Liposome and liposome-containing composition

Abstract

To provide a technique for enhancing the dermal delivery of a composition and, furthermore, enhancing the delivery of the composition to macrophage-surrounding areas.SOLUTION: The present invention provides a liposome with a particle diameter of 300 nm or less, comprising (A) polyglycerin fatty acid ester, (B) phospholipid, and (C) sterol. In a preferred embodiment, the liposome further comprises (D) an amphiphilic molecule having a disaccharide-to-trisaccharide hydrophilic group and an alkyl-chain hydrophobic group within its molecular structure.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a liposome and a liposome-containing composition suitable for use as an external preparation for the skin. [Background technology]

[0002] When a cosmetic is applied to the surface of the skin, it is important for it to penetrate into the dermis in order to achieve the desired effect, for active ingredients to reach the inside of the skin, and for the cosmetic to give a satisfactory feeling to the user.

[0003] Conventionally, in the field of pharmaceuticals, techniques have been developed for delivering drugs to desired cells or tissues. For example, a pharmaceutical composition has been proposed in which a drug is encapsulated in a capsule formed with a specific surfactant (e.g., Patent Document 1). Conventionally, various techniques have been proposed to enhance the dermal delivery of cosmetics, such as forming an emulsion composition using a specific surfactant or adjusting the viscosity. In addition, a technique for encapsulating an active ingredient to be delivered to the depths of the skin in a vesicle has also been proposed. For example, Patent Document 2 describes that a vesicle formed by a specific alkyl glycoside and mannosylerythritol lipid is fine, and enhances the skin permeability of the composition. In addition, Patent Document 3 describes the formation of a stable liposome encapsulating an oil-soluble active ingredient by using phospholipids, cholesterol derivatives, etc. In addition, Patent Document 4 describes a liposome beauty essence containing hydrogenated soybean lecithin and fatty acid polyglyceryl, and Patent Document 5 describes a liposome-containing composition containing lecithin and phytothreitol. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2012-116863 A [Patent Document 2] JP 2020-033335 A [Patent Document 3] JP 2003-081737 A [Patent Document 4] Patent No. 5756602 [Patent Document 5] JP 2023-032103 A Summary of the Invention [Problem to be solved by the invention]

[0005] The dermal delivery properties of conventional cosmetics are not necessarily satisfactory, and further improvements are required. Therefore, a first object of the present invention is to provide a liposome-containing composition having excellent dermal delivery properties.

[0006] In addition, macrophages are cells that are mainly responsible for biological defense, and in the skin, they are deeply involved in various inflammations and diseases in the skin. Therefore, not only delivering an active ingredient to the dermis, but also delivering it to the vicinity of macrophages and exposing the macrophages to the active ingredient can be useful for improving undesirable events in the skin. Therefore, a second object of the present invention is to provide a technology for improving the delivery of a composition to the vicinity of macrophages. [Means for solving the problem]

[0007] The present inventors have discovered that a liposome containing a polyglycerol fatty acid ester, a phospholipid, and a sterol and having a specific particle size has excellent dermal delivery properties. Furthermore, the present inventors have found that liposomes containing amphiphilic molecules having sugar chains in addition to polyglycerol fatty acid esters, phospholipids, and sterols are easily adsorbed onto the surface of macrophages. The inventors have come to the conclusion that the above-mentioned compound has excellent properties and have completed the present invention.

[0008] That is, the present invention is as follows. [1] A liposome having a particle size of 300 nm or less, comprising (A) a polyglycerol fatty acid ester, (B) a phospholipid, and (C) a sterol. [2] The liposome according to [1], further comprising (D) an amphiphilic molecule having a disaccharide to trisaccharide hydrophilic group and an alkyl chain hydrophobic group within the molecule. [3] The liposome according to [1] or [2], wherein component (A) contains polyglyceryl oleate. [4] The liposome according to [3], wherein the polyglyceryl oleate is polyglyceryl-5 oleate. [5] The liposome according to any one of [1] to [4], wherein component (B) contains hydrogenated lecithin. [6] The liposome according to any one of [1] to [5], wherein component (C) contains phytosterol. [7] The liposome according to [2], wherein component (D) contains glycosyl inositol phosphoceramide. [8] The liposome according to any one of [2] to [7], wherein the total content of component (B) and component (C) is 2.0 times or more the total content of component (A) and component (D). [9] The liposome according to [2], wherein the ratio of the content of component (D) to the content of component (A) ((D) / (A)) is 1.5 or more.

[10] The liposome according to any one of [1] to

[10] , which is used for transporting a substance contained therein to the dermis.

[11] The liposome according to [2], which is used for promoting adhesion to macrophages.

[12] A composition comprising the liposome according to any one of [1] to [9].

[13] The composition described in

[12] , which is a cosmetic. Effect of the Invention

[0009] The present invention provides liposomes with high dermal deliverability and compositions containing the same. It is expected that the improved dermal deliverability of the composition will facilitate the active ingredient encapsulated in the liposome to reach the depths of the skin, making it easier to obtain the desired effects of the ingredient. In addition, a preferred embodiment of the present invention provides a liposome having high adsorption activity to macrophages and a composition containing the same. Such a composition can deliver the liposome and its encapsulation to the vicinity of macrophages to expose the macrophages to the active ingredient, and therefore can be useful for improving undesirable events in the skin. Therefore, such a composition is suitable for use as an external skin preparation such as a cosmetic. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The liposome of the present invention comprises (A) a polyglycerol fatty acid ester, (B) a phospholipid, and (C) a sterol.

[0011] (A) Polyglycerol fatty acid ester is preferably an ester of polyglycerol with a linear or branched fatty acid having preferably 8 or more carbon atoms, more preferably 10 or more carbon atoms, and preferably 24 or less carbon atoms, more preferably 22 or less carbon atoms. Although not particularly limited, monovalent esters are preferred. Although the degree of polymerization of the polyglycerol may be any, for example, a degree of polymerization of 5 or more is preferred, and the upper limit may be 10 or less, although not particularly limited. In addition, the polyglycerol fatty acid ester in the present invention preferably has an HLB value of 10-16. Specific examples of polyglycerol fatty acid esters in the present invention include polyglycerol oleate. Seryl is preferred, and polyglyceryl-5 oleate is particularly preferred, but is not limited thereto.

[0012] The content of the (A) polyglycerol fatty acid ester in the liposome-containing composition of the present invention is preferably 0.01 to 0.5 wt %, more preferably 0.015 to 0.3 wt %, and even more preferably 0.020 to 0.2 wt %, of the total composition. By setting the particle size within this range, it becomes easier to form the liposomes of the present invention having a particle size of 300 nm or less, and delivery to the dermis can be improved.

[0013] (B) Examples of phospholipids include glycerophospholipids and sphingophospholipids. Glycerophospholipids are substances having a glycerophosphate backbone and have fatty acid esters, long-chain alkyl ethers, vinyl ethers, etc. as lipophilic groups. Specific examples include phosphatidylcholine (lecithin), phosphatidylethanolamine, phosphatidylserine, phosphadiyl inositol, phosphatidylinositol polyphosphate, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), phosphatidic acid, lysophosphatidylcholine (lysolecithin), lysophosphatidylethanolamine, lysophosphatidylserine, lysophosphatidylinositol, lysophosphatidylglycerol, lysophosphatidic acid, etc. Sphingophospholipids have a long-chain base such as sphingosine or phytosphingosine, or a long-chain fatty acid, and a phosphoric acid or a phosphonic acid. Specific examples include ceramide 1-phosphate derivatives (such as sphingomyelin) and ceramide 1-phosphonic acid derivatives (such as ceramide aminoethylphosphonic acid).

[0014] In the present invention, the phospholipid may be a natural product extracted and purified from animals and plants, a chemically synthesized product, or a product that has been processed by hydrogenation, hydroxylation, or the like. For example, lecithin and lysolecithin, which may be hydrogenated, are preferred, and hydrogenated lecithin is more preferred. As a natural product, lecithin, which is extracted and purified from soybeans or egg yolk, is preferred because it is easily available commercially.

[0015] The content of the (B) phospholipid in the liposome-containing composition of the present invention is preferably 0.005 to 1.0 wt %, more preferably 0.007 to 0.8 wt %, and even more preferably 0.01 to 0.6 wt %, of the total composition. By setting the particle size within this range, it becomes easier to form the liposomes of the present invention having a particle size of 300 nm or less, and delivery to the dermis can be improved.

[0016] (C) Sterols include animal sterols, plant sterols (phytosterols), fungal sterols, etc., with plant sterols (phytosterols) being more preferred. Examples of animal sterols include cholesterol, cholestanol, and 7-dehydrocholesterol. Examples of plant sterols (phytosterols) include campesterol, sitosterol, stigmasterol, fucosterol, spinasterol, brassicasterol, etc. Also included are hydrogenated phytostanols. Fungal sterols include ergosterol. Sterols can be obtained by extracting raw materials such as grain germ with an organic solvent and removing the water-soluble portion, but they can also be purchased and used as they are already available on the market.

[0017] The content of the (C) sterol in the liposome-containing composition of the present invention is preferably 0.0006 to 0.125% by weight, more preferably 0.001 to 0.11% by weight, and even more preferably 0.02 to 0.10% by weight, of the total composition. By setting the particle size within such a range, the liposome of the present invention having a particle size of 300 nm or less can be formed. This makes it easier to synthesize the compound, thereby improving delivery to the dermis.

[0018] The liposome of the present invention preferably further contains an amphipathic molecule (D) having a disaccharide to trisaccharide hydrophilic group and an alkyl chain hydrophobic group in the molecule. Such an amphipathic molecule is not particularly limited, but preferred examples include glycosyl inositol phosphoceramide (GIPC), mannosyl erythritol lipid (MEL), sucrose fatty acid ester, alkyl glycoside, etc. Note that a phospholipid having a disaccharide to trisaccharide hydrophilic group in the molecule may be included in the liposome of the present invention as both component (B) and component (D).

[0019] GIPC is a sphingophospholipid found in plants, and rice bran-derived GIPC is easily available and can be preferably used.

[0020] MEL is a type of biosurfactant found in yeast, and generally has a structure represented by general formula (1) or (2). In general formulas (1) and (2), R 1 are each a saturated or unsaturated, linear or branched aliphatic acyl group having 4 to 24 carbon atoms, preferably 8 to 14 carbon atoms, which may be the same or different. 1 The carbon number of R can vary depending on the MEL producing bacteria, production medium, production conditions, etc., so multiple types of R are usually used. 1 It is a mixture of MEL having the following structure: In addition, in the general formulas (1) and (2), R 2 is hydrogen or an acetyl group, R 3 is hydrogen or an acetyl group, R 4 is hydrogen or an aliphatic acyl group having 2 to 24 carbon atoms. In general, R 2 and R 3 MEL-A and R are both acetyl groups. 2 is hydrogen and R 3 is an acetyl group, MEL-B is 2 is an acetyl group and R 3 is hydrogen, MEL-C, R 2 and R 3 and MEL-C are each a hydrogen atom. In the present invention, any of MEL-A, MEL-B, MEL-C and MEL-D can be used, but MEL-B is more preferred.

[0021] [ka]

[0022] [ka]

[0023] Preferred examples of sucrose fatty acid esters include esters of sucrose with linear or branched fatty acids having a carbon number of preferably 10 or more, more preferably 12 or more, preferably 20 or less, and more preferably 18 or less. Specific preferred examples include sucrose laurate, sucrose myristic acid ester, sucrose palmitate, sucrose stearate, and sucrose oleate. Commercially available products can also be used.

[0024] The alkyl glycoside is preferably one having a structure represented by general formula (3) in which a sugar and an aliphatic alcohol are condensed at the 1-position hydroxyl group of the terminal sugar.

[0025] [ka]

[0026] In the general formula (3), G represents a sugar residue, which may be a residue of a monosaccharide or polysaccharide, may be either α- or β-isomer, and constitutes the hydrophilic portion of the alkyl glycoside. The sugar residue G may be selected from glucose, galactose, xylose, mannose, lyxose, arabinose, fructose, maltose, xylobiose, isomaltose, cellobiose, lactose, gentiobiose, maltotriose, isomaltotriose, cellotriose, maltotetraose, maltopentaose, maltohexaose, maltoheptaose, isomaltotetraose, isomaltopentaose, isomaltohexaose, and isomaltoheptaose.

[0027] The fatty chain in the alkyl glycoside represented by the general formula (3) constitutes the hydrophobic portion. It may or may not have a branched chain, but preferably has a branched chain. That is, in the general formula (3), R 5 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, preferably an alkyl group having 1 to 3 carbon atoms; and n represents an integer of 1 to 4.

[0028] The alkyl glycoside represented by the general formula (3) is more preferably a compound represented by the following general formula (4).

[0029] [ka]

[0030] In the general formula (4), N represents an integer of 1 to 7. 5 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and is more preferably a methyl group. n represents an integer of 1 to 4, and is more preferably 2 or 3. Specific examples of alkyl glycosides represented by the general formula (4) include the glycosides of maltose and hexahydrofarnesol (Mal 2 Far), and the glycoside of maltotriose and hexahydrofarnesol (Mal 3 Far), maltotriose and dihydrophytol glycosides (Mal 3 Phyt) and Mal 2 Far is especially preferred. The alkyl glycoside represented by the general formula (4) may be used either alone or in combination of two or more.

[0031] The alkyl glycoside represented by the general formula (4) can be prepared by, for example, glycosylation using sugar bromide. These can be obtained by various well-known methods such as a glycosylation method using a sugar fluoride, a glycosylation method using trichloroacetimidate, and a glycosylation method using an acetylated sugar. More specific examples of the synthesis processes include those described in Japanese Patent Nos. 3882067, 4817435, and 5207420, JP-A Nos. 2013-129660 and 2012-17318.

[0032] The content of the amphiphilic molecule (D) having a disaccharide to trisaccharide hydrophilic group and an alkyl chain hydrophobic group in the molecule in the composition of the present invention is preferably 0.01 to 1.0 wt %, more preferably 0.03 to 0.6 wt %, and even more preferably 0.04 to 0.4 wt %, of the total composition. By setting the particle size within this range, it becomes easier to form the liposomes of the present invention having a particle size of 300 nm or less, which improves the delivery to the dermis and makes it easier for the liposomes to be adsorbed by macrophages.

[0033] When the liposome of the present invention contains component (D), adjusting the content ratio of components (A), (B), (C) and (D) can further increase the adsorption activity to macrophages. That is, the total content of components (B) and (C) is preferably 2.0 times or more the total content of components (A) and (D). Also, the ratio of the content of component (D) to the content of component (A) ((D) / (A)) is preferably 1.5 or more. For the adsorption of liposomes to macrophages, it is important that the sugar chain of component (D) is present on the liposome surface, and therefore, in consideration of the balance between this effect and the stability of the liposome, it is preferable to set the content ratio within the above range. By setting the content ratio of each component in the system when preparing liposomes to the above ratio, the content ratio of each component in the formed liposomes can be set to the above preferred range.

[0034] The liposome according to the present invention is a small sphere formed of a bilayer membrane containing (A) polyglycerol fatty acid ester, (B) phospholipid, and (C) sterol, and preferably (D) an amphiphilic molecule having a disaccharide to trisaccharide hydrophilic group and an alkyl chain hydrophobic group in the molecule. The liposome may have a structure capable of encapsulating other components in the bilayer membrane (shell portion) and / or inside the sphere (core portion). In the liposome-containing composition of the present invention, the components (A), (B), (C) and (D) may be present outside the liposome in addition to being present by forming the liposome.

[0035] The formation of liposomes can be confirmed by measuring the particle size, for example, by dynamic light scattering (DLS) etc. For example, the composition is measured using a dynamic light scattering particle size distribution analyzer (ELSZ-2000, manufactured by Otsuka Electronics Co., Ltd.), and the particle size can be measured as the number-converted average particle size value obtained from the particle size distribution calculated using the CONTIN method, which is a method of histogram analysis. The liposomes according to the present invention have an average particle size of 300 nm or less, preferably 250 nm or less, and usually 50 nm or more. Such particle sizes facilitate the delivery of the liposomes to the dermis. When the liposome contains component (D), the particle size of the liposome is preferably 100 nm or more so that the amount of sugar chain of component (D) exposed on the liposome surface is not too small. If the amount of sugar chain of component (D) exposed on the liposome surface is too small, the liposome may not have sufficient adsorption activity to macrophages.

[0036] The liposomes of the present invention can be prepared by a conventional method. Specifically, a method of preparing liposomes by regulating the particle size using a homomixer, a dispersing mixer, an extruder, a microfluidizer, etc. can be mentioned. The liposomes thus obtained can be uniformly and stably dispersed in the composition, and are excellent in delivery to the dermis. In addition, the liposomes Alternatively, a composition containing liposomes at a high concentration may be prepared first, and then the composition may be diluted with other components such as water or incorporated into an emulsion composition to obtain a liposome-containing composition. When the liposome-containing composition of the present invention is in the form of an external skin preparation described below, the content of liposomes is preferably 0.001 to 10% by mass, more preferably 0.01 to 1% by mass, based on the total mass of the composition.

[0037] The liposome and liposome-containing composition of the present invention have excellent delivery properties to the dermis. It is expected that the enhanced dermal delivery properties of the composition will promote the delivery of other ingredients contained in the composition, particularly when the liposome encapsulates an active ingredient, to the dermis inside the skin to which the composition is applied, and that the ingredient will be more likely to exhibit its desired effect in the dermis. Therefore, the liposome of the present invention may be used for delivering a substance contained therein to the dermis.

[0038] Furthermore, the liposome of the present invention has excellent adsorption activity to macrophages. Macrophages are known to have many types of receptors that phagocytose foreign substances, and the main receptors include those that bind via opsonization, which binds via antibodies or complements, and those that do not. The present inventors have focused on the fact that the mannose receptor (C-type lectin receptor), which is one of the receptors that binds to foreign substances without opsonization, can recognize various sugar chains such as fucose, N-acetylglucosamine, and zymosan in addition to mannose. The liposome of the present invention that contains component (D) can bind to the mannose receptor, and therefore the liposome can be efficiently delivered to the vicinity of macrophages. Therefore, the liposome of the present invention may be used to promote adhesion to macrophages.

[0039] The liposome of the present invention and a composition containing the same are preferably in the form of an external preparation for skin. The skin external preparation is not particularly limited as long as it is administered externally to the skin, and examples thereof include cosmetics, quasi-drugs, medicines, skin external miscellaneous goods, etc., and cosmetics are particularly preferred. As the cosmetics, any of basic cosmetics, hair cosmetics, and make-up cosmetics can be applied, but basic cosmetics are particularly preferred. The dosage form of the external skin preparation is not limited and may be any of a lotion, emulsion, essence, cream, and powder-containing dosage form.

[0040] In addition to the above-mentioned components, the composition of the present invention may contain any other components as long as they do not impair the effects of the present invention. When the composition is used as a skin external preparation, such optional components include various active ingredients, oils, surfactants, polyhydric alcohols, thickeners, powders, UV protection agents, moisturizers, pH adjusters, preservatives, antibacterial agents, antioxidants, antioxidant assistants, etc., which are usually blended into cosmetics.

[0041] The active ingredients include whitening ingredients, anti-wrinkle ingredients, anti-inflammatory ingredients, and extracts derived from plants and animals. These active ingredients may be encapsulated in liposomes. These active ingredients may be water-soluble or oil-soluble, and if they are water-soluble, they are usually encapsulated inside the liposome (core portion), and if they are oil-soluble, they are usually encapsulated inside the bilayer membrane of the liposome (shell portion).

[0042] There are no particular limitations on the whitening ingredient, so long as it is one that is commonly used in cosmetics, such as 4-n-butylresorcinol, ascorbic acid glucoside, 3-O-ethyl ascorbic acid, tranexamic acid, arbutin, ellagic acid, kojic acid, linoleic acid, and nicotine. Acid amide, 5,5'-dipropylbiphenyl-2,2'-diol, 5'-adenylic acid dinamate Examples of effective antihistamines include thorium, cetyl tranexamate, potassium 4-methoxysalicylate, hydroquinone, and pantothenic acid.

[0043] The wrinkle improving ingredient is not particularly limited as long as it is one generally used in cosmetics, for example, sodium trifluoride isopropyl oxopropyl aminocarbonyl pyrrolidine carbonyl methyl propyl aminocarbonyl benzoyl aminoacetate, nicotinic acid amide, vitamin A or its derivatives (retinol, retinal, retinoic acid, tretinoin, isotretinoin, tocopherol retinoate, retinol palmitate, retinol acetate, etc.), ursolic acid benzyl ester, ursolic acid phosphate, benzylic acid benzyl ester, benzilic acid phosphate.

[0044] The extracts derived from animals and plants are not particularly limited as long as they are generally used in medicines, cosmetics, foods, etc. For example, akebia extract, asparagus extract, avocado extract, amacha extract, almond extract, arnica extract, aloe extract, aronia extract, apricot extract, ginkgo extract, indian kinoko extract, fennel extract, udo extract, eijutsu extract, eleuthero extract, enmeiso extract, scutellaria root extract, phellodendron bark extract, coptis japonica extract, ginseng extract, hypericum extract, white lamb extract, orange extract, kakyoku extract, pueraria root extract, chamomile extract, and carrot extract. , Artemisia capillaris extract, Kiwi extract, Cucumber extract, Guava extract, Sophora root extract, Gardenia extract, Sasa veitchii extract, Sophora flavescens extract, Walnut extract, Grapefruit extract, Black rice extract, Chlorella extract, Mulberry extract, Cerastium officinalis extract, Alpinia speciosa extract, Gentiana extract, Geranium herb extract, Black tea extract, Burdock extract, Rice extract, Fermented rice extract, Fermented rice bran extract, Rice germ oil, Cowberry extract, Salvia extract, Soapwort extract, Bamboo grass extract, Hawthorn extract, Sanshou extract, Sanshi Root extract, Shiitake mushroom extract, Rehmannia root extract, Lithospermum root extract, Perilla extract, Linden extract, Meadowsweet extract, Peony extract, Ginger extract, Calamus root extract, Birch extract, Horsetail extract, Stevia extract, Stevia fermentation product, Ivy extract, Hawthorn extract, Elderberry extract, Yarrow extract, Peppermint extract, Sage extract, Mallow extract, Cnidium rhizome extract, Swertia japonica extract, Soybean extract, Tahitian extract, Imu extract, dandelion extract, tea extract, clove extract, tangerine extract, sweet tea extract, chili pepper extract, angelica extract, calendula extract, peach kernel extract, spruce extract, dokudami extract, tomato extract, natto extract, carrot extract, garlic extract, wild rose extract, hibiscus extract, bamboo shoot extract, lotus extract, parsley extract, birch extract, witch hazel extract, Japanese knotweed extract, cypress extract, loquat extract, coltsfoot extract, butterbur bud extract, bupleurum extract, butcher's broom extract,Preferred examples of the extract include grape extract, grape seed extract, loofah extract, safflower extract, peppermint extract, linden extract, peony extract, hop extract, pine extract, mayonnaise extract, horse chestnut extract, skunk cabbage extract, soapberry extract, melissa extract, mozuku extract, peach extract, cornflower extract, eucalyptus extract, saxifrage extract, yuzu extract, lily extract, coix seed extract, mugwort extract, lavender extract, green tea extract, apple extract, rooibos tea extract, lychee extract, lettuce extract, lemon extract, forsythia extract, astragalus extract, rose extract, rosemary extract, Roman chamomile extract, royal jelly extract, and burnet extract.

[0045] Examples of the anti-inflammatory component include allantoin, isopropylmethylphenol, clarinone, glabridin, salicylic acid, tocopherol acetate, tocopherol nicotinate, tranexamic acid, nicotinamide, pantothenic acid, pantothenyl alcohol, and the like. Among them, salicylic acid and its derivatives, tranexamic acid and its derivatives, pantothenyl alcohol, and the like are preferable. pantothenyl alcohol and pantothenic acid and its salts.

[0046] Examples of oils include silicone oils, polar oils, natural oils, and hydrocarbons.

[0047] Silicone oils include dimethylpolysiloxane (dimethicone), cyclopentasiloxane, decamethylcyclopentasiloxane, caprylyl methicone, trimethylsiloxysilicate, (dimethicone / vinyl dimethicone) crosspolymer, (dimethicone / phenylvinyl Ludimethicone crosspolymer, etc.

[0048] As polar oils, synthetic ester oils include isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearyl acid, ethylene glycol di-2-ethylhexylate, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, glyceryl di-2-heptylundecanoate, trimethylolpropane tri-2-ethylhexylate, trimethylolpropane triisostearate, pentaneerythritol tetra-2-ethylhexylate, glyceryl tri-2-ethylhexanoate, trime triisostearate, Tyrolpropane, cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, glyceryl trimyristate, tri-2-heptylundecanoic acid glyceride, castor oil fatty acid methyl ester, oleic acid oil, cetostearyl alcohol, acetoglyceride, 2-heptylundecyl palmitate, diisobutyl adipate, N-lauroyl-L-glutamic acid-2-octyldodecyl ester, di-2-heptylundecyl adipate, ethyl Examples of suitable oleic acid salts include ethyl acetate, butyl acetate, amyl acetate, triethyl citrate, octyl methoxycinnamate, 2-ethylhexyl paramethoxycinnamate, and diethylamino hydroxybenzoyl hexyl benzoate.

[0049] Examples of natural oils include avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, persic oil, wheat germ oil, sasanqua oil, castor oil, linseed oil, safflower oil, cottonseed oil, perilla oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, Chinese giri oil, Japanese tung oil, jojoba oil, germ oil, sunflower oil, triglycerin, glyceryl trioctanoate, and glyceryl triisopalmitate.

[0050] Examples of the hydrocarbon oil include isododecane, isohexadecane, squalane, hydrogenated poly(C6-12) olefin, and hydrogenated polyisobutene.

[0051] Examples of surfactants include anionic surfactants such as fatty acid soaps (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, and alkyl sulfate triethanolamine ether; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, and laurylamine oxide; betaine-based surfactants (alkylbetaines, amidobetaines, sulfobetaines, etc.); imidazoline-based amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc.); and amphoteric surfactants such as acylmethyltaurine. Sorbitan fatty acid esters (sorbitan monostearate, sorbitan sesquioleate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate ole, etc.), hydrogenated castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbitol fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE 2-octyldodecyl ether, etc.), POE alkyl phenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE·POP alkyl ethers (POE·POP 2-decyltetradecyl ether, etc.), Tetronics, nonionic surfactants such as POE castor oil·hydrogenated castor oil derivatives (POE castor oil, POE hydrogenated castor oil, etc.), etc. However, since the effects of components (A), (B), (C) and (D) may be impaired, it is preferable that the liposome of the present invention and the liposome-containing composition containing the same are substantially free of other surfactants. Here, "substantially free" means that the amount of other surfactants is preferably 0.1% by mass or less, more preferably 0.01% by mass or less, of the entire composition.

[0052] Examples of polyhydric alcohols include polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexylene glycol, 1,2-hexanediol, and 1,2-octanediol.

[0053] Examples of thickening agents include guar gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, curdlan, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methylhydroxypropyl cellulose, chondroitin sulfate, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratan sulfate, chondroitin, mucoitin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, keratosulfuric acid, locust bean gum, succinoglucan, caronic acid, chitin, chitosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer, sodium polyacrylate, polyethylene glycol, and bentonite.

[0054] Examples of powders include powders such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, and barium sulfate, which may be surface-treated; inorganic pigments such as red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, iron blue, titanium oxide, and zinc oxide, which may be surface-treated; pearling agents such as titanium mica, fish phosphorus foil, and bismuth oxychloride, which may be surface-treated; Examples of organic pigments include Red No. 202, Red No. 228, Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, etc., which may be compounded; and organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, and organopolysiloxane elastomers.

[0055] Examples of the ultraviolet protection agent include ultraviolet absorbers and ultraviolet scattering agents. Examples of the ultraviolet absorbers include para-aminobenzoic acid-based ultraviolet absorbers, anthranilic acid-based ultraviolet absorbers, salicylic acid-based ultraviolet absorbers, cinnamic acid-based ultraviolet absorbers, benzophenone-based ultraviolet absorbers, sugar-based ultraviolet absorbers, 2-(2'-hydroxy-5'-t-octylphenyl)benzotriazole, 4- and ultraviolet absorbents such as methoxy-4'-t-butyldibenzoylmethane. Examples of the ultraviolet scattering agent include fine particle metal oxides such as fine particle titanium oxide and fine particle zinc oxide.

[0056] Moisturizing agents include polyethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, xylitol, sorbitol, maltitol, chondroitin sulfate, hyaluronic acid, mucoitin sulfate, caronic acid, atelocollagen, cholesteryl-12-hydroxystearate, sodium lactate, bile salts, dl-pyrrolidone carboxylate, short-chain soluble collagen, diglycerin (EO)PO adduct, Rosa rugosa extract, Achillea millefolium extract, and Melilot extract. Examples of pH adjusters include buffers such as lactic acid-sodium lactate, citric acid-sodium citrate, and succinic acid-sodium succinate. Preservatives include ethylparaben, butylparaben, and the like. Preferred examples of the antibacterial agent include synthetic antibacterial agents such as 1,3-butylene glycol and paraoxybenzoic acid esters, as well as natural antibacterial substances such as caprylyl glycol, glyceryl caprylate, ethylhexylglycerin, and caprylhydroxamic acid. Examples of the antioxidant include tocopherols, dibutylhydroxytoluene, butylhydroxyanisole, gallic acid esters, etc. Examples of the antioxidant assistant include phosphoric acid, citric acid, ascorbic acid, maleic acid, malonic acid, succinic acid, fumaric acid, cephalin, hexametaphosphate, phytic acid, ethylenediaminetetraacetic acid, etc. EXAMPLES

[0057] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples as long as it does not depart from the gist of the present invention.

[0058] <Test Example 1> The liposome-containing compositions of the Examples and Comparative Examples were prepared by stirring and mixing the components shown in Table 1. Specifically, components (A), (B), and (C) and 1,3-butylene glycol were mixed, heated and stirred at 80°C or higher, and mixed uniformly. After that, component (D) was added and further mixed to obtain a mixture. The mixture was added all at once while the other components were being stirred at room temperature at 500 rpm, and after stirring for 10 minutes, it was cooled to 30°C to obtain a liposome-containing composition.

[0059] The following items were evaluated for each of the prepared compositions, and the results are shown in Table 1. (1) Stability After storage at 50°C for one month, the presence or absence of settling or aggregation and transparency were visually observed by experts (n=5, comprehensive evaluation) and rated on the following 4-point scale. ◎: Excellent transparency, no sediment or aggregates 〇: Excellent transparency, but slight sedimentation △: High transparency, but noticeable sedimentation ×: Overall opaque

[0060] (2) Deliverability to the dermis Calcein Na (Tokyo Chemical Industry Co., Ltd.) was added to the liposome-containing composition prepared according to the formula in Table 1 at a final concentration of 0.02% by weight to be encapsulated in the liposomes. The dermal delivery of the prepared calcein Na-encapsulated liposomes was evaluated by measuring the fluorescence intensity transmitted through a three-dimensional cultured epidermal model. Specifically, a three-dimensional cultured epidermal model (Labcyte EPI-MODEL24, J-TEC) was pre-cultured for 1 hour under conditions of 37°C and 5% CO2. The epidermal model was placed together with the dish in a vial filled with PBS as a receiver, and 50 μl / well of each sample aqueous solution was applied, followed by incubation at 37°C and 5% CO2. The plate was exposed for 2 hours. The fluorescence intensity of the PBS was measured (multimode plate rea The amount of transmitted fluorescent material was calculated using a microscope (ARVO-X4, PerkinElmer Japan). The evaluation was made on the basis of the fluorescence intensity in the sample of Example 12, into the following four stages (comprehensive evaluation with n=5). ◎: Fluorescence intensity equivalent to that of Example 12 ◯: Fluorescence intensity slightly weaker than in Example 12 △: Fluorescence intensity is significantly weaker than that of Example 12 ×: Fluorescence cannot be observed

[0061] (3) Particle size For each of the compositions prepared, the formation of liposomes was confirmed using a dynamic light scattering particle size distribution analyzer (ELSZ-2000, manufactured by Otsuka Electronics Co., Ltd., measurement temperature: 20°C), and the number-converted average particle size was measured (the average value was calculated for n = 5).

[0062] (4) Macrophage Adsorption Activity A liposome-containing composition was prepared according to the formula in Table 1 using the component (B) labeled with Nile Red, and the adsorption activity to macrophages was evaluated using this composition according to the following test procedure. Human monocyte-derived M2 macrophages (C-12915, PromoCell) were placed in a 96-well chamber containing 150 μL / well of Macrophage Base Medium XF medium (PromoCell) at 3.2 × 1 0 4 After seeding cells / well and culturing for 24 hours, 150 μL / well of fluorescently labeled liposome sample dissolved in fresh medium was added and incubated at 37°C for 24 hours. The medium was removed, and the cells were washed once with PBS, and then observed under a confocal microscope (excitation wavelength: 553 nm, fluorescence (Light wavelength: 637 nm). Cells were detected from the bright field image, superimposed on the fluorescent image, and the fluorescence on the cell region was extracted to quantify the liposome area on the cells, which was used to evaluate the adsorption activity to macrophages (n=12, Student's test). The evaluation was made on the basis of the liposome area in the sample of Example 12, with the following four levels. ◯: Significantly greater than Example 12 △: No significant difference from Example 12 ×: Significantly smaller than Example 12

[0063] [Table 1]

[0064] [Table 2] [Industrial Applicability]

[0065] The present invention provides a liposome-containing composition with high dermal delivery properties. Furthermore, a preferred embodiment of the present invention provides a liposome-containing composition with high macrophage adsorption activity. By increasing the dermal delivery properties and macrophage adsorption activity of the composition, it is expected that the active ingredient encapsulated in the liposome will be more likely to reach the dermis and will be more likely to be phagocytosed by macrophages and function within the cells, making it easier to obtain the desired effects of the ingredient. Therefore, the composition of the present invention can be preferably applied to external skin preparations such as cosmetics, and is industrially useful.

Claims

1. A liposome having a particle size of 300 nm or less, comprising (A) a polyglycerol fatty acid ester, (B) a phospholipid, and (C) a sterol.

2. The liposome according to claim 1, further comprising (D) an amphiphilic molecule having a disaccharide to trisaccharide hydrophilic group and an alkyl chain hydrophobic group in the molecule.

3. The liposome of claim 1 , wherein component (A) comprises polyglyceryl oleate.

4. The liposome of claim 3, wherein the polyglyceryl oleate is polyglyceryl-5 oleate.

5. The liposome of claim 1 , wherein component (B) comprises hydrogenated lecithin.

6. The liposome of claim 1 , wherein component (C) comprises a phytosterol.

7. The liposome of claim 2 , wherein component (D) comprises a glycosyl inositol phosphoceramide.

8. 3. The liposome according to claim 2, wherein the total content of the components (B) and (C) is 2.0 times or more the total content of the components (A) and (D).

9. 3. The liposome according to claim 2, wherein the ratio of the content of component (D) to the content of component (A) ((D) / (A)) is 1.5 or more.

10. The liposome according to claim 1, which is used for transporting a content to the dermis.

11. The liposome according to claim 2, which is used for promoting adhesion to macrophages.

12. A composition comprising the liposome according to any one of claims 1 to 9.

13. The composition according to claim 12, which is a cosmetic product.

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