Topical skin preparations

Abstract

To provide a topical skin preparation that offers enhanced skincare effects, such as collagen enhancement, as well as superior formulation stability and user experience. [Solution] The present invention is a topical skin preparation containing cannabidiol, phospholipids, and 3% by mass or more of a polyhydric alcohol, and also containing liposomes. Preferably, the liposomes further contain sterols. Preferably, the polyhydric alcohol is a dihydric alcohol having 4 or more carbon atoms. Preferably, the polyhydric alcohol has 2 to 10 hydroxyl groups in its molecule.

Description

Technical Field

[0001] The present invention relates to a skin external preparation.

Background Art

[0002] Cannabidiol (CBD) has attracted attention as a component with an expected new pharmacological action. Cannabidiol is one of the cannabinoids contained in hemp, and for example, therapeutic agents for epilepsy and therapeutic compositions for tuberous sclerosis have been developed (Patent Documents 1 and 2). Regarding cannabidiol, its use as an external preparation has also been developed.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] However, for conventional skin external preparations, there is none that can obtain excellent skin care effects, excellent formulation stability, and usability, and a skin external preparation with improved these properties is desired.

Means for Solving the Problems

[0005] The present invention provides a skin external preparation containing cannabidiol, a phospholipid, and a polyhydric alcohol of 3 mass% or more, and containing liposomes.

Effects of the Invention

[0006] According to the present invention, it is possible to provide a skin external preparation excellent in skin care effect, usability, and formulation stability.

Brief Description of the Drawings

[0007] [Figure 1] Figure 1 is a graph showing the relative expression levels of the COL1A1 gene in the examples and comparative examples. [Modes for carrying out the invention]

[0008] The present invention is described below in terms of preferred embodiments. In this specification, skincare effects include collagen production promoting effects such as collagen gene expression promoting effects. User experience includes the spreadability of the topical skin preparation, how well it blends with the skin, moisturizing effect, and whether or not it is sticky. Formulation stability includes the stability of appearance such as color, viscosity, and odor, as well as the stability of liposome particle size.

[0009] The inventors have discovered that by creating a liposome-containing formulation containing cannabidiol, phospholipids, and polyhydric alcohols, with a specific composition in which the polyhydric alcohol content exceeds a certain value, it is possible to surprisingly enhance formulation stability, improve usability, and obtain excellent collagen production promoting effects.

[0010] (A) Cannabidiol One of the features of the topical skin preparation of the present invention is that it contains 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 moisturizing, anti-aging, anti-inflammatory, antibacterial, and anti-acne effects. These effects can be obtained by using cannabidiol in the present invention. Furthermore, the topical skin preparation of the present invention contains liposomes containing cannabidiol under specific conditions. Since cannabidiol is oil-soluble, this configuration allows for smooth transdermal absorption of cannabidiol, and the effects attributed to cannabidiol can be obtained effectively.

[0013] In particular, the present invention, which uses liposomes containing cannabidiol, phospholipids, and polyhydric alcohols, and in which the polyhydric alcohol content is above a certain level, has a collagen production promoting effect as described in the examples below. The reason for this is not clear, but it is presumed that by applying cannabidiol, which has anti-aging and moisturizing effects, and phospholipids, which are known to have moisturizing effects, to the skin as fine liposomes, it contributes to the activation and improvement of fibroblast function, resulting in an excellent collagen production promoting effect. Furthermore, in the present invention, even if cannabidiol, an oily substance that is prone to stickiness and difficult to emulsify, is included in liposomes together with phospholipids and polyhydric alcohols, and the polyhydric alcohol content is above a certain amount, the fine liposomes containing cannabidiol are easily stabilized. As a result, improved permeability and reduced stickiness are obtained, resulting in a superior feel and improved formulation stability. Cannabidiol is thought to be primarily covered by a phospholipid membrane, which constitutes the membrane of liposomes.

[0014] In this invention, cannabidiol can be extracted and purified from plants such as hemp or citrus fruit peels, or synthesized. From the standpoint of safety, skincare effects such as collagen production promotion, antioxidant effects, and moisturizing effects of cannabidiol, it is preferable to use a product purified from a natural source or a synthesized product, and it is even more preferable to use a product purified from a natural source.

[0015] Cannabidiol is preferably contained in the topical skin preparation of the present invention in an amount of 10% by mass or less, more preferably 5.0% by mass or less, even more preferably 3.0% by mass or less, particularly preferably 1.0% by mass or less, particularly more preferably 0.9% by mass or less, even more preferably 0.7% by mass or less, even more preferably 0.5% by mass or less, particularly preferably 0.3% by mass or less, particularly preferably 0.1% by mass or less, particularly more preferably 0.09% by mass or less, and most preferably 0.08% by mass or less, from the viewpoint of further enhancing the collagen production promoting effect, usability, and manufacturing stability of the present invention. Cannabidiol is preferably contained in the topical skin preparation of the present invention at a concentration of 0.0001% by mass or more, more preferably 0.001% by mass or more, even more preferably 0.005% by mass or more, particularly preferably 0.01% by mass or more, and especially preferably 0.02% by mass or more, in order to further enhance the collagen production promoting effect, usability, and manufacturing stability of the present invention.

[0016] Cannabidiol is preferably contained in an amount of 100 parts by mass or less, more preferably 80 parts by mass or less, even more preferably 60 parts by mass or less, particularly preferably 40 parts by mass or less, and most preferably 30 parts by mass or less, per 100 parts by mass of phospholipid, in order to further enhance the collagen production promoting effect, usability, and manufacturing stability of the present invention. Cannabidiol is preferably contained in an amount of 1 part by mass or more, more preferably 3 parts by mass or more, even more preferably 5 parts by mass or more, particularly preferably 10 parts by mass or more, and especially more preferably 15 parts by mass or more, per 100 parts by mass of phospholipid.

[0017] The topical skin preparation of the present invention may contain cannabinoids other than cannabidiol in addition to cannabidiol. Cannabinoids mean compounds that can bind to cannabinoid (CB) receptors. By using cannabinoids as an active ingredient, the function of the ECS (endocannabinoid system) that maintains homeostasis in the body can be enhanced, and the ECS can be properly adjusted. Cannabinoids can be classified into phytocannabinoids, endogenous cannabinoids, synthetic cannabinoids, and the like. Specific compounds include, for example, cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabinocyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitol (CBO), cannabidiol-C1 (CBD-C1), cannabidiol-C4 (CBD-C4), and cannabidiol-C6 (CBD-C6).

[0018] When the topical skin preparation of the present invention contains cannabinoids other than cannabidiol, the ratio of cannabinoids other than 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, per 100 parts by mass of cannabidiol.

[0019] (B) Phospholipid The topical skin preparation of the present invention contains phospholipids for producing liposomes. Examples of the phospholipids include diacyl glycerophospholipids having polar groups such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid; lecithin obtained from plants such as soybeans, rapeseeds, sunflowers, safflowers, peanuts, cottonseeds, corns, rice, barley, etc. and egg yolk, and hydrogenated products thereof. Furthermore, these may be derivatives modified with polyoxyalkylene groups such as polyethylene glycol. These phospholipids may be used alone or in combination of two or more. Among these, from the viewpoints of availability and better exertion of the effects of the present invention, lecithin and its hydrogenated products are preferably mentioned, and particularly hydrogenated lecithin is preferred. Phospholipids constitute the membrane of liposomes.

[0020] As lecithin or hydrogenated lecithin, those having different phosphatidylcholine (hereinafter referred to as PC) contents depending on the degree of purification are commercially available. From the viewpoints of the dispersion stability of liposomes described later and better exertion of the effects of the present invention, it is preferable to use hydrogenated lecithin having a PC content of 60% by mass or more, preferably 70% by mass or more, more preferably 75% by mass or more. Also, the PC content may be, for example, 95% by mass or less, 90% by mass or less, or 85% by mass or less.

[0021] The content of the phospholipids is preferably 0.001% by mass or more in the topical skin preparation in terms of enhancing the skin permeability of the topical skin preparation and making the effects of the present invention excellent, more preferably 0.01% by mass or more, still more preferably 0.05% by mass or more, and particularly preferably 0.1% by mass or more. Also, the content of the phospholipids is preferably 20% by mass or less in the topical skin preparation in terms of excellent usability, more preferably 10% by mass or less, still more preferably 5% by mass or less, and particularly preferably 2% by mass or less.

[0022] (C) Polyhydric alcohol In the present invention, by containing polyhydric alcohols and maintaining a constant amount of polyhydric alcohols in the topical skin preparation, the formulation stability of liposomes can be improved, the feel of the topical skin preparation can be enhanced, and a collagen production promoting effect can be achieved. The reasons for this are presumed to be as follows: Polyhydric alcohols have the function of increasing the solubility of sterols and phospholipids, thereby facilitating liposome formation. More specifically, when polyhydric alcohols are included in liposomes together with phospholipids and cannabidiol, they enable the miniaturization of liposomes. It is also preferable for liposomes to contain polyhydric alcohols. In this specification, "liposomes containing polyhydric alcohols" refers, for example, to a state in which polyhydric alcohols are present on the inside of the liposome membrane. This state is usually achieved by using polyhydric alcohols as a solvent for phospholipids during liposome preparation. Furthermore, even when polyhydric alcohols are present in an external phase other than liposomes, they also function to maintain liposome stability and enhance skin penetration, resulting in a good user experience. These functions are thought to be fully exhibited by including a specific amount or more of polyhydric alcohols in topical skin preparations.

[0023] From the above viewpoint, the amount of polyhydric alcohol in the topical skin preparation is preferably 3% by mass or more, more preferably 3.5% by mass or more, and particularly preferably 4% by mass or more. Furthermore, from the viewpoint of phospholipid solubility and usability, the amount of polyhydric alcohol in the topical skin preparation is preferably 50% by mass or less, and preferably 25% by mass or less.

[0024] In this specification, a polyhydric alcohol refers to an alcohol having two or more hydroxyl groups (-OH) in its molecule. Alcohols are a general term for substances in which hydrogen atoms of aliphatic hydrocarbons are replaced by hydroxyl groups (-OH). The hydrocarbons referred to here may contain ether bonds.

[0025] Polyhydric alcohols typically include those with three or more carbon atoms. For example, alcohols with three carbon atoms (propylene glycol, glycerin, etc.), alcohols with four carbon atoms (butylene glycol, etc.), alcohols with five carbon atoms (pentylene glycol, pentaerythritol, xylitol, etc.), alcohols with six carbon atoms (trimethylolpropane, 1,2,6-hexanetriol, diglycerin, dipropylene glycol, triethylene glycol, etc.), and polyhydric alcohol polymers with seven or more carbon atoms (e.g., polyethylene glycol, polyglycerin, etc.). From the standpoint of high liposome miniaturization effect, solubility, and usability, polyhydric alcohols preferably have 2 to 10 hydroxyl groups in the molecule, more preferably 2 to 6, even more preferably 2 to 5, particularly preferably 2 to 4, particularly preferably 2 to 3, and most preferably 2.

[0026] In particular, the topical skin preparation of the present invention preferably contains a polyhydric alcohol having 4 or more carbon atoms because the liposomes are easily micronized, and it is excellent in terms of the feel of the topical skin preparation and formulation stability. It is more preferable to contain a polyhydric alcohol having 5 or more carbon atoms because it is excellent in formulation stability. The upper limit of the number of carbon atoms in the polyhydric alcohol having 4 or more carbon atoms is preferably 15 or less, more preferably 10 or less, even more preferably 8 or less, and particularly preferably 6 or less. In particular, it is preferable to contain a combination of a polyhydric alcohol having 4 carbon atoms and a polyhydric alcohol having 5 carbon atoms as the polyhydric alcohol because it is excellent in promoting collagen production. When a polyhydric alcohol having 4 carbon atoms and a polyhydric alcohol having 5 carbon atoms are combined, it is preferable that the amount of polyhydric alcohol having 5 carbon atoms is 10 to 250 parts by mass, more preferably 10 to 80 parts by mass, and particularly preferably 20 to 50 parts by mass per 100 parts by mass of polyhydric alcohol having 4 carbon atoms, in order to further improve the collagen production promoting effect. In particular, it is preferable that the polyhydric alcohol constituting the liposomes contains a polyhydric alcohol having 4 or more carbon atoms.

[0027] When the topical skin preparation of the present invention contains a polyhydric alcohol having 4 or more carbon atoms, the proportion of the polyhydric alcohol having 4 or more carbon atoms in the topical skin preparation is preferably 20% by mass or more, more preferably 30% by mass or more, even more preferably 50% by mass or more, and particularly preferably 60% by mass or more.

[0028] In particular, to further enhance the collagen production promoting effect, usability, and manufacturing stability of the present invention, the proportion of polyhydric alcohol contained in the topical skin preparation is preferably more than 3 parts by mass, more preferably 10 parts by mass or more, even more preferably 25 parts by mass or more, and especially preferably 40 parts by mass or more, per 1 part by mass of cannabidiol. Furthermore, the proportion of polyhydric alcohol contained in the topical skin preparation is preferably 500 parts by mass or less, more preferably 200 parts by mass or less, and even more preferably 150 parts by mass or less, per 1 part by mass of cannabidiol.

[0029] Furthermore, in order to further enhance the collagen production promoting effect, usability, and manufacturing stability of the present invention, it is preferable that the proportion of polyhydric alcohol contained in the topical skin preparation 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, per 1 part by mass of phospholipid. It is preferable that the proportion of polyhydric alcohol per 1 part by mass of phospholipid is preferably 300 parts by mass or less, even more preferably 100 parts by mass or less, and particularly preferably 60 parts by mass or less.

[0030] Furthermore, the content of polyhydric alcohols used as solvents for phospholipids, cannabidiol, and optionally sterols (hereinafter also referred to as "phospholipids, etc.") during liposome preparation in the topical skin preparation of the present invention is preferably 0.1% by mass or more, and more preferably 0.5% by mass or more. Furthermore, the content of polyhydric alcohols used as solvents for phospholipids, etc. during liposome preparation is preferably 30% by mass or less, and more preferably 20% by mass or less. Examples of polyhydric alcohols used as solvents for phospholipids, etc. during liposome preparation include polyhydric alcohols used as solvents to dissolve phospholipids, etc. during liposome preparation.

[0031] In particular, to further enhance the collagen production promoting effect, usability, and manufacturing stability of the present invention, it is preferable that the proportion of polyhydric alcohol used as a solvent such as phospholipids during liposome preparation is more than 2.2 parts by mass, more preferably 2.3 parts by mass or more, even more preferably 5 parts by mass or more, particularly preferably 10 parts by mass or more, and particularly more preferably 20 parts by mass or more, per 1 part by mass of cannabidiol. Furthermore, it is preferable that the proportion of polyhydric alcohol used as a solvent such as phospholipids during liposome preparation is more preferably 100 parts by mass or less, more preferably 70 parts by mass or less, particularly preferably 50 parts by mass or less, particularly preferably 40 parts by mass or less, and most preferably 35 parts by mass or less, per 1 part by mass of cannabidiol.

[0032] Furthermore, in order to further enhance the collagen production promoting effect, usability, and manufacturing stability of the present invention, it is preferable that the proportion of polyhydric alcohol used as a solvent for phospholipids, etc., during liposome preparation is preferably 0.45 parts by mass or more, more preferably 2 parts by mass or more, even more preferably 4 parts by mass or more, particularly preferably 6 parts by mass or more, and particularly more preferably 7 parts by mass or more, per 1 part by mass of phospholipid. It is preferable that the proportion of polyhydric alcohol used as a solvent for phospholipids, etc., during liposome preparation is preferably 500 parts by mass or less, even more preferably 400 parts by mass or less, and particularly preferably 300 parts by mass or less, per 1 part by mass of phospholipid.

[0033] (D) Sterols Topical skin preparations preferably contain sterols. The inclusion of sterols in the topical skin preparation allows for the reinforcement of liposomes. Specifically, this stabilizes the emulsified structure (vesicle structure) formed by phospholipids, improving the manufacturing stability and usability of liposomes, and enhancing the collagen production-promoting effect.

[0034] Examples of sterols include cholesterol, dihydrocholesterol, lanosterol, dihydrolanosterol, desmosterol, stigmasterol, sitosterol, campesterol, brassicasterol, phytosterol, ergosterol, and oryzanol. One of these may be used as the sterol, or a mixture of two or more may be used. In particular, the present invention prefers to contain phytosterol as the sterol. Phytosterol is a general term for phytosterols contained in plants, and the main components known are β-sitophytosterol, stigmaphytosterol, campephytosterol, brassicaphytosterol, etc. One of these may be used as the phytosterol, or a mixture of two or more may be used.

[0035] If sterols are present, their content is preferably 0.001% by mass or more in the topical skin preparation, more preferably 0.005% by mass or more, and particularly preferably 0.01% by mass or more, from the viewpoint mentioned above. Furthermore, if phytosterols are present, their content is preferably 10% by mass or less in the topical skin preparation, as this makes it easier to obtain a topical skin preparation with a smooth feel and excellent skin penetration, and also allows for the acquisition of a stable composition, more preferably 5% by mass or less, even more preferably 3% by mass or less, and particularly preferably 1% by mass or less.

[0036] In the topical skin preparation of the present invention, from the viewpoint of collagen production promoting effect, feel, and formulation stability, the amount of sterol is more preferably 5 parts by mass or less, and particularly preferably 1 part by mass or less, per 1 part by mass of cannabidiol. In the topical skin preparation of the present invention, the amount of sterol is preferably 0.01 parts by mass or more, per 1 part by mass of cannabidiol, in order to enhance the penetration of the topical skin preparation into the skin and to improve the effects of the present invention. From this viewpoint, in order to further improve the effects of the present invention, the amount of sterol is more preferably 0.1 parts by mass or more, per 1 part by mass of cannabidiol, in order to easily obtain a topical skin preparation with a smooth feel and excellent penetration into the skin, and even more preferably 0.5 parts by mass or more.

[0037] In topical skin preparations, liposomes having an average particle size of 500 nm or less is preferable because it improves the penetration of liposomes into the skin, thereby enhancing the effects of the present invention. From these points of view, the average particle size of liposomes is preferably 300 nm or less, and more preferably 200 nm or less. On the other hand, an average particle size of liposomes of, for example, 20 nm or more is preferable in terms of ease of material availability and ease of manufacturing, and more preferably 50 nm or more. 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. 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. Furthermore, the average particle size is measured specifically by the following method. (1) Pre-measurement processing Dilute the topical skin preparation with purified water to a concentration of 0.1%, and stir for 30 seconds using a magnetic stirrer or vortex mixer. (2) Measurement The skin topical preparation sample obtained above is added to a polystyrene cell provided in 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 measured by a dynamic light scattering particle size distribution analyzer in the range of 50 nm to 500 nm.

[0038] (E) Other ingredients In addition to the above-mentioned components, other components may be used in topical skin preparations. Examples of other components include organic solvents other than polyhydric alcohols, oils other than sterols, emulsifiers other than phospholipids, thickeners, chelating agents, pH adjusters, fragrances, surfactants, and preservatives—commonly used components in topical skin preparations.

[0039] Examples of organic solvents other than polyhydric alcohols include monohydric alcohols with 4 or fewer carbon atoms such as ethanol, 2-propanol (isopropyl alcohol), butanol, and isobutyl alcohol; glycol ethers such as diethylene glycol monoethyl ether (ethoxydiglycol), ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, triethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, propylene glycol monoethyl ether, and dipropylene glycol monoethyl ether; glycol ether esters such as ethylene glycol monoethyl ether acetate, diethylene glycol monoethyl ether acetate, and propylene glycol monoethyl ether acetate; and glycol esters such as diethoxyethyl succinate and ethylene glycol disuccinate.

[0040] The oils used include vegetable oils such as safflower oil, soybean oil, evening primrose oil, grape seed oil, rosehip oil, kukui nut oil, almond oil, sesame oil, wheat germ oil, corn oil, cottonseed oil, avocado oil, olive oil, camellia oil, peach kernel oil, castor oil, peanut oil, hazelnut oil, macadamia nut oil, and meadowfoam oil; animal oils such as squalane; hydrocarbon oils such as liquid paraffin, liquid isoparaffin, and petrolatum; ethyl oleate, ethyl linoleate, and myristic acid. Isopropyl acid, isopropyl palmitate, isopropyl isostearate, isopropyl lanolinate, hexyl laurate, myristyl myristate, cetyl myristate, octyldodecyl myristate, decyl oleate, octyldodecyl oleate, hexyldecyl dimethyloctanoate, cetyl octanoate, isocetyl octanoate, cetostearyl octanoate, stearyl octanoate, isostearyl octanoate, cetyl palmitate, cetyl lactate, Examples of suitable ester oils include diisostearyl malate, dioctyl succinate, glyceryl tricaprylate, glyceryl tri-2-ethylhexanoate (triethylhexanoin), glyceryl trilaurate, glyceryl tripalmitate, glyceryl tristearate, glyceryl trioxystearate, glyceryl triisostearate, glyceryl trioleate, glyceryl triundecylenate, glyceryl tribehenate, glycerin trimyristate, caprylic / capric acid triglycerin, propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol dinonanoate, propylene glycol dicaprylate, propylene glycol distearate, propylene glycol diisodistearate, and propylene glycol dioleate, as well as silicone oils such as cyclic silicones, methylphenyl silicones, and dimethicone. One or more of these can be selected and used.

[0041] As emulsifiers, glycerin fatty acid esters such as glyceryl stearate (SE); polyglyceryl fatty acid esters such as polyglyceryl-6 laurate, polyglyceryl-10 myristate, polyglyceryl-10 stearate, and polyglyceryl-10 isostearate; and polyoxyethylene esters such as PEG-5 glyceryl stearate, PEG-15 glyceryl stearate, PEG-15 glyceryl isostearate, PEG-20 glyceryl triisostearate, and PEG-5 glyceryl oleate. Sorbitan fatty acid esters such as sorbitan coconut fatty acid, sorbitan oleate, sorbitan sesquioleate, and sorbitan palmitate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 40, polysorbate 60, polysorbate 80, and PEG-20 sorbitan isostearate; and polyoxyethylene sorbitan fatty acids such as sorbeth-6 laurate, sorbeth-6 tetraoleate, sorbeth-30 tetraoleate, and sorbeth-60 tetraoleate. Fatty acid esters; polyoxyethylene hydrogenated castor oil such as PEG-20 hydrogenated castor oil, PEG-30 hydrogenated castor oil, PEG-60 hydrogenated castor oil, and PEG-50 hydrogenated castor oil triisostearate; polyoxyethylene alkyl ethers such as polyoxyethylene cetyl ether (ceteth-20), polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether; PPG-4 ceteth-1, PPG-8 ceteth-20, and PPG-6 decyltetradeceth-12 Examples include polyoxyethylene polyoxypropylene alkyl ethers such as PPG-6 decyltetradeceth-20; polyethylene glycol fatty acid esters such as PEG-10 laurate, PEG-10 stearate, PEG-25 stearate, PEG-40 stearate, PEG-45 stearate, PEG-55 stearate, PEG-10 oleate, PEG-150 distearate, and PEG-8 diisostearate; and these can be used individually or in combination of two or more.

[0042] Examples of thickening agents include various types that can be used in the cosmetics field. For example, natural polysaccharides, cellulosic polymers, synthetic polymers, and clay minerals can be used.

[0043] Natural polysaccharides include polysaccharides derived from plants and animals or from microbial fermentation. Specifically, these include xanthan gum, succinoglycans, carrageenan, guar gum, locust bean gum, galactan, gum arabic, tragacanth gum, tamarind gum, agar, agarose, mannan, curdlan, alginic acid or its salts, gum arabic, pectin, quince seed, starch, algae colloid, chondroitin sulfate or its salts, chitosan and its derivatives, nucleic acids or their salts, ribonucleic acid or its salts, water-soluble proteins such as casein, collagen, gelatin, albumin, fibroin, elastin, keratin, and sericin, hyaluronic acid or its salts, and mucopolysaccharides such as chondroitin sulfate. Among these, xanthan gum is preferred in terms of usability.

[0044] Cellulosic polymers are polymers composed of cellulose or its derivatives as units. Specifically, examples include carboxymethylcellulose or its salts, methylcellulose, ethylcellulose, propylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and sulfonated cellulose derivatives.

[0045] Synthetic polymers are polymers artificially synthesized using monomers as constituent units. Specifically, examples include vinyl polymers such as carboxyvinyl polymers and polyvinyl alcohol; acrylic acid polymers such as acrylic acid / alkyl methacrylate copolymers, acrylates / alkyl acrylate crosspolymers, and polyacrylic acid; acrylamide polymers such as polyacrylamide and polyalkylacrylamide / polyacrylamide copolymers; and (PEG-240 / decyltetradeceth-20 / HDI) copolymers. Among these, carboxyvinyl polymers and acrylic acid / alkyl methacrylate copolymers are preferred in terms of usability.

[0046] Clay minerals refer to substances commonly known as the main constituent minerals of clay. Specifically, these include laponite, bentonite, smectite kaolinite, and montmorillonite.

[0047] The amount of thickener in the topical skin preparation is preferably 0.01 to 2% by mass, and more preferably 0.05 to 1% by mass.

[0048] As antibacterial and preservative agents, parabens (hydroxybenzoic acid esters) such as methylparaben, ethylparaben, propylparaben, and butylparaben; phenoxyethanol; alkyl glyceryl ethers such as 2-ethylhexylglyceryl ether (ethylhexylglycerin); salicylic acid; lanolin fatty acids and their salts; sodium benzoate; isothiazolinone derivatives such as methylchloroisothiazolinone and methylisothiazolinone; imidazolinium urea; dehydroacetic acid and its salts; phenols; halogens such as triclosan Examples include bisphenol derivatives, acid amides, quaternary ammonium salts; trichlorocarbanides, zinc pyrithione, benzalkonium chloride, benzethonium chloride, sorbic acid, chlorhexidine, chlorhexidine gluconate, halocarbans, hexachlorophene, hinokitiol; phenols, isopropylphenol, cresol, thymol, parachlorophenol, phenylphenol, sodium phenylphenol, and other phenols; phenylethyl alcohol, photosensitizers, antibacterial zeolites, and silver ions.

[0049] The amount of antibacterial and preservative agents in the topical skin preparation is preferably 0.01 to 1% by mass, and more preferably 0.05 to 0.5% by mass.

[0050] Examples of chelating agents include EDTA salts (ethylenediaminetetraacetate) such as EDTA, EDTA2Na, EDTA3Na, and EDTA4Na; hydroxyethylethylenediaminetriacetate such as HEDTA3Na; pentetates (diethylenetriaminepentaacetate); phytic acid; phosphonic acids such as etidronic acid and their sodium salts; sodium oxalate; polypolyamino acids such as polyaspartic acid and polyglutamic acid; sodium polyphosphate, sodium metaphosphate, phosphoric acid; sodium citrate, and citric acid.

[0051] Preferred pH adjusters, acids, and alkalis include acetic acid, sodium acetate, hydrochloric acid, sulfuric acid, monoethanolamine, diethanolamine, triethanolamine, isopropanolamine, triisopropanolamine, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-hydroxymethyl-1,3-propanediol, arginine, sodium hydroxide, potassium hydroxide, aqueous ammonia, guanidine carbonate, and ammonium carbonate.

[0052] While not limited to these, for example, the amount of water in the topical skin preparation is preferably 50 to 99% by mass, and more preferably 75 to 97% by mass.

[0053] In the present invention, it is preferable that the topical skin preparation does not contain medium-chain triglycerides. This is because the presence of medium-chain triglycerides makes it difficult for liposomes to form properly as phospholipids and sterols dissolve in the medium-chain triglycerides, and also has the disadvantage that an increase in medium-chain triglycerides leads to a dominance of emulsion particle formation rather than liposome formation. Medium-chain triglycerides refer to trisubstituted triglycerides with fatty acids having an aliphatic tail 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, triesters 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 triesters of glycerol and three fatty acids whose aliphatic chains are of the same length (for example, each having a length of 8). The absence of medium-chain triglycerides means that the amount in the topical skin preparation 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.

[0054] The method for producing the topical skin preparation of the present invention is not particularly limited and can be produced in accordance with known methods. For example, the topical skin preparation of the present invention can be prepared by mixing liposomes obtained by the method described above with other components (external phase components).

[0055] In the case of cosmetic preparations, preferred dosage forms for the topical skin preparations of the present invention include aqueous cosmetics, emulsified cosmetics such as oil-in-water (O / W) type, water-in-oil (W / O) type, water-in-oil (W / O) type, O / W / W type, oily cosmetics, solid cosmetics, liquid cosmetics, paste cosmetics, stick cosmetics, volatile oil cosmetics, powder cosmetics, jelly cosmetics, gel cosmetics, paste cosmetics, emulsified polymer cosmetics, sheet cosmetics, mist cosmetics, and spray cosmetics. A composition with water as a continuous phase is preferable in that it allows liposomes to penetrate the skin easily. Having water as a continuous phase means that the total amount of oil is very small, 10% by mass or less, or that it is an emulsion with water as a continuous phase. Examples of emulsions with water as a continuous phase include oil-in-water emulsions and water-in-oil emulsions.

[0056] The following describes a preferred method for producing the topical skin preparation of the present invention. The topical skin preparation of the present invention comprises a step of preparing liposomes by mixing and emulsifying an organic phase containing phospholipids, cannabidiol, and polyhydric alcohols with an aqueous phase.

[0057] (1) First, prepare the liposomes using the following method. First, the organic phase is prepared by mixing phospholipids, cannabidiol, and polyhydric alcohol. When using sterols, it is preferable to add the sterols to the polyhydric alcohol and dissolve them before mixing the phospholipids or cannabidiol with the polyhydric alcohol. To successfully obtain liposomes, the preparation of the organic phase is preferably carried out at 80-90°C, and more preferably at 80-85°C.

[0058] The ratios of polyhydric alcohols, cannabidiol, and phospholipid components used to prepare the organic phase are those mentioned above, which are the ratios of polyhydric alcohols, cannabidiol, and phospholipids used when preparing liposomes.

[0059] Next, the aqueous phase is prepared. The amount of water used to prepare the aqueous phase may be 1 to 3 parts by mass, or 2 to 5 parts by mass, per 1 part by mass of the total amount of cannabidiol, phospholipids, and polyhydric alcohols. The aqueous phase is preferably prepared at 80 to 90°C, and more preferably at 80 to 85°C.

[0060] Next, the organic phase and the aqueous phase are mixed. This mixing is preferably carried out at 80-90°C, and more preferably at 80-85°C. Known conditions can be used for the mixing speed and stirring method based on the desired particle size, etc.

[0061] Once liposomes are obtained as described above, the desired topical skin preparation can be obtained by mixing the obtained liposomes with other components.

[0062] Applicable areas for the topical skin preparation of the present invention include the face (e.g., forehead, cheeks, mouth area, etc.), body (whole body, chest, back, arms, fingers, legs, etc.), head (scalp), and delicate areas.

[0063] The topical skin preparation of the present invention is particularly preferable to be used as a cosmetic, as it allows it to exhibit its skincare effects, feel, and formulation stability.

[0064] Examples of cosmetic products include hair cosmetics, skin cosmetics, makeup cosmetics, fragrance cosmetics, and body cosmetics. The topical skin preparation of the present invention can be manufactured according to conventional methods.

[0065] To further describe the types of topical skin preparations of the present invention, preferred hair cosmetics include shampoos such as oil shampoos, cream shampoos, conditioning shampoos, anti-dandruff shampoos, hair color shampoos, and rinse-integrated shampoos; hair care products such as rinses, conditioners, treatments, hair packs, hair mists, and hair oils; hair styling products such as hair foams, hair mousses, hair sprays, hair waxes, hair gels, hair creams, water greases, setting lotions, pomades, and hair sticks; hair dyes such as color lotions, hair color treatments, hair manicures, and oxidative hair dyes; and hair tonics, hair liquids, hair blowers, split end coats, permanent wave agents, straight perm agents, hair bleaches, hair color pre-treatments, hair color after-treatments, perm pre-treatments, perm after-treatments, and hair growth agents.

[0066] Skin cosmetics include lotions such as softening lotions, astringent lotions, cleansing lotions, multi-layer lotions, and liposome lotions; emulsions such as emollient lotions, moisturizing lotions, milky lotions, nourishing lotions, nourishing milks, skin moisturizers, moisturizing emulsions, massage lotions, exfoliating smoothers, elbow lotions, hand lotions, and body lotions; and emollient creams, nourishing creams, vanishing creams, moisturizing creams, night creams, massage creams, cleansing creams, makeup creams, base creams, pre-makeup creams, sunscreen creams, suntan creams, hair removal creams, deodorant creams, and shaving creams. Preferred products include creams such as moisturizing creams and exfoliating creams; gels such as moisturizing gels, whitening gels, and all-in-one gels; serums such as moisturizing essences, whitening essences, moisturizing serums, and whitening serums; sunscreens such as sun protectors, sun protection products, UV care milks, and sunscreens; packs and masks such as peel-off packs, powder packs, washing packs, oil packs, and cleansing masks; makeup removers such as cleansing foams, cleansing creams, cleansing milks, cleansing lotions, cleansing gels, and cleansing oils; and facial cleansers such as paste facial cleansing foams, gel facial cleansing foams, foaming facial cleansing foams, facial cleansing powders, cosmetic soaps, clear soaps, medicated soaps, liquid soaps, and shaving soaps.

[0067] Preferred makeup products include lipstick, lip gloss, foundation, blush, face powder, concealer, eyeliner, mascara, eyeshadow, eyebrow pencil, eyebrow products, nail polish, nail polish remover, and nail treatment.

[0068] Preferred fragranced cosmetics include perfumes, fragrances, parfums, eau de parfums, eau de toilettes, eau de colognes, solid perfumes, fragrance powders, fragranced soaps, body lotions, and bath oils.

[0069] Preferred body cosmetics include body washes such as body shampoos, deodorant lotions, deodorant powders, deodorant sprays, deodorant sticks, deodorizing cosmetics, bleaching agents, hair removal agents, bath additives, and insect repellents such as insect repellent sprays.

[0070] In particular, among the types of topical skin preparations of the present invention, skin cosmetics and body cosmetics are preferred in terms of their moisturizing effect and effect of improving the feel of use.

[0071] Furthermore, as shown in the examples described later, the topical skin preparation of the present invention is a composition that has a collagen production promoting effect and can also be used as a collagen production promoter.

[0072] Collagen is a major structural protein that makes up about one-third of mammalian tissue and is an essential component of many matrix tissues such as skin, bone, cartilage, tendons, and ligaments. Therefore, it is known that a decrease in collagen production can cause various diseases. The skin is exposed daily to various physical and chemical stresses such as ultraviolet rays, dryness, cold, heat, and drugs. As a result, the function of the skin deteriorates, and various skin aging phenomena become apparent. Skin aging phenomena include the formation of wrinkles, sagging skin, loss of firmness, decreased barrier function, and decreased moisturizing ability of the stratum corneum. It is known that there are two types of wrinkles: epidermal wrinkles and dermal wrinkles. Dermal wrinkles are caused by a decrease in the collagen production capacity of dermal fibroblasts due to ultraviolet rays and aging. Furthermore, a decrease in collagen production also causes sagging skin and loss of firmness. Therefore, promoting collagen production is important for preventing and improving dermal wrinkles, sagging skin, and loss of firmness. Promoting collagen production is important for preventing and improving skin aging due to the effects described above.

[0073] Collagen is classified into types based on its function and structure. The type of collagen used in this invention is not particularly limited, but it is preferably type I, type III, or type V collagen, and more preferably type I collagen.

[0074] The topical skin preparation of the present invention is expected to promote the production of collagen, particularly collagen in the skin, and prevent and improve skin aging caused by a decrease in collagen, thereby suppressing diseases such as wrinkle formation, skin sagging, loss of firmness, decreased barrier function, and decreased moisturizing properties of the stratum corneum, as well as promoting wound healing of the skin.

[0075] As described above, the topical skin preparation of this embodiment is preferably prepared by dissolving cannabidiol and phospholipids in a polyhydric alcohol. However, even if the manufacturing method is included when the liposomes produced by this method are specified in this specification, it is not practical to specify the form of the liposomes containing the polyhydric alcohol, cannabidiol, and phospholipids in more detail using parameters than described herein, as this would require the development of new measurement methods, and thus there are unavoidable circumstances that necessitate expressing it in terms of the manufacturing method. [Examples]

[0076] 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 to 3 were used in the examples and comparative examples. The procedure for preparing the topical skin preparation was as follows. For hydrogenated lecithin, a commercially available powder with a PC content of 75-85% by mass was used. For phytosterols, phytosterol-SKP (manufactured by Tama Biochemical Co., Ltd.) was used.

[0077] (Comparative Examples 1-3, 5; Examples 1-4, 6, 8) (1) The polyhydric alcohol was heated to 80°C. Hydrogenated lecithin and cannabidiol were added and dissolved. In Comparative Examples 3 and 5, other oils and / or surfactants were added and dissolved (organic phase). (2) Separately, purified water was heated to 80°C and slowly added to the prepared organic phase while stirring (mixed phase). While maintaining 80°C, the mixture was processed for 10 minutes at a rotation speed of 8,000 rpm using a homomixer (TK Robomix, manufactured by Primix Corporation). After processing, it was cooled to room temperature to obtain the liposome phase. (3) Separately, the components of the external phase (purified water, thickener, polyhydric alcohol (glycerin), pH adjuster (sodium hydroxide), phenoxyethanol) were mixed to obtain a base solution. The sodium hydroxide was adjusted so that the pH of the external phase at 25°C was 6.5. (4) The liposome phase obtained in (2) was gradually added to the base solution in (3) while stirring, and homogenized to obtain a topical skin preparation.

[0078] (Examples 5, 7, 9 and 10) (1) Polyhydric alcohol was heated to 80°C. Sterols (phytosterols or dihydrocholesterol) were added and dissolved. Hydrogenated lecithin and cannabidiol were then added and dissolved to prepare the organic phase. (2) From this point onward, a topical skin preparation was obtained in the same manner as in Example 1.

[0079] (Comparative Example 4) (1) A polyhydric alcohol was heated to 80°C and dissolved. Cannabidiol was then added and dissolved. A surfactant was then added to prepare the organic phase. (2) From this point onward, a topical skin preparation was obtained in the same manner as in Example 1.

[0080] (Comparative Example 6) The procedure for mixing and heating hydrogenated lecithin, cannabidiol, phytosterols, and caprylic / capric triglyceride was as follows: (1) Tri(caprylic / capric acid)glyceryl and phytosterol were mixed and heated to 80°C to dissolve. Hydrogenated lecithin and cannabidiol were then added and dissolved to prepare the organic phase. (2) From this point onward, a topical skin preparation was obtained in the same manner as in Example 1.

[0081] The topical skin preparations of the examples and comparative examples were evaluated using the following method. The results are shown in Tables 1-3. The results for COL1A1 gene expression levels (COL1A1 / GAPDH) are also shown in Figure 1. The average particle size of liposomes in each example was within the range of 100-800 nm.

[0082] <COL1A1 gene expression level (COL1A1 / GAPDH)> The topical skin preparations of the examples and comparative examples were used as test substances for the following tests. (1) Normal human dermal fibroblasts (NHDF) were cultured in 10% FBS-DMEM using a 75 cm 2 flask in an incubator at 37 °C with 5% CO2. (2) Cells suspended by trypsin treatment were seeded at a cell density of 1.0×10 4 cells / well in each well of a collagen-coated 96-well plate and pre-cultured for 24 hours in an incubator at 37 °C with 5% CO2. (3) After removing the medium from each well, 100 μL / well of the test substance-containing medium was added and cultured for 24 hours in an incubator at 37 °C with 5% CO2. 10% FBS-DMEM was used for the test substance preparation medium, and the total concentration of the test substance in the medium was set to 0.01%. (4) After culturing for 24 hours, the medium was removed and RNA was recovered using CellAmp (trademark) Direct RNA Prep Kit for RT-PCR (Real Time) (manufactured by Takara). (5) Real-time PCR was performed using the obtained RNA with One Step TB Green (registered trademark) PrimeScript (trademark) RT-PCR Kit II (Perfect Real Time) (manufactured by Takara). (6) The gene expression level of COL1A1 was measured using primers for COL1A1 (manufactured by QIAGEN). Also, as an endogenous control, the gene expression level of GAPDH was measured using primers for GAPDH (manufactured by QIAGEN). (7) For the gene expression level of COL1A1, the relative value was calculated when the value of the control without adding the test substance was set to 1.

[0083] (Presence or absence of liposome formation) The prepared topical skin preparations were measured for particle size using a particle size analyzer (Malvern's "ZetaSizer Nano-ZS"), and liposome formation 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.

[0084] (Formulation stability) The prepared topical skin preparations were stored at 40°C for 30 days, and changes in color, viscosity, separation, particle size (liposome stability), and odor were evaluated. Particle size changes were evaluated using a particle size analyzer (Malvern Zetasizer Nano-ZS), while other items were evaluated by sensory assessment. In each case, among Comparative Examples 1-6 and Examples 1-10, the one with the slightest change was evaluated on a scale of 1 to 10, the one with the largest change on a scale of 1 to 10, and the others on a scale of 1 to 10. Regarding viscosity changes, the degree of viscosity change from the time of sample preparation was numerically evaluated when viscosity was measured using a viscometer (Brookfield DV1 VISCOMETER). For separation, in the case of topical skin preparations, it was evaluated whether separation of oil and water due to creaming or precipitation of solid matter was observed.

[0085] (Feeling of use) Five panelists were selected to evaluate the feel of each product (spreadability, skin compatibility, moisturizing effect, stickiness, etc.) based on their sensory perception. The best-rated product in each category was assigned a score of 10, while the lowest total score was assigned a score of 1, resulting in a 10-point scale from 10 to 1.

[0086] [Table 1]

[0087] [Table 2]

[0088] [Table 3]

[0089] As shown in Tables 1-3, the topical skin preparations of each example, which contained liposomes with cannabidiol, phospholipids, and polyhydric alcohols, and had a polyhydric alcohol content of 3% by mass or more, exhibited good usability and excellent COL1A1 gene expression levels. In contrast, Comparative Example 4, which contained cannabidiol but lacked phospholipids, did not generate liposomes, and Comparative Examples 1-3, 5, and 6, which contained less than 3% by mass of polyhydric alcohols, either did not generate liposomes or resulted in insufficient usability and collagen gene expression levels (COL1A1 / GAPDH). Furthermore, among the various examples, Examples 4-10, which contained 0.05-0.4% by mass of cannabidiol, showed superior formulation stability, usability, and gene expression levels (COL1A1 / GAPDH). Comparisons between Examples 1, 2, and 3 also revealed that the combined use of butylene glycol and pentylene glycol improved liposome formation and collagen gene expression. Comparisons between Examples 4 and 5, 6 and 7, and 8-10 further demonstrated that the inclusion of sterols improved formulation stability, usability, and gene expression levels (COL1A1 / GAPDH).

[0090] Examples 1 to 9 of formulations relating to the present invention are shown below. The topical skin preparations of Examples 1 to 9 were prepared in the same manner as in Examples 1 to 10. These preparations exhibit excellent collagen-enhancing effects, liposome stability, improved usability, and formulation stability.

[0091] [Table 4] [Industrial applicability]

[0092] The topical skin preparation of the present invention is industrially useful because it exhibits excellent collagen-enhancing effects, liposome stability, improved usability, and formulation stability.

Claims

1. A topical skin preparation containing cannabidiol, phospholipids, and 3% or more by mass of polyhydric alcohols, and also containing liposomes.

2. The topical skin preparation according to claim 1, further comprising sterols.

3. The topical skin preparation according to claim 1 or 2, wherein the polyhydric alcohol is a dihydric alcohol having 4 or more carbon atoms.

Images