Compositions containing liposomes and oral compositions

Abstract

This invention provides a liposome composition containing cannabidiol and exhibiting excellent stability, as well as an oral composition using the same. [Solution] The present invention relates to a composition containing cannabidiol, lecithin, a divalent to trivalent alcohol, and a lipid with a melting point of 130°C or higher, and also contains liposomes, and an oral composition using the same. Preferably, the lipid with a melting point of 130°C or higher contains phytosterols. Preferably, the divalent to trivalent alcohol is glycerin.

Description

Technical Field

[0001] The present invention relates to a composition containing liposomes and an oral composition.

Background Art

[0002] Cannabidiol (CBD) has attracted attention as a component expected to have new pharmacological effects. Cannabidiol is one of the cannabinoids contained in hemp, and for example, therapeutic agents for epilepsy seizures and compositions for treating tuberous sclerosis have been developed. Various forms of oral administration of cannabidiol have been proposed. Patent Document 1 describes a lipid-based particle composition, which is nanoparticles containing cannabidiol, phosphatidylcholine, sterol, and medium-chain triglyceride, having an average size in the range of about 75 nm to about 200 nm, and when stored for a period of one month, the change in the average size of the nanoparticles is less than about 20%.

[0003] Patent Document 2 describes a method for treating chemotherapy-induced nausea and vomiting by administering a pharmaceutical preparation containing a pharmaceutically effective amount of cannabidiol and delta-9-tetrahydrocannabinol to a patient who needs it, wherein the weight ratio of cannabidiol to delta-9-tetrahydrocannabinol in the preparation is from 2:0:0.5 to 0.5 to 2.0, the preparation includes a solid oral dosage form, and the administering is performed before and / or after the patient undergoes chemotherapy treatment.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

[0005] However, cannabidiol has a high melting point and is difficult to emulsify, and even conventional cannabidiol-containing formulations have not shown sufficient stability, including emulsification stability. In oral compositions containing cannabidiol that are not emulsified or are not sufficiently emulsified, there are concerns about the separation of components in the emulsion and solubility in water. [Means for solving the problem]

[0006] The present invention provides a composition containing cannabidiol, lecithin, a divalent to trivalent alcohol, and a lipid with a melting point of 130°C or higher, and also containing liposomes, and an oral composition containing the same. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a liposome-containing composition having cannabidiol and excellent stability such as emulsification stability, and an oral composition that, by containing it, not only exhibits the effects of cannabidiol but also prevents the separation of components in the emulsion and can be expected to have good solubility in water. [Modes for carrying out the invention]

[0008] The present invention will now be described in terms of preferred embodiments. In this specification, stability includes not only the stability of the emulsion state, but also the stability of liposome formation, the absence of grittiness, the absence of separation and aggregation, the stability of the average particle size, low turbidity, and low refractive index. In particular, emulsion stability is important in the present invention.

[0009] The inventors have discovered that, surprisingly, by using a specific composition of liposomes containing cannabidiol, lecithin, a specific alcohol, and a specific lipid, it is possible to obtain an oral composition that is highly stable, has a pleasant feel, and is of superior quality. The liposome-containing composition according to the present invention (hereinafter also simply referred to as "liposome composition") may be in a hydrated state or in a solid state such as a dry powder without a solvent. Examples of solvents include water and ethanol.

[0010] (A) Cannabidiol The liposome composition of the present invention is characterized by containing cannabidiol (CBD, a compound of the following formula).

[0011] [ka]

[0012] Cannabidiol is a type of cannabinoid and is known to be found in hemp. Cannabidiol is known to have different pharmacological effects from tetrahydrocannabinol, another type of cannabinoid. Cannabidiol is known to have anti-aging, anti-inflammatory, antibacterial, anxiolytic, neuroprotective, bone growth promoting, sleep promoting, hair growth promoting, skin care, fem care, and oral care effects. In the present invention, these effects can be obtained by using cannabidiol. Furthermore, the liposome composition of the present invention contains liposomes containing cannabidiol under specific conditions. Since cannabidiol is oil-soluble, this composition allows for smooth oral absorption of cannabidiol, and the effects attributed to cannabidiol can be obtained effectively. Cannabidiol is thought to be primarily surrounded by a phospholipid membrane, forming liposomes.

[0013] In particular, the present invention, which uses liposomes containing cannabidiol, lecithin, a specific alcohol, and a specific lipid, exhibits excellent stability. Although the reason for this is not entirely clear, it is thought that even though cannabidiol is an oily substance that is difficult to emulsify, incorporating it into liposomes together with lecithin, a divalent to trivalent alcohol, and a specific lipid makes the fine liposomes containing cannabidiol more stable.

[0014] In this invention, cannabidiol can be extracted and purified from plants such as hemp or citrus peels, or synthesized. It is preferable to use cannabidiol that has been purified from natural sources or synthesized, and it is even more preferable to use cannabidiol that has been purified from natural sources, in order to enhance safety and the anti-aging, anti-inflammatory, antibacterial, anti-anxiety, neuroprotective, bone growth promoting, sleep promoting, hair growth promoting, skin care, fem care, and oral care effects of cannabidiol.

[0015] To further enhance stability, cannabidiol is preferably contained in the solid content of the liposome composition at a concentration of 30% by mass or less, more preferably 25% by mass or less, even more preferably 20% by mass or less, particularly preferably 15% by mass or less, particularly more preferably 12% by mass or less, even more preferably 10% by mass or less, and even more preferably 8% by mass or less. To further enhance stability, cannabidiol is preferably contained in the solid content of the liposome composition at a concentration of 0.1% by mass or more, more preferably 0.5% by mass or more, even more preferably 1% by mass or more, particularly preferably 2% by mass or more, and particularly more preferably 5% by mass or more. In this specification, any amount where "solid content of the liposome composition" is used as the denominator can be interpreted as "of the solid content of the liposome." Here, "solid content" refers to the amount excluding solvents such as water and ethanol. In this specification, "solvent" refers to a substance with a boiling point of 100°C or less at normal pressure.

[0016] Furthermore, in order to further enhance stability, cannabidiol is preferably contained in the liposome composition at a concentration of 15% by mass or less, more preferably 12% by mass or less, even more preferably 10% by mass or less, particularly preferably 8% by mass or less, particularly more preferably 6% by mass or less, even more preferably 5% by mass or less, even more preferably 4% by mass or less, and especially preferably 3% by mass or less. Cannabidiol is preferably contained in the liposome composition at 0.001% by mass or more, more preferably 0.01% by mass or more, still more preferably 0.05% by mass or more, particularly preferably 0.1% by mass or more, especially preferably 0.5% by mass or more, still more preferably 0.6% by mass or more, even more preferably 0.7% by mass or more, particularly preferably 0.8% by mass or more, from the viewpoint of enhancing its effects.

[0017] Cannabidiol is preferably contained at 400 parts by mass or less, more preferably 350 parts by mass or less, still more preferably 300 parts by mass or less, particularly preferably 250 parts by mass or less, most preferably 200 parts by mass or less, even more preferably 150 parts by mass or less, particularly preferably 130 parts by mass or less, per 100 parts by mass of lecithin, from the viewpoint of being contained in liposomes and further enhancing stability.

[0018] Cannabidiol is preferably contained at 1 part by mass or more, more preferably 10 parts by mass or more, still more preferably 20 parts by mass or more, particularly preferably 30 parts by mass or more, most preferably 40 parts by mass or more, even more preferably 60 parts by mass or more, particularly preferably 90 parts by mass or more, per 100 parts by mass of lecithin.

[0019] The liposome composition in the present invention may contain cannabinoids other than cannabidiol in addition to cannabidiol. A cannabinoid means a compound that can bind to a cannabinoid (CB) receptor. By using a cannabinoid as an active ingredient, the function of the ECS (endocannabinoid system) that maintains homeostasis in the body can be reinforced, and the ECS can be appropriately adjusted. Cannabinoids can be classified into phytocannabinoids, endogenous cannabinoids, synthetic cannabinoids, etc. Specific compounds include, for example, 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), cannabitol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and tetrahydrocannabivarinic acid (THCVA), cannabidiol-C1 (CBD-C1), cannabidiol-C4 (CBD-C4), and cannabidiol-C6 (CBD-C6).

[0020] When the liposomal composition of the present invention contains cannabinoids other than cannabidiol, the ratio of cannabinoids other than cannabidiol to 100 parts by mass of cannabidiol is preferably 100 parts by mass or less, more preferably 80 parts by mass or less, still more preferably 60 parts by mass or less, particularly preferably 40 parts by mass or less, particularly more preferably 30 parts by mass or less, even more preferably 20 parts by mass or less, particularly preferably 10 parts by mass or less, even more preferably 5 parts by mass or less, particularly preferably 1 part by mass or less, and especially preferably 0.3 parts by mass or less.

[0021] (B) Lecithin The liposome composition of the present invention contains lecithin for the production of liposomes. Examples of lecithin include lecithin obtained from plants such as rice and barley, or from egg yolk, and hydrogenated versions thereof. Furthermore, these may also be derivatives modified with polyoxyalkylene groups such as polyethylene glycol. These lecithins may be used alone or in mixtures of two or more types. Of these, lecithin and its hydrogenated versions are preferred from the viewpoint of availability and for better demonstrating the effects of the present invention, and hydrogenated lecithin is particularly preferred. Lecithin constitutes the membrane of the liposome.

[0022] While commercially available lecithins vary in phosphatidylcholine (PC) content depending on their degree of purification, it is preferable to use hydrogenated lecithin with a PC content of 40% by mass or more, more preferably 45% by mass or more, and even more preferably 50% by mass or more, from the viewpoint of better achieving the stability of liposomes described later. Alternatively, the PC content may be, for example, 99% by mass or less.

[0023] Furthermore, it is preferable to use lecithin with an HLB of 8 or higher to further enhance stability, more preferably 9 or higher, and even more preferably 10 or higher. The HLB may also be, for example, 14 or lower, 13 or lower, or 12 or lower.

[0024] The lecithin content in the liposome composition is preferably 0.01% by mass or more in terms of achieving excellent effects of the present invention, more preferably 0.1% by mass or more, particularly preferably 0.5% by mass or more, particularly preferably 0.7% by mass or more, and particularly preferably 1.0% by mass or more. Furthermore, the lecithin content in the liposome composition is preferably 20% by mass or less in terms of emulsification stability, more preferably 10% by mass or less, even more preferably 5% by mass or less, particularly preferably 2% by mass or less, and particularly preferably 1.5% by mass or less.

[0025] The lecithin content of the liposome composition is preferably 0.1% by mass or more in terms of the effectiveness of the present invention, more preferably 0.5% by mass or more, particularly preferably 1.0% by mass or more, particularly preferably 2.0% by mass or more, particularly preferably 3.0% by mass or more, and especially preferably 5.0% by mass or more. Furthermore, the lecithin content of the liposome composition is preferably 30% by mass or less in terms of emulsification stability, more preferably 20% by mass or less, even more preferably 15% by mass or less, particularly preferably 10% by mass or less, and especially preferably 9% by mass or less.

[0026] (C) Alcohols with a valency of 2 or higher and 3 or lower The inventors have found that when a divalent to trivalent alcohol is included in liposomes together with lecithin, cannabidiol, and specific lipids, the stability of the liposomes can be effectively improved. In this specification, a divalent to trivalent alcohol refers to an alcohol having two to three hydroxyl groups in its molecule. Alcohol is a general term for substances in which a hydrogen atom of an aliphatic hydrocarbon is replaced by a hydroxyl group (-OH). The hydrocarbon referred to here may contain an ether bond in its group. Examples of dihydric alcohols include polyethylene glycol. Examples of trihydric alcohols include glycerin. In particular, the present invention prefers to contain glycerin. These alcohols are thought to play an amphiphilic role within liposomes.

[0027] From the viewpoint of further enhancing stability, the liposome composition of the present invention preferably contains 10% by mass or more of divalent to trivalent alcohols, more preferably 20% by mass or more, even more preferably 30% by mass or more, even more preferably 40% by mass or more, particularly preferably 50% by mass or more, particularly preferably 60% by mass or more, and especially preferably 70% by mass or more, in the solid content of the liposome composition. Furthermore, from the viewpoint of emulsification stability, the amount of divalent to trivalent alcohols in the solid content of the liposome composition is preferably 95% by mass or less, more preferably 90% by mass or less, and even more preferably 85% by mass or less.

[0028] In the liposome composition, the amount of divalent to trivalent alcohol is preferably 1% by mass or more, more preferably 2% by mass or more, even more preferably 3% by mass or more, even more preferably 4% by mass or more, particularly preferably 5% by mass or more, particularly preferably 6% by mass or more, and especially preferably 10% by mass or more. Furthermore, from the viewpoint of emulsification stability, the amount of divalent to trivalent alcohol in the liposome composition is preferably 40% by mass or less, more preferably 30% by mass or less, and even more preferably 20% by mass or less.

[0029] In particular, to further enhance liposome stability, in the liposome composition, the proportion of divalent to trivalent alcohol per 1 part by mass of cannabidiol is preferably more than 2 parts by mass, more preferably 4 parts by mass or more, and even more preferably 8 parts by mass or more. Furthermore, in the liposome composition, the proportion of divalent to trivalent alcohol per 1 part by mass of cannabidiol is preferably 100 parts by mass or less, more preferably 50 parts by mass or less, and even more preferably 30 parts by mass or less.

[0030] Furthermore, in order to further enhance the stability of liposomes and improve emulsification stability, it is preferable that the proportion of divalent to trivalent alcohol per 1 part by mass of lecithin in the liposome composition is preferably 0.6 parts by mass or more, more preferably 4 parts by mass or more, even more preferably 8 parts by mass or more, and particularly preferably 10 parts by mass or more. It is preferable that the proportion of divalent to trivalent alcohol per 1 part by mass of lecithin is preferably 200 parts by mass or less, more preferably 100 parts by mass or less, even more preferably 60 parts by mass or less, particularly preferably 30 parts by mass or less, and especially preferably 17 parts by mass or less.

[0031] (D) Lipids with a melting point of 130°C or higher The liposome composition of the present invention contains a lipid with a melting point of 130°C or higher (hereinafter also referred to as "specific lipid"). The inclusion of specific lipid in the liposome composition stabilizes the emulsified structure (vesicle structure) formed by lecithin within the liposome, thereby improving the stability of the liposome. The reason why lipids with a melting point of 130°C or higher contribute to liposome stabilization is thought to be the improvement of the temperature dependence that causes instability in heat-induced emulsification. Specific lipids are typically contained in liposomes.

[0032] Phytosterols are preferred as lipids with a melting point of 130°C or higher. Phytosterols are a general term for phytosterols found in plants, and the main components include β-cytophytosterol, stigmaphytosterol, campephytosterol, and brassicaphytosterol. One of these phytosterols may be used, or a mixture of two or more may be used. In this specification, the melting point can be measured by a visual method that confirms the temperature at the point of dissolution by heating, based on JIS K0064. For lipids with a melting point of 130°C or higher, a melting point of 180°C or lower is preferred, 160°C or lower is more preferred, and 150°C or lower is particularly preferred.

[0033] If a specific lipid is present, its content is preferably 0.001% by mass or more in the liposome composition from the above viewpoint, more preferably 0.05% by mass or more, particularly preferably 0.1% by mass or more, and even more preferably 0.12% by mass or more. Furthermore, if a specific lipid is present, its content is preferably 10% by mass or less in the liposome composition from the viewpoint of emulsification stability, more preferably 5% by mass or less, even more preferably 1% by mass or less, particularly preferably 0.5% by mass or less, and especially preferably 0.4% by mass or less.

[0034] If a specific lipid is included, its content is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, particularly preferably 0.3% by mass or more, and even more preferably 0.8% by mass or more, based on the solid content of the liposome composition. Furthermore, if a specific lipid is included, its content is preferably 20% by mass or less, based on the solid content of the liposome composition, based on the ability to obtain a stable composition, more preferably 10% by mass or less, even more preferably 5% by mass or less, particularly preferably 3% by mass or less, and especially preferably 2.4% by mass or less, based on the solid content of the liposome composition.

[0035] In terms of enhancing the effects of the present invention, the amount of specific lipid is preferably 0.01 parts by mass or more per 1 part by mass of cannabidiol, more preferably 0.05 parts by mass or more, more preferably 0.1 parts by mass or more in terms of easily obtaining liposomes with excellent stability. The amount of specific lipid is preferably 5.0 parts by mass or less per 1 part by mass of cannabidiol, more preferably 1.0 part by mass or less, even more preferably 0.5 parts by mass or less, and particularly preferably 0.3 parts by mass or less.

[0036] (Average particle size) In the liposome composition of the present invention, the average particle diameter of the liposomes is preferably, for example, 100 nm or more, from the viewpoint of safety for in vivo use, 200 nm or more is more preferable, 300 nm or more is particularly preferable, and from the viewpoint of reducing manufacturing costs, 750 nm or more is preferable, and 800 nm or more is particularly preferable. Furthermore, from the viewpoint of improving the oral absorption of the liposomes, the average particle diameter of the liposomes is preferably 1200 nm or less, more preferably 1100 nm or less, and from this viewpoint, it may also be 1000 nm or less, or 500 nm or less. The average particle size of liposomes can be measured using commercially available particle size analyzers such as laser diffraction particle size analyzers and light scattering photometers, but preferably, it is measured using a dynamic light scattering particle size analyzer. As a dynamic light scattering particle size analyzer, the Malvern Zetasizer Nano-ZS can be used, and the average particle size is obtained by zeta potential measurement. Furthermore, the average particle size is measured while the particles are dispersed (emulsified) in a suspension, and specifically, it is measured using the following method. (1) Pre-measurement processing The liposome composition is diluted with purified water to a concentration of 0.1% by mass relative to the total volume of the sample to be measured, and the mixture is stirred for 30 seconds using a magnetic stirrer or vortex mixer. (2) Measurement The sample obtained above is added to a polystyrene cell provided with the instrument, and DLS measurement is performed under the sample conditions (particle refractive index: 1.59, dispersion medium refractive index: 1.33, measurement temperature: 25°C, count rate: 192 Kcps, measurement time: 50 seconds) and measurement conditions (measurement angle: 173° backscatter light detection) to measure the average particle diameter. Liposomes preferably have a peak in the particle size distribution range of 50 nm to 100 nm, as measured by a dynamic light scattering particle size distribution analyzer. To achieve the above average particle size, stirring conditions, temperature conditions, etc., can be adjusted in the preferred manufacturing method described later.

[0037] (HLB) Furthermore, from the viewpoint of stability, the liposome composition preferably has an HLB of 3 to 18, more preferably 5 to 14, even more preferably 6 to 11, even more preferably 6 to less than 10, and most preferably 6 to 9. The HLB can be measured by the method described in the examples below.

[0038] Furthermore, the liposome composition is preferably turbidity 4 or less, more preferably 3.8 or less, and even more preferably 3.6 or less, from the viewpoint of increased transparency, improved appearance, and stability. Also, the liposome composition may have a turbidity of 1 or more, 2 or more, or 3 or more, from the viewpoint of increased transparency, improved appearance, and stability. Turbidity can be measured by the method described in the examples below.

[0039] (E) Other ingredients In addition to the components mentioned above, other components may be used in the liposome composition. Examples of other components include emulsifiers other than lecithin.

[0040] Examples of emulsifiers other than lecithin include sucrose fatty acid esters, monoglycerin fatty acid esters, polyglycerin fatty acid esters, polyglycerin condensed ricinoleic acid esters, propylene glycol fatty acid esters; nonionic emulsifiers such as monoglyceride acetate, monoglyceride lactate, polysorbate, and sorbitan fatty acid esters; and anionic emulsifiers such as monoglyceride diacetyl tartaric acid, monoglyceride citrate, and monoglyceride succinic acid. These can be used individually or in combination of two or more. In particular, in the present invention, emulsifiers with an HLB of 7 or less are preferred, and emulsifiers with an HLB of 5 or less are especially preferred. One or more selected from monoglycerin fatty acid esters, polyglycerin fatty acid esters, monoglyceride acetate, monoglyceride lactate, polyglycerin condensed linosileic acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, and propylene glycol fatty acid ester are especially preferred. One or more selected from monoglyceride acetate, polyglycerin fatty acid ester, polyglycerin condensed linosileic acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, and propylene glycol fatty acid ester are more preferred. One or more selected from monoglyceride acetate, polyglycerin fatty acid ester, and sucrose fatty acid ester are especially preferred, and sucrose fatty acid ester is particularly preferred.

[0041] If an emulsifier other than lecithin is included, the amount is preferably 0.1% by mass or more and 15% by mass or less, and more preferably 1% by mass or more and 10% by mass or less, relative to the solid content of the liposome composition. Furthermore, when emulsifiers other than lecithin are included, the content of emulsifiers other than lecithin is preferably 1 to 300 parts by mass per 100 parts by mass of lecithin, more preferably 2 to 200 parts by mass, even more preferably 5 to 100 parts by mass, and particularly preferably 30 to 95 parts by mass.

[0042] While not limited to these, if the liposome composition is a liquid composition, the amount of water is preferably 10 to 90% by mass, more preferably 50 to 90% by mass, and particularly preferably 80 to 90% by mass. "Liquid" preferably means, for example, that the viscosity at 25°C is 1000 mPa·s or less. The viscosity of the liquid composition is more preferably 10 mPa·s or more and 100 mPa·s or less. The viscosity of the liquid composition can be measured with a B-type viscometer (e.g., a Brookfield B-type viscometer).

[0043] In the present invention, it is preferable that the liposome composition does not contain medium-chain triglycerides. This is because the presence of medium-chain triglycerides results in a disadvantage of insufficient hydrophilic function. Medium-chain triglycerides refer to trisubstituted triglycerides with fatty acids having aliphatic tails in the range of 6 to 12 carbon atoms (e.g., 6, 7, 8, 9, 10, 11, or 12). The fatty acids include caproic acid, heptanoic acid, octanoic acid, nonanoic acid, capric acid, undecanoic acid, and / or lauric acid, or any combination thereof. Medium-chain triglycerides may include, for example, a triester of glycerol with one fatty acid having an aliphatic chain length of 8, one fatty acid having an aliphatic chain length of 9, and one fatty acid having an aliphatic chain length of 10. Medium-chain triglycerides may include a triester of glycerol with three fatty acids having aliphatic chains of the same length (e.g., each having a length of 8). Being free of medium-chain triglycerides means that the amount of medium-chain triglycerides in the liposome composition is less than 2.5% by mass, preferably 2% by mass or less, more preferably 1% by mass or less, even more preferably 0.5% by mass or less, and particularly preferably 0.1% by mass or less.

[0044] In the present invention, the liposome composition may not contain 1,2-heptanediol and / or 2,3-heptanediol. The amount of 1,2-heptanediol and / or 2,3-heptanediol in the liposome composition may be 0.1% by mass or less, more preferably 0.01% by mass or less, and particularly preferably 0.001% by mass or less.

[0045] The compositions of the present invention do not necessarily have to be used as pharmaceutical compositions for the treatment or prevention of ocular conditions. Examples of ocular conditions include dry eye, blepharitis, meibomian gland inflammation, keratitis, bacterial keratitis, protozoan keratitis, fungal keratitis, viral keratitis, conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, episcleritis, scleritis, corneal detachment, ocular inflammation, injury to the eye from ocular surgery scars, blepharoconjunctivitis, ocular rosacea, glaucoma, and contact lens intolerance. The compositions of the present invention may not be used for the treatment of Prader-Willi syndrome (PWS).

[0046] The composition of the present invention does not have to be the following composition: A Bifasix multilayer lipid vesicle cannabinoid composition comprising (a) a first phase comprising a first oil-in-water emulsion; and (b) a second phase suspended in the first phase, the second phase comprising multilayer lipid vesicles, the multilayer lipid vesicles encapsulating the second oil-in-water emulsion, wherein at least one of the first and second oil-in-water emulsions comprises a therapeutically effective amount of a cannabis-derived compound.

[0047] The composition of the present invention may not be any of the following compositions. A method for treating chemotherapy-induced nausea and vomiting by administering a formulation containing a pharmaceutically effective amount of cannabidiol and delta-9-tetrahydrocannabinol to a patient in need thereof, wherein the weight ratio of cannabidiol to delta-9-tetrahydrocannabinol in the formulation is 2:0:0.5 to 0.5 to 2.0, the formulation comprises a solid oral dosage form, and the administration is performed before and / or after the patient receives chemotherapy treatment.

[0048] The composition of the present invention may not be any of the following compositions. At least one plant extract transient receptor potential cation channel, subfamily A, Member 1 (TRPA1) Antagonist, A compound containing at least one thiol amino acid, At least one vitamin, At least one chelating agent, and at least one antioxidant A pharmaceutical composition comprising the plant extract TRPA1 antagonist, wherein the TRPA1 antagonist is selected from the group consisting of 1,8-cineole, borneol, camphor, 2-methylisoborneol, fenquil alcohol, cardamonin, and combinations thereof. The compound containing the thiol amino acid is selected from the group consisting of glutathione, N-acetylcysteine, carbocysteine, taurine, methionine, and combinations thereof, and the vitamin is selected from the group consisting of cobalamin, methylcobalamin, hydroxycobalamin, adenosylcobalamin, cyanocobalamin, cholecalciferol, thiamine, dexpanthenol, biotin, nicotinic acid, nicotinamide, and nicotinamide riboside, ascorbic acid, and combinations thereof. The chelating agent is selected from the group consisting of glutathione, N-acetylcysteine, citric acid, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), and combinations thereof. A pharmaceutical composition in which the antioxidant is selected from the group consisting of berberine, catechin, curcumin, epicatechin, epigallocatechin, epigallocatechin-3-gallate, β-carotene, quercetin, kaempferol, luteolin, ellagic acid, resveratrol, silymarin, nicotinamide adenine dinucleotide, thymoquinone, 1,8-cineole, glutathione, N-acetylcysteine, cobalamin, methylcobalamin, hydroxycobalamin, adenosylcobalamin, cyanocobalamin, β-caryophyllene, and combinations thereof.

[0049] The method for producing the liposome composition of the present invention is not particularly limited and can be produced according to known methods. For example, the liposome composition of the present invention can be prepared by mixing the liposomes obtained by the method described above with other components (external phase components).

[0050] The following describes a preferred method for producing the liposome composition of the present invention. The liposome composition of the present invention comprises a step of preparing liposomes by mixing and emulsifying an organic phase containing lecithin, cannabidiol, a divalent to trivalent alcohol and a specific lipid with an aqueous phase.

[0051] (1) First, prepare the liposomes using the following method. First, lecithin, cannabidiol, a divalent to trivalent alcohol, and a specific lipid are mixed to prepare the organic phase. It is preferable to add the specific lipid to the divalent to trivalent alcohol and dissolve it before mixing the lecithin or cannabidiol with the divalent to trivalent alcohol. To successfully obtain liposomes, it is preferable to prepare the organic phase by heating the divalent to trivalent alcohol to 80-90°C. For example, the following procedure is preferable. A divalent to trivalent alcohol is heated to 80-90°C, and a specific lipid is gradually added and dissolved while stirring, preferably at 100-500 rpm. Subsequently, lecithin is added and dissolved while stirring (preferably at 500-1000 rpm) to prepare a polyol phase. Next, a solution obtained by adding cannabidiol to ethanol (preferably at 10-30°C) is added to the polyol phase prepared in (1) above, and the mixture is preferably stirred at 500-1000 rpm to dissolve it.

[0052] The ratios of divalent to trivalent alcohols, cannabidiol, lecithin, and specific lipids used to prepare the organic phase are as described above, representing the ratios of each component in the liposome composition: divalent to trivalent alcohols, cannabidiol, and lecithin. The amount of ethanol used is not particularly limited and should be an amount suitable for handling, taking into account particle size, etc.

[0053] Next, the aqueous phase is prepared. The amount of water used to prepare the aqueous phase may be 1 to 80 parts by mass, or 2 to 80 parts by mass, per 1 part by mass of the total amount of cannabidiol, lecithin, trivalent or less alcohol (or divalent or more but less than or equal to trivalent alcohol), and specific lipids. The aqueous phase is preferably prepared at 80 to 90°C.

[0054] Next, the organic phase and the aqueous phase are mixed. This mixing is preferably carried out at 80-90°C. Known conditions can be used for the mixing speed and stirring method based on the desired particle size, etc. For example, the solution obtained above is preferably heated to 80-90°C, and the aqueous phase is added while stirring (preferably at 1000-3000 rpm), and then preferably stirred and mixed at 5000-10000 rpm.

[0055] If a liposome composition is obtained as described above, the obtained liposome composition may be used as is as an oral composition, dried by a known method and used as an oral composition, or mixed with other components in these states to form an oral composition.

[0056] Other ingredients that can be added include antioxidants such as tocopherol and ascorbic acid, organic acids such as lactic acid and citric acid, lipids such as phosphatidylethanolamine, thickeners such as xanthan gum and carboxymethylcellulose, natural polymers such as chitosan, fucoidan and hyaluronic acid, synthetic polymers such as carboxyvinyl polymer, and carbohydrates such as sucrose, trehalose, lactulose, and maltitol.

[0057] In this invention, the liposome composition contains cannabidiol, which provides an advantage in water solubility when ingested orally compared to cases without liposomes. Furthermore, the excellent stability of the liposomes in this invention is expected to improve absorption when ingested orally.

[0058] In the present invention, the intake of cannabidiol is preferably 1 to 20 mg per day for adults, more preferably 5 to 18 mg, and even more preferably 10 to 15 mg.

[0059] Oral compositions containing liposomes can be taken in one or more doses (preferably two to three doses). While humans are preferred as the target population, non-human mammals may also be targeted. Even when the target population is non-human mammals (e.g., pets or livestock, more specifically dogs, cats, monkeys, cattle, pigs, sheep, etc.), the dosage or intake for humans can be appropriately determined based on reference.

[0060] Oral compositions can preferably be used as pharmaceutical compositions or food compositions (including beverage compositions and food additive compositions). Oral compositions can be used for anti-aging, anti-inflammatory, antibacterial, anti-anxiety, neuroprotection, bone growth promotion, sleep promotion, hair growth, skin care, femcare, oral care, and more.

[0061] When used as a pharmaceutical composition, other components may include pharmaceutically acceptable bases, carriers, and / or additives (e.g., solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, etc.). Furthermore, the form of the pharmaceutical composition is not particularly limited, and examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, etc. Pharmaceutical preparations in these forms can be prepared by conventional methods by combining the liposome composition with the other components as needed.

[0062] When used as a food composition, other components may include food hygiene-approved bases, carriers, additives, and other components and materials that can be used as food. Furthermore, the form of the food composition is not particularly limited, and examples include processed foods, health foods (nutritional supplements, functional foods, foods for the sick, foods for specified health uses, functional food products, etc.), supplements, and foods for the sick (hospital meals, sick person meals, or nursing care meals, etc.). These can be prepared by conventional methods. In particular, when preparing a food composition as a health food (nutritional supplement, functional food, foods for the sick, foods for specified health uses, functional food products, etc.) or supplement, it is preferable to prepare it in the form of granules, capsules, tablets (including chewable tablets, etc.), beverages (beverage powders, drinks, etc.) to facilitate continuous intake. Among these, capsules, tablets, beverage powders, and drinks are preferred in terms of ease of intake, but are not limited to these. Furthermore, when used as a food additive composition within a food composition, its form may include, for example, liquid, powder, flake, granule, or paste. [Examples]

[0063] The present invention will be described below based on examples, but the present invention is not limited to the following examples. The compositions in Tables 1 and 2 were used in the examples and comparative examples. The procedure for preparing the liposome solution was as follows. Note that the percentages in the table represent mass percentages. For hydrogenated lecithin, a commercially available powder with a PC content of 50-99% by mass (HLB10) was used. For phytosterols, phytosterol-SKP (manufactured by Tama Biochemical Co., Ltd.) was used (melting point 131-146°C). For medium-chain triglycerides, a reaction product obtained by esterifying a mixture of medium-chain fatty acids, caprylic acid and capric acid (mass ratio 6:4), with glycerol was used. For sucrose fatty acid esters, those with an HLB of 2 were used.

[0064] (Examples 1-6) (1) Glycerin was heated to 80°C, and phytosterols were gradually added and dissolved while stirring with a propeller stirrer (250-500 rpm). Subsequently, hydrogenated lecithin was gradually added and dissolved while stirring with a propeller stirrer (500-1000 rpm) to prepare the polyol phase. (2) A solution obtained by adding CBD to ethanol (at room temperature) was added to the polyol phase prepared in (1) above, and dissolved by stirring with a propeller stirrer (550 rpm for 5 min). (3) The solution obtained in (2) was heated to 80°C, and purified water was gradually added while stirring with a homomixer (1500 rpm). After all the purified water had been added, the mixture was stirred with a homomixer (8000 rpm, 5 min) and allowed to cool at room temperature to obtain the liposome composition. In each example, the viscosity of the obtained composition at 25°C was between 10 mPa·s and 100 mPa·s. In Example 6, sucrose fatty acid ester was added at the time of oil phase preparation.

[0065] (Comparative Example 1) In (1), a medium-chain triglyceride was used instead of glycerin. Aside from this, the liposome composition was obtained in the same manner as in Example 2.

[0066] (Comparative Example 2) In (1), phytosterols were not used, and the amount of water was increased accordingly. Aside from this, the liposome composition was obtained in the same manner as in Comparative Example 1.

[0067] (Comparative Example 3) In (1), phytosterols were not used. The amount of water was increased accordingly. Except for this point, the liposome composition was obtained in the same manner as in Example 2.

[0068] The liposome compositions of the examples and comparative examples were evaluated by the following method. The results are shown in Tables 1 and 2.

[0069] (HLB value) The calculation was based on the HLB value of the emulsifier used and the weight fraction of each emulsifier. (Liposome formation) The prepared liposome composition was measured for particle size using a particle size analyzer (Malvern's "ZetaSizer Nano-ZS"), and the formation of liposomes was confirmed based on the presence or absence of particle size peaks in the 50-100 nm range according to the following criteria. ○ A peak was observed within the 50-100 nm range. △ A peak was observed above 100 nm. × Measurement was not possible due to reasons such as precipitation. (Emulsified state) The liposome composition was visually inspected immediately after preparation to check for separation and aggregation. ○ Separation and aggregation cannot be confirmed. △ Some separation and aggregation can be observed. × They are separated and aggregated.

[0070] (exterior) The liposome composition immediately after preparation was checked for roughness by visual inspection and touch. ○ No roughness is felt. △ Some roughness can be felt. × It feels rough.

[0071] (Turbidity) The absorbance of the composition at 660 nm was measured using a UV-Vis spectrophotometer (Shimadzu Corporation "UV-1800").

[0072] (Emulsification stability) After preparation, the liposome compositions were stored at 22°C for 6 days, and the presence or absence of separation or aggregation was visually inspected. ○ No separation or aggregation was observed. △ Some separation and aggregation can be observed. × They are separated and aggregated.

[0073] [Table 1]

[0074] [Table 2]

[0075] As shown in Table 1, each of the examples, which contained cannabidiol, lecithin, a divalent to trivalent alcohol, and a lipid with a melting point of 130°C or higher, and also contained liposomes, exhibited excellent emulsification stability. In particular, Example 6, which combined two or more emulsifiers, yielded the best results. In contrast, Comparative Examples 1 and 2, which did not contain a divalent to trivalent alcohol, and Comparative Example 3, which did not contain a lipid with a melting point of 130°C or higher, did not achieve sufficient emulsification stability. [Industrial applicability]

[0076] The liposome composition of the present invention and the oral composition using the same are industrially useful because, despite using cannabidiol, they exhibit excellent stability, such as emulsification stability.

Claims

1. A composition containing cannabidiol, lecithin, a divalent to trivalent alcohol, and a lipid with a melting point of 130°C or higher, and also containing liposomes.

2. An oral composition containing the composition described in claim 1.

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