulose (HPMC: Methocel, manufactured by Dow Chemical Co.) and 0.12 g of emulsifier (sucrose fatty acid ester: Ryoto Sugar Ester, manufactured by Mitsubishi Chemical Co.) were dissolved in 19.58 g of purified water. Separately, 0.72 g of cannabidiol isolate raw material powder provided by CannaTech Inc. was dissolved in 7.28 g of ethanol to prepare a cannabidiol solution. Then, 2 g of the cannabidiol solution was added dropwise to the HPMC / emulsifier solution under stirring conditions. The sample was freeze-dried at 5°C for approximately 16 hours to obtain a powder.

[0038] Comparative Example 1 Cannabidiol isolate raw material powder provided by CannaTech Co., Ltd. was used.

[0039] Comparative Example 2: 0.42 g of hydroxypropyl methylcellulose (HPMC: Methocel, manufactured by Dow Chemical Company) was dissolved in 19.58 g of purified water. Separately, 0.72 g of cannabidiol isolate raw material powder provided by CannaTech Inc. was dissolved in 7.28 g of ethanol to prepare a cannabidiol solution. Then, 2 g of the cannabidiol solution was added dropwise to the HPMC solution under stirring. The sample was freeze-dried at 5°C for approximately 16 hours to obtain a powder.

[0040] Test Example 1: The crystallinity of cannabidiol in the prepared amorphous cannabidiol-containing powder composition (Example 1) was examined using a powder X-ray diffractometer (MiniFlex 600, manufactured by Rigaku Corporation). Cannabidiol isolate raw material powder (Comparative Example 1) was used as a control. The results are shown in Figure 1. It can be seen that the cannabidiol in the composite powder composition of the present invention is amorphous. The X-ray diffraction patterns of the powders obtained in Examples 2 and 3 were similar to those of Example 1.

[0041] Test Example 2 The amorphous cannabidiol-containing powder compositions obtained in Examples 1 to 3 were used. Comparative Example 1 used cannabidiol raw material powder, and Comparative Example 2 used an amorphous cannabidiol powder composition containing no emulsifier.

[0042] Plasma cannabidiol concentrations were measured using heparinized plasma obtained by drawing approximately 0.5 mL of blood from the jugular vein of unanesthetized rats 0.5, 1, 2, 4, and / or 6 hours after the start of oral administration of 10 mg / kg, using the following method.

[0043] a. Pretreatment: 150 μL of phosphate buffer (pH 6.8) and 15 μL of β-glucuronidase solution (approximately 5,000 units / mL) were added to 30 μL of collected plasma and incubated at 37°C for 4 hours. Subsequently, 15 μL of methanol containing 500 ng / mL of phenprocoumon (an internal standard) and 0.5 mL of a 1:1 mixture of ethyl acetate and hexane were added, stirred for 10 seconds using a vortex mixer, and then mixed for 10 minutes using an ultrasonic generator. The mixture was then stirred again for 10 seconds using a vortex mixer, followed by 30 inversions. The resulting extract was then centrifuged (11,000 rpm, 5 minutes, room temperature) to separate the ethyl acetate / hexane layer and aqueous layer. The separated aqueous layer was then subjected to extraction by adding an ethyl acetate / hexane mixture in the same manner as above. Next, the ethyl acetate / hexane mixture layer was collected and evaporated to dryness by distilling off the solvent using a vacuum centrifugal concentrator. 180 μL of 50% (v / v) acetonitrile containing 0.1% formic acid was added thereto, and the mixture was centrifuged (11,000×rpm, 5 minutes, room temperature) to collect the supernatant.

[0044] b. Measurement Method: 2 μL of the supernatant prepared above was analyzed using LC-MS / MS (Bruker) to measure the cannabidiol concentration in plasma. The LC-MS / MS analysis conditions were: LC column: Atlantis C18 (2.1 × 150 mm, 3 mm, Waters), column temperature: 40°C, flow rate: 0.2 mL / min, mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid / acetonitrile, gradient elution was performed under the conditions shown in Table 1. The MS analysis conditions were Electron Spray Thermos Ionization (ESI) Positive, Multiple Reaction Monitoring (MRM) measurement mode, with cannabidiol 315.2 → 192.8 (m / z) and phenprocoumon 281.8 → 202.7 (m / z). The standard solution used to quantify the amount of cannabidiol contained in the sample was prepared by mixing 200 μL of a 0.1% formic acid acetonitrile solution with 100 μL of a 0.1% formic acid acetonitrile solution containing 500 ng / mL cannabidiol and 33.3 μL of a methanol solution containing 500 ng / mL phenprocoumon, and measuring under the same conditions as above.

[0045]

[0046] The results of cannabidiol concentration in plasma (ng / mL), maximum blood concentration (Cmax (ng / mL)), and area under the blood concentration-time curve (AUC (ng / mL·0-6 hr)) are shown in Table 2. It can be seen that the oral absorbability of the amorphous cannabidiol obtained by the present invention is significantly improved compared to Comparative Example 1. In addition, the effect of the presence or absence of an emulsifier on oral absorbability was compared, and it can be seen that Example 3 is improved compared to Comparative Example 2.

[0047]

Claims

1. A composite composition comprising: (a) an amorphous cannabinoid; (b) a hydrophilic polymer; and (c) an emulsifier.

2. The composite composition according to claim 1, wherein the hydrophilic polymer (b) is at least one polymer selected from the group consisting of hydrophilic cellulose-based polymers, polyvinylpyrrolidone, copovidone, and polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymers.

3. The composite composition according to claim 1, wherein the hydrophilic polymer (b) is at least one polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and carboxymethylcellulose.

4. The composite composition according to claim 1, wherein the emulsifier (c) has an HLB of 8 or more and 19 or less.

5. The composite composition according to claim 1, wherein (c) the emulsifier is at least one selected from glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, sucrose fatty acid esters, lecithin and saponin.

6. A method for producing a composite composition containing amorphous cannabidiol, comprising the steps of obtaining a fine emulsion containing (a) a cannabinoid, (b) a hydrophilic polymer and (c) an emulsifier, and drying the fine emulsion.

7. A pharmaceutical composition, a food composition or a cosmetic composition comprising the composite composition according to any one of claims 1 to 5.

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