W / O / W type emulsion composition

Abstract

Provided is a W / O / W type emulsion composition having good transdermal permeability of a water-soluble drug. A W / O / W type emulsion composition comprising an inner aqueous phase, an oil phase in which the inner aqueous phase is dispersed, and an outer aqueous phase in which the oil phase is dispersed, the composition comprising a water-soluble agent in which at least 99% of the total amount of the water-soluble agent is contained in the inner aqueous phase, the inner aqueous phase comprising an osmotic pressure regulator, and an osmotic pressure regulator for generating osmotic pressure between the inner water phase and the outer water phase, the composition containing one or more substances selected from the group consisting of a polyglycerol fatty acid ester having an average degree of polymerization of glycerol of 2-9 and a polyethylene glycol dipolyhydroxystearate as a surfactant for emulsifying the inner water phase in an oil phase, the outer aqueous phase includes a thickener having an alkyl group.

Description

Technical Field

[0001] The present invention relates to a W / O / W type emulsified composition. Background Art

[0002] Skin external use compositions such as ointments, emulsions, creams, lotions, gels, etc. contain various water-soluble agents such as antioxidants, blood circulation promoters, whitening agents, moisturizing agents, vitamins, etc. When the skin external use composition is applied to the skin, these water-soluble agents penetrate into the skin during the process of dissolving in water. However, when the moisture in the matrix evaporates and crystallizes on the skin surface, the penetration into the skin stops. Therefore, there is a problem that the absorption into the skin is small and the sufficient effect cannot be exerted.

[0003] In order to improve the permeability of water-soluble agents in skin external use compositions to the skin, various researches have been conducted in the past. For example, attempts have been made to form micelles in the composition (Patent Document 1) and to blend specific components that can improve the permeability of water-soluble agents in the composition (Patent Document 2).

[0004] However, these methods cannot be applied to all skin external use compositions, and when using an oily matrix or the like to formulate water-soluble agents, their usability deteriorates, and since the water-soluble agents do not come into direct contact with the skin, there is also a problem that the transdermal absorption of the water-soluble agents themselves cannot be sufficiently improved.

[0005] Therefore, there is still a need to develop a skin external use composition having excellent transdermal permeability of water-soluble agents.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: Japanese Patent Laid-Open No. 8-245339

[0009] Patent Document 2: Japanese Patent Laid-Open No. 9-157129 Summary of the Invention

[0010] The present inventors have found that a water-soluble agent in a W / O / W type emulsified composition containing a specific emulsifier and having at least 99% of the water-soluble agent contained in the inner aqueous phase exhibits excellent transdermal permeability. The present invention has been completed based on this finding.

[0011] Therefore, the present invention provides a W / O / W type emulsified composition having good transdermal permeability of a water-soluble agent.

[0012] According to the present invention, the following aspects can be provided.

[0013] (1) A W / O / W type emulsified composition, comprising:

[0014] an inner aqueous phase,

[0015] an oil phase in which the inner aqueous phase is dispersed, and

[0016] an outer aqueous phase in which the oil phase is dispersed,

[0017] the composition contains a water-soluble medicament,

[0018] in the water-soluble medicament, at least 99% of the total amount is contained in the inner aqueous phase,

[0019] the inner aqueous phase contains an osmotic pressure regulator, and here, the osmotic pressure regulator creates an osmotic pressure between the inner aqueous phase and the outer aqueous phase,

[0020] as a surfactant for emulsifying the inner aqueous phase in the oil phase, the composition contains one or more selected from the group consisting of polyglycerol fatty acid esters having an average degree of polymerization of 2 to 9 of glycerol and polyethylene glycol dihydroxystearate,

[0021] the outer aqueous phase contains a thickener having an alkyl group.

[0022] (2) The composition according to (1), wherein the water-soluble medicament is a cyclic carboxamide derivative represented by the following formula (I) or a salt thereof,

[0023]

[0024] [In the formula, n is an integer of 1 to 3, R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms optionally substituted by a hydroxyl group, X is a group represented by -CH 2 - or -N(R 2 )-, and R 2 refers to a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms optionally substituted by a hydroxyl group.].

[0025] (3) The composition according to (2), wherein the cyclic carboxamide derivative is 1-(2-hydroxyethyl)-2-imidazolidinone.

[0026] (4) The composition according to (1), wherein the water-soluble medicament is a peptide composed of the amino acid sequence shown in SEQ ID NO: 1 or the amino acid sequence shown in SEQ ID NO: 2 or a salt thereof.

[0027] (5) The composition according to (4), wherein the amino acid is a D-amino acid or an L-amino acid.

[0028] (6) The composition according to (4) or (5), wherein the amino acid at the N-terminus is acetylated.

[0029] (7) The composition according to any one of (4) to (6), wherein the amino acid at the C-terminus is amidated.

[0030] (8) The composition according to any one of (4) to (7), wherein the peptide is acetyl hexapeptide-8.

[0031] (9) The composition according to any one of (1) to (8), wherein the osmotic pressure regulator is one or more selected from the group consisting of sodium L-glutamate, maltitol, and trehalose.

[0032] (10) The composition according to any one of (1) to (9), wherein the osmotic pressure regulator is trehalose.

[0033] (11) The composition according to any one of (1) to (10), wherein the blending amount of the osmotic pressure regulator relative to the composition is 0.1 to 0.5% by weight.

[0034] (12) The composition according to any one of (1) to (11), wherein, as the surfactant for emulsifying the internal aqueous phase in the oil phase, it contains polyglycerol fatty acid esters with an average degree of polymerization of glycerol of 2 to 9, and the polyglycerol fatty acid esters are one or more selected from the group consisting of polyglycerol oleate, polyglycerol isostearate, polyglycerol diisostearate, polyglycerol dimer hydroxystearate, and polyglycerol polyricinoleate.

[0035] (13) The composition according to any one of (1) to (12), wherein, as the surfactant for emulsifying the internal aqueous phase in the oil phase, it contains one or more polyglycerol fatty acid esters selected from the group consisting of polyglycerol-4 oleate, polyglycerol-6 oleate, polyglycerol-2 isostearate, polyglycerol-6 polyricinoleate, polyglycerol-2 diisostearate, and polyglycerol-2 dimer hydroxystearate.

[0036] (14) The composition according to any one of (1) to (13), wherein the oil phase contains one or more oil components selected from the group consisting of polar oils with an IOB value of 0.1 to 0.80.

[0037] (15) The composition according to (14), wherein the oil component is one or more selected from the group consisting of castor oil, bis-diglycerol polyacyl adipate-2, and dipentaerythritol hexahydroxystearate.

[0038] (16) The composition according to (14) or (15), wherein the blending amount of the oil component relative to the composition is 3 to 20% by weight.

[0039] (17) The composition according to any one of (1) to (16), wherein the thickener having an alkyl group is at least one selected from the group consisting of an alkyl-modified carboxyvinyl polymer, an acryloyldimethyltaurate / behenyl alcohol polyether-25 methacrylate crosslinked polymer, and an acrylate / stearyl alcohol polyether-20 methacrylate copolymer.

[0040] (18) The composition according to any one of (1) to (17), which is a cosmetic composition.

[0041] (19) A method for improving the biofilm permeability of a water-soluble medicament, which includes the step of applying the composition according to any one of (1) to (18) to a biofilm.

[0042] According to the present invention, it is possible to provide a W / O / W type emulsified composition with good percutaneous permeability of a water-soluble medicament. In addition, according to the present invention, it is also possible to provide a W / O / W type emulsified composition showing excellent stability. Detailed Description

[0043] According to one aspect of the present invention, there is provided a W / O / W type emulsified composition, which includes: an inner aqueous phase, an oil phase in which the inner aqueous phase is dispersed, and an outer aqueous phase in which the oil phase is dispersed. The composition contains a water-soluble medicament, and at least 99% of the total amount of the water-soluble medicament is contained in the inner aqueous phase, preferably at least 99.9% of the total amount is contained in the inner aqueous phase. Thus, an effect of improving the percutaneous permeability of the water-soluble medicament can be expected. In addition, the inner aqueous phase in the composition contains an osmotic pressure regulator, which creates an osmotic pressure between the inner aqueous phase and the outer aqueous phase, causing water to move from the outer aqueous phase to the inner aqueous phase. Thus, a high internal phase (oil phase + inner aqueous phase) ratio can be obtained with a relatively small amount of the oil phase, and an effect of obtaining high viscosity and a moist feeling, and at the same time obtaining a unique phase transition feeling accompanied by the release of the inner aqueous phase when applied to the skin can be expected. As the surfactant for emulsifying the inner aqueous phase in the oil phase, the composition contains at least one selected from the group consisting of polyglycerol fatty acid esters with an average degree of polymerization of glycerol of 2 to 9 and polyethylene glycol dihydroxystearate. In addition, the outer aqueous phase in the composition contains a thickener having an alkyl group.

[0044] The W / O / W type emulsified composition of the present invention has a structure in which a W / O type emulsion is dispersed in an outer aqueous phase.

[0045] In the W / O type emulsion forming the internal phase in the present invention, an osmotic pressure regulator is contained in the aqueous phase as the innermost phase. The osmotic pressure regulator in the present invention is not limited, but is preferably one or more selected from the group consisting of sodium L-glutamate, maltitol, and trehalose, and more preferably trehalose. The blending amount of the osmotic pressure regulator in the present invention relative to the total amount of the emulsifying composition is preferably 0.01 to 1% by weight, and more preferably 0.01 to 0.5% by weight.

[0046] In the present invention, the internal aqueous phase and the oil phase are emulsified using one or more surfactants selected from the group consisting of polyglycerol fatty acid esters having an average degree of polymerization of glycerol of 2 to 9 and polyethylene glycol dihydroxystearates to form a W / O type emulsion.

[0047] The water-soluble medicament in the present invention is not particularly limited as long as it is a compound soluble in water, and can be either a low-molecular compound or a high-molecular compound.

[0048] According to one embodiment of the present invention, in the W / O / W type emulsifying composition of the present invention, as the water-soluble medicament, it contains a cyclic carboxamide derivative represented by the following formula (I) or a salt thereof.

[0049]

[0050] [In the formula, n is an integer of 1 to 3, R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms optionally substituted by a hydroxyl group, X is a group represented by -CH 2 - or -N(R 2 )-, and R 2 refers to a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms optionally substituted by a hydroxyl group.], as the water-soluble medicament, it preferably contains the cyclic carboxamide derivative (non-salt) represented by the above formula (I).

[0051] The "hydrocarbon group" of the cyclic carboxamide derivative represented by the above formula (I) in the present invention is not particularly limited, and can be, for example, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a cycloalkylalkyl group, a haloalkyl group, an alkoxyalkyl group, an alkoxycarbonylalkyl group, etc., and is preferably an alkyl group.

[0052] The "n" of the cyclic carboxamide derivative represented by the above formula (I) in the present invention is an integer of 1 to 3, and preferably n = 1.

[0053] According to a preferred embodiment of the present invention, in the W / O / W type emulsified composition of the present invention, as a water-soluble medicament, it contains one or more selected from the group consisting of 2-imidazolidinone, 1-(2-hydroxyethyl)-2-imidazolidinone (HEI), and 1-(2-hydroxyethyl)-2-pyrrolidone, or a salt thereof; as a water-soluble medicament, it is more preferably one or more selected from the group consisting of 2-imidazolidinone (non-salt), 1-(2-hydroxyethyl)-2-imidazolidinone (non-salt), and 1-(2-hydroxyethyl)-2-pyrrolidone (non-salt). According to a more preferred embodiment of the present invention, in the W / O / W type emulsified composition of the present invention, as a water-soluble medicament, it contains 1-(2-hydroxyethyl)-2-imidazolidinone (HEI) or a salt thereof, and as a water-soluble medicament, it is more preferably 1-(2-hydroxyethyl)-2-imidazolidinone (non-salt).

[0054] The salt of the cyclic carboxamide derivative in the present invention is not particularly limited as long as it is an acceptable substance in cosmetics, pharmaceuticals, etc. For example, as inorganic salts, hydrochlorides, sulfates, phosphates, hydrobromides, sodium salts, potassium salts, magnesium salts, calcium salts, ammonium salts, etc. can be cited; as organic salts, acetates, lactates, maleates, fumarates, tartrates, citrates, methanesulfonates, p-toluenesulfonates, triethanolamine salts, diethanolamine salts, amino acid salts, etc. can be cited.

[0055] In the W / O / W type emulsified composition of the present invention, as a water-soluble medicament, it may contain only one kind of the cyclic carboxamide derivative or its salt represented by the above formula (I), or may contain two or more of the cyclic carboxamide derivatives of the above formula (I) or their salts in any combination and ratio.

[0056] The content of the cyclic carboxamide derivative or its salt represented by the above formula (I) in the W / O / W type emulsified composition of the present invention can be appropriately selected according to its use, and is preferably 0.1 to 10% by mass relative to the total amount of the W / O / W type emulsified composition. In the case of using two or more of the cyclic carboxamide derivatives or their salts represented by the above formula (I), it is sufficient to make the total amount thereof satisfy the above range.

[0057] According to another embodiment of the present invention, in the W / O / W type emulsified composition of the present invention, as a water-soluble medicament, it contains a peptide composed of the amino acid sequence represented by SEQ ID NO: 1 (EEMQRR), or a peptide having the same function as it, or a salt thereof; as a water-soluble medicament, it preferably contains a peptide (non-salt) composed of the amino acid sequence represented by SEQ ID NO: 1 or a peptide having the same function as it (non-salt). In the present invention, "functionally equivalent" means that the peptide in question has at least one of the biological activities (such as the ability to at least partially inhibit neuronal exocytosis, etc.) of the peptide composed of the amino acid sequence represented by SEQ ID NO: 1.

[0058] The salts of the peptides in the present invention are not particularly limited as long as they are substances acceptable in cosmetics, pharmaceuticals, etc., and include salts formed by adding salts or free acids or bases commonly used to form metal salts. The salts of the peptides in the present invention can be obtained from organic or inorganic acids or bases by reacting a suitable acid or base with the peptides of the present invention by a method well-known to those skilled in the art.

[0059] The amino acids constituting the structural units of the above peptides in the present invention can have a D-configuration or an L-configuration. In addition, the amino-terminal amino acid of the above peptides in the present invention can have an acetylated terminal amino group, and the carboxyl-terminal amino acid can have an amidated terminal carboxyl group.

[0060] According to a preferred embodiment of the present invention, in the W / O / W type emulsified composition of the present invention, as a water-soluble pharmaceutical agent, it contains a peptide or a salt thereof composed of the amino acid sequence shown in SEQ ID NO: 1 or the amino acid sequence shown in SEQ ID NO: 2 (ELEEMQRRADQLA); as a water-soluble pharmaceutical agent, it is more preferably a peptide (non-salt) composed of the amino acid sequence shown in SEQ ID NO: 1 or the amino acid sequence shown in SEQ ID NO: 2. According to a more preferred embodiment of the present invention, in the W / O / W type emulsified composition of the present invention, as a water-soluble pharmaceutical agent, it contains a peptide (acetyl hexapeptide-8 (AH-8)) or a salt thereof composed of the amino acid sequence shown in SEQ ID NO: 1, and as a water-soluble pharmaceutical agent, it is more preferably AH-8 (non-salt).

[0061] The content of the above peptide or its salt in the W / O / W type emulsified composition of the present invention can be appropriately selected according to its use, and is preferably 0.001 to 1% by mass based on the total amount of the W / O / W type emulsified composition. In the case of using two or more of the above peptides or their salts, it is only necessary to make the total amount thereof satisfy the above range.

[0062] If commercially available products of the water-soluble pharmaceutical agents in the present invention are available, they can also be used.

[0063] According to an embodiment of the present invention, in the W / O / W type emulsified composition of the present invention, as a surfactant for emulsifying the internal aqueous phase in the oil phase, it contains one or more polyglycerol fatty acid esters having an average degree of polymerization of glycerol of 2 to 9. The polyglycerol fatty acid esters having an average degree of polymerization of glycerol of 2 to 9 in the present invention are preferably one or more polyglycerol fatty acid esters selected from the group consisting of polyglycerol oleates, polyglycerol isostearates, polyglycerol diisostearates, polyglycerol dimer hydroxystearates, and polyglycerol polyricinoleates having an average degree of polymerization of glycerol of 2 to 9, and more preferably one or more polyglycerol fatty acid esters selected from the group consisting of polyglycerol-4 oleate, polyglycerol-6 oleate, polyglycerol-2 isostearate, polyglycerol-6 polyricinoleate, polyglycerol-2 diisostearate, and polyglycerol-2 dimer hydroxystearate.

[0064] According to another embodiment of the present invention, the W / O / W emulsified composition of the present invention contains one or more polyethylene glycol dipolyhydroxystearate as a surfactant for emulsifying the internal aqueous phase in the oil phase.

[0065] According to a preferred embodiment of the present invention, the W / O / W emulsified composition of the present invention contains one or more polyglycerol fatty acid esters having an average polymerization degree of glycerol of 2 to 9 as a surfactant for emulsifying the internal aqueous phase in the oil phase.

[0066] In the W / O / W emulsified composition of the present invention, one or more surfactants selected from the group consisting of polyglycerol fatty acid esters having an average polymerization degree of glycerol of 2 to 9 and polyethylene glycol dipolyhydroxystearate may be used if they are commercially available.

[0067] The amount of one or more surfactants selected from the group consisting of polyglycerol fatty acid esters having an average degree of polymerization of glycerol of 2 to 9 and polyethylene glycol dipolyhydroxystearate in the W / O / W emulsion composition of the present invention is not limited, but is preferably 0.5 to 2% by weight.

[0068] According to a preferred embodiment of the present invention, the W / O / W type emulsion composition of the present invention comprises one or more oils selected from the group consisting of polar oils having an IOB value of 0.1 to 0.80. Such oils are oils commonly used in cosmetics, medicines, foods, etc., preferably one or more selected from the group consisting of pentaerythritol tetra(ethylhexanoate), glyceryl diisostearate, di(phytosterol / octyldodecanol) lauroyl glutamate, bis-diglycerol polyacyl adipate-2, dipentaerythritol hexahydroxystearate and castor seed oil, more preferably one or more selected from the group consisting of castor seed oil, bis-diglycerol polyacyl adipate-2 and dipentaerythritol hexahydroxystearate. It should be noted that the IOB value refers to the abbreviation of the inorganic organic balance value (Inorganic / Organic Balance, inorganic / organic ratio), which is a value indicating the ratio of the inorganic value to the organic value, and is an indicator indicating the degree of polarity of the organic compound. Specifically, the IOB value is expressed as "IOB value = inorganic value / organic value". Here, regarding the "inorganic value" and "organic value", for example, the "organic value" of one carbon atom in a molecule is 20, and the "inorganic value" of one hydroxyl group in a molecule is 100, the "inorganic value" and "organic value" corresponding to various atoms or functional groups are set respectively, and the IOB value of the organic compound can be calculated by accumulating the "inorganic value" and "organic value" of all atoms and functional groups in the organic compound (for example, see "The Field of Chemistry (Japanese: 化の界界)" by Fujita, Vol. 11, No. 10, pp. 719-725, 1957).

[0069] The blending amount of one or more oil components selected from the group consisting of polar oils having an IOB value of 0.1 to 0.80 in the W / O / W type emulsion composition of the present invention relative to the total amount of the composition is not particularly limited, and is preferably 3 to 20% by weight, more preferably 5 to 10% by weight. It should be noted that the W / O / W type emulsion composition of the present invention may further contain oil components commonly used in cosmetics, pharmaceuticals, foods, etc. Such oil components are not particularly limited, and examples thereof include: hydrocarbon oils, ester oils, silicone oils, higher alcohols having 12 to 22 carbon atoms, fatty acids having 12 to 22 carbon atoms, fats and oils, etc.

[0070] Examples of the hydrocarbon oil in the present invention include: liquid paraffin, squalane, squalene, pristane, paraffin, isoparaffin, hydrogenated polyisobutene, olefin oligomers, volatile hydrocarbon oils (such as isododecane, isocetane, undecane, tridecane, etc.).

[0071] Examples of the ester oil in the present invention include: isopropyl myristate, cetyl ethylhexanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyl decyl dimethyl octanoate, cetyl lactate, myristyl lactate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene glycol bis(2-ethylhexanoate), dipentaerythritol fatty acid ester, mono-N-alkyl glycol isostearate, neopentyl glycol didecanoate, diisostearyl malate, di-2-heptylundecanoin, trimethylolpropane tris(2-ethylhexanoate), trimethylolpropane triisostearate, glyceryl triisostearate, pentaerythritol tetra(ethylhexanoate), tri(ethylhexanoate) glycerin (glycerol tri(2-ethylhexanoate)), cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, trimyristin, tri-2-heptylundecanoin, methyl ricinoleate, oleyl oleate, cetearyl alcohol, acetyl glyceride, 2-heptylundecyl palmitate, diisobutyl adipate, 2-octyldodecyl N-lauroyl-L-glutamate, bis(2-heptylundecyl) adipate, ethyl laurate, bis(2-ethylhexyl) sebacate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, diisopropyl sebacate, 2-ethylhexyl succinate, polypropylene glycol dipivalate, ethyl acetate, butyl acetate, amyl acetate, triester oils such as triethyl citrate, etc.

[0072] Examples of the silicone oil in the present invention include: linear polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, methylhydrogenpolysiloxane, etc., cyclic polysiloxanes such as decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, tetramethyltetrahydrocyclosiloxane, etc.

[0073] Examples of the higher alcohols having 12 to 22 carbon atoms in the present invention include oleyl alcohol, 2-decyltetradecanol, dodecanol, isostearyl alcohol, octyldodecanol, etc. Examples of the fatty acids having 12 to 22 carbon atoms include oleic acid, isostearic acid, linoleic acid, linolenic acid, etc.

[0074] Examples of the oils and fats in the present invention include cocoa butter, avocado oil, camellia seed oil, macadamia integrifolia seed oil, corn oil, olive fruit oil, rapeseed oil, sesame oil, peach kernel oil, wheat germ oil, camellia oil, castor oil, linseed oil, safflower oil, cottonseed oil, perilla oil, soybean oil, peanut oil, tea seed oil, Torreya nucifera seed oil, rice bran oil, Chinese tung oil, Japanese tung oil, jojoba oil, germ oil, triglycerol, glyceryl trioctanoate, glyceryl triisopalmitate, etc.

[0075] The thickener having an alkyl group in the present invention is not limited as long as it is a compound having an alkyl group and can be used as a thickener, and it is included in the outer aqueous phase to disperse the oil phase (W / O emulsion) into the outer aqueous phase. The blending amount of the thickener having an alkyl group in the present invention is preferably 0.01 to 2% by weight based on the total amount of the emulsifying composition. The thickener having an alkyl group in the present invention is not limited, and is preferably at least one selected from the group consisting of an alkyl-modified carboxyvinyl polymer, acryloyldimethyltaurine ammonium / montanox 25 methacrylate cross-linked polymer, and acrylate / stearyl alcohol polyether-20 methacrylate copolymer.

[0076] The alkyl-modified carboxyvinyl polymer in the present invention is preferably an acrylate / C10-30 alkanol acrylate cross-linked polymer, which functions as an emulsifier and a thickener. The alkyl-modified carboxyvinyl polymer in the present invention is not limited, but preferably has a molecular weight of about 500,000 to 3,000,000. For the alkyl-modified carboxyvinyl polymer in the present invention, if there are commercially available products, they can also be used. For example, "CARBOPOL 1342", "PEMULEN TR-1", "PEMULEN TR-2" (all manufactured by Lubrizol Corporation) can be used.

[0077] In order to improve the freeze resistance, the W / O / W type emulsifying composition of the present invention preferably may also contain a polyol in the outer aqueous phase. Examples of such polyols include glycerol, 1,3-butanediol, dipropylene glycol, etc. In addition, the blending amount of such polyol is preferably 5 to 25% by weight based on the total amount of the emulsifying composition.

[0078] As needed, within the scope that does not impair the effects of the present invention, the W / O / W type emulsified composition of the present invention may further contain any additive components that are usually blended in cosmetics and the like. Examples of such additive components include: thickeners such as cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, quince seed, carrageenan, pectin, mannan, curdlan, chondroitin sulfate, starch, galactan, dermatan sulfate, glycogen, gum arabic, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratan sulfate, chondroitin, xanthan gum, mucopolysaccharide sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, guar gum, dextran, keratin sulfate, locust bean gum, succinoglucan, calonic acid, chitin, chitosan, carboxymethyl chitosan, agar; lower alcohols such as ethanol; antioxidants such as butylated hydroxytoluene, tocopherol, phytic acid; antibacterial agents such as benzoic acid, salicylic acid, sorbic acid, alkyl p-hydroxybenzoates, hexachlorophene; benzoic acid-based ultraviolet absorbers such as p-aminobenzoic acid (hereinafter abbreviated as "PABA"), monoglyceryl PABA ester, N,N-dipropoxyethyl PABA, N,N-diethoxyethyl PABA, N,N-dimethyl PABA methyl ester, N,N-dimethyl PABA ethyl ester, N,N-dimethyl PABA butyl ester, N,N-dimethyl PABA 2-ethylhexyl ester; anthranilic acid-based ultraviolet absorbers such as N-acetylanthranilic acid permanganate; salicylic acid-based ultraviolet absorbers such as amyl salicylate, menthyl salicylate, permanganate salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropylphenyl salicylate; cinnamic acid-based ultraviolet absorbers such as octyl cinnamate, ethyl 4-isopropylcinnamate, methyl 2,5-diisopropylcinnamate, ethyl 2,4-diisopropylcinnamate, methyl 2,4-diisopropylcinnamate, propyl p-methoxycinnamate, isopropyl p-methoxycinnamate, isopentyl p-methoxycinnamate, octyl p-methoxycinnamate (2-ethylhexyl p-methoxycinnamate), 2-ethoxyethyl p-methoxycinnamate, cyclohexyl p-methoxycinnamate, ethyl α-cyano-β-phenylcinnamate, 2-ethylhexyl α-cyano-β-phenylcinnamate, 2-ethylhexanoyl monoglyceryl di-p-methoxycinnamate;Silicone-based cinnamic acid UV absorbers such as [[3-bis(trimethylsilyloxy)methylsilyl-1-methylpropyl]]-3,4,5-trimethoxycinnamate, [[3-bis(trimethylsilyloxy)methylsilyl-3-methylpropyl]]-3,4,5-trimethoxycinnamate, [[3-bis(trimethylsilyloxy)methylsilylpropyl]]-3,4,5-trimethoxycinnamate, [[3-bis(trimethylsilyloxy)methylsilylbutyl]]-3,4,5-trimethoxycinnamate, [[3-tris(trimethylsilyloxy)silylbutyl]]-3,4,5-trimethoxycinnamate, [[3-tris(trimethylsilyloxy)silylbutyl]]-3,4,5-trimethoxycinnamate, [[3-tris(trimethylsilyloxy)silyl-1-methylpropyl]]-3,4-dimethoxycinnamate; Benzophenone-based UV absorbers such as 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,2',4,4'-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonate, 4-phenylbenzophenone, 4'-phenyl-benzophenone-2-carboxylic acid (2-ethylhexyl) ester, 2-hydroxy-4-n-octyloxybenzophenone, 4-hydroxy-3-carboxybenzophenone; UV absorbers such as 3-(4'-methylbenzylidene)-d,l-camphor, 3-benzylidene-d,l-camphor, ethyl urocanate, 2-phenyl-5-methylbenzoxazole, 2,2'-hydroxy-5-methylphenylbenzotriazole, 2-(2'-hydroxy-5'-tert-octylphenyl)benzotriazole, 2-(2'-hydroxy-5'-methylphenyl)benzotriazole, dibenzaladine, dianisoylmethane, 4-methoxy-4'-tert-butyldibenzoylmethane, 5-(3,3'-dimethyl-2-norbornenyl)-3-pentan-2-one; Organic acids such as acylsarcosine (e.g., sodium lauroylsarcosine), glutathione, citric acid, malic acid, tartaric acid, lactic acid; Vitamin Bs such as vitamin A and its derivatives, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 and its derivatives, vitamin B12, vitamin B15 and its derivatives; Vitamin Es such as α-tocopherol, β-tocopherol, γ-tocopherol, vitamin E acetate; Vitamin Ds, vitamin H, pantothenic acid, pantethine, nicotinamide, benzyl nicotinate;γ-oryzanol, allantoin, glycyrrhizic acid (salt), glycyrrhetinic acid and its derivatives, tranexamic acid and its derivatives [as tranexamic acid derivatives, dimers of tranexamic acid (e.g., trans-4-(trans-aminomethylcyclohexanecarbonyl)aminomethylcyclohexane carboxylic acid hydrochloride, etc.), esters of tranexamic acid and hydroquinone (e.g., 4'-hydroxyphenyl trans-4-aminomethylcyclohexane carboxylate, etc.), esters of tranexamic acid and gentisic acid (e.g., 2-(trans-4-aminomethylcyclohexylcarbonyloxy)-5-hydroxybenzoic acid and its salts, etc.), amides of tranexamic acid (e.g., methylamide of trans-4-aminomethylcyclohexane carboxylic acid and its salts, trans-4-(p-methoxybenzoyl)aminomethylcyclohexane carboxylic acid and its salts, trans-4-guanidinomethylcyclohexane carboxylic acid and its salts, etc.)], hinokitiol, bisabolol, eucalyptone, thymol, inositol, saikosaponin, ginsenoside, luffasaponin, saponins such as sapindus saponin, panthenol ethyl ether, ethinyl estradiol, tranexamic acid, arbutin, cepharanthine, (animal) placental protein and other various medicaments; extracts of plants such as Rumex japonicus, Sophora flavescens, Nuphar japonica, Citrus sinensis, Salvia officinalis leaves, Achillea millefolium, Malva sylvestris leaf powder, Swertia japonica powder, Thymus vulgaris, Angelica acutiloba, Citrus aurantium, Betula platyphylla, Equisetum arvense, Luffa cylindrica, Aesculus hippocastanum, Saxifraga stolonifera, Arnica montana, Lilium candidum, Artemisia princeps, Paeonia lactiflora, Aloe vera, Gardenia jasminoides, Chamaecyparis pisifera and the like; pigments; porous and / or water-absorbent powders (e.g., starches obtained from corn, potato, etc., silica, talc, kaolin, magnesium aluminum silicate, calcium alginate and other powders); nonionic surfactants such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyethylene glycol monooleate, polyoxyethylene alkyl ether, polyglycol diether, lauroyl diethanolamide, fatty acid isopropanolamide, maltitol hydroxy fatty acid ether, alkylated polysaccharide, alkyl glucoside, sugar ester, etc.; cationic surfactants such as stearyl trimethyl ammonium chloride, benzalkonium chloride, lauryldimethylamine oxide, etc.; anionic surfactants such as sodium palmitate, sodium laurate, sodium laurate, potassium lauryl sulfate, triethanolamine ether of alkyl sulfate, Turkey red oil, linear dodecylbenzenesulfonic acid, polyoxyethylene hydrogenated castor oil maleate, acyl methyl taurine, etc.; amphoteric surfactants; neutralizing agents; preservatives; fragrances; pigments, etc.

[0079] The method for manufacturing the W / O / W type emulsified composition of the present invention is not particularly limited and can be manufactured by a conventional method. For example, a W / O type emulsion can be prepared by stirring and mixing with an emulsifier such as a homogenizer or a disperser, and then it is mixed and emulsified with an external aqueous phase containing a thickener having an alkyl group to obtain.

[0080] The composition of the present invention can be used as a cosmetic composition. The cosmetic composition in the present invention refers to a composition for cosmetic purposes.

[0081] According to an embodiment of the present invention, there is provided a method for improving the biofilm permeability of a water-soluble pharmaceutical agent, the method comprising the step of applying the W / O / W type emulsified composition of the present invention to a biofilm.

[0082] The method for improving the biofilm permeability of the water-soluble pharmaceutical agent of the present invention can be carried out in either in vivo or in vitro.

[0083] The application object of the method for improving the biofilm permeability of the water-soluble pharmaceutical agent of the present invention is not limited. For example, it can be listed as: mammals such as primates including humans and chimpanzees, pet animals such as dogs and cats, livestock animals such as cows, horses, sheep, and goats, and rodents such as mice and rats. As the application object of the method for improving the biofilm permeability of the water-soluble pharmaceutical agent of the present invention, humans are preferred.

[0084] The biofilm in the present invention is not particularly limited. For example, it can be listed as: the biofilm on the skin, the biofilm on mucous membranes (such as oral mucosa, eye mucosa, nasal mucosa, cavity mucosa, rectal mucosa, etc.). Preferably, it is the biofilm on the skin. Therefore, according to a preferred embodiment of the present invention, there is provided a method for improving the skin permeability of a water-soluble pharmaceutical agent, the method comprising the step of applying the W / O / W type emulsified composition of the present invention to the skin.

[0085] Examples

[0086] The present invention will be specifically described based on the following examples, but the present invention is not limited to these examples. Unless otherwise specified, the content is expressed in weight %.

[0087] Four oil components with different polarities (hydrogenated polydecene, cetyl alcohol ethylhexanoate, pentaerythritol tetra(ethylhexanoate), castor oil) were used to prepare the W / O / W type emulsified compositions shown in Table 1 below. An aqueous phase containing an osmotic pressure regulator was added to an oil phase containing a surfactant, and W / O emulsification was carried out using a homogenizer. Then, the W / O emulsion was added to the outer aqueous phase and dispersed using a disperser to obtain a W / O / W type emulsified composition. For each sample, the viscosity on the next day was measured at a sample temperature of 30 °C using a VISCOMETER TVB-15 (manufactured by Toki Sangyo Co., Ltd.), No. 7 rotor, and 10 rpm. In addition, for each sample, the viscosity after storage at 50 °C for 4 weeks or in a frozen state for 4 weeks was also measured. The case where the viscosity after the change over time was greater than 80% of the viscosity on the next day was evaluated as A, the case where the viscosity after the change over time was 30% - 80% of the viscosity on the next day was evaluated as B, and the case where the viscosity after the change over time was less than 30% of the viscosity on the next day was evaluated as C. The results are shown in Table 1.

[0088] Table 1

[0089] Table 1: List of Formulations of W / O / W-Type Emulsion Compositions

[0090]

[0091] From the results in Table 1, it can be seen that for the W / O / W-type emulsion compositions of Formulation Examples 1 to 4, substantially no change in viscosity over time was confirmed, and good freeze-thaw stability was exhibited.

[0092] Next, W / O / W-type emulsion compositions shown in Table 2 below were prepared using highly polar oils or combinations thereof. The change in viscosity over time and freeze-thaw stability were evaluated using the same methods and evaluation criteria as above. The results are shown in Table 2.

[0093] Table 2

[0094] Table 2: Change in Viscosity over Time of W / O / W-Type Emulsion Compositions

[0095]

[0096] From the results in Table 2, it can be seen that for the W / O / W-type emulsion compositions of Formulation Examples 5 to 8, substantially no change in viscosity over time was confirmed, and good freeze-thaw stability was exhibited.

[0097] Next, W / O / W-type emulsion compositions shown in Table 3 below were prepared using other surfactants. The change in viscosity over time and freeze-thaw stability were evaluated using the same methods and evaluation criteria as above. The results are shown in Table 3.

[0099] Table 3

[0100] Table 3: List of Formulations of W / O / W-Type Emulsion Compositions

[0101]

[0102] From the results in Table 3, it can be seen that for the W / O / W-type emulsion compositions of Formulation Examples 9 to 11, substantially no change in viscosity over time was confirmed, and good freeze-thaw stability was exhibited.

[0103] Next, W / O / W-type emulsion compositions shown in Table 4 below were prepared using various osmotic pressure regulators (trehalose, sodium glutamate, maltitol). The change in viscosity over time and freeze-thaw stability were evaluated using the same methods and evaluation criteria as above. The results are shown in Table 4.

[0104] Table 4

[0105] Table 4: List of Formulations of W / O / W-Type Emulsion Compositions

[0106]

[0107] As can be seen from the results in Table 4, the W / O / W type emulsified compositions of Formulation Examples 12 to 15 also basically did not show any change in viscosity over time and exhibited good stability.

[0108] From the above results, it can be seen that the W / O / W type emulsified compositions of Formulation Examples 1 to 15 can inhibit the decrease in viscosity when stored at 50°C and exhibit good stability.

[0109] Other formulations

[0110] Formulation Examples 16 to 19 of other W / O / W type emulsified compositions are shown in Table 5.

[0111] Table 5

[0112] Table 5: Formulation Examples 16 to 19

[0113]

[0114] Next, the compositions of Example 1 and Comparative Examples 1 to 2 shown in Table 6 were prepared according to the following steps.

[0115] Preparation of Example 1

[0116] The water-soluble peptide acetyl hexapeptide-8 (AH-8) was blended at a ratio of 0.1% and dissolved while stirring well to prepare the innermost aqueous phase portion by a conventional method. The prepared innermost aqueous phase portion was added to the oil phase portion and stirred to prepare the W / O portion. The prepared W / O portion was further added to the outer aqueous phase portion and stirred for emulsification to prepare the W / O / W type emulsified composition of Example 1. The mass of AH-8 added to the outer aqueous phase portion and the oil phase portion was 0%.

[0117] Preparation of Comparative Example 1

[0118] The innermost aqueous phase portion was prepared by a conventional method. The prepared innermost aqueous phase portion was added to the oil phase portion and stirred to prepare the W / O portion. AH-8 was blended at a ratio of 0.1% into the outer aqueous phase portion, and the prepared W / O portion was further added to the outer aqueous phase portion and stirred for emulsification to prepare the W / O / W type emulsified composition of Comparative Example 1. The mass of AH-8 added to the innermost aqueous phase portion and the oil phase portion was 0%. It should be noted that the components and their blending amounts of Comparative Example 1 were the same as those of Example 1.

[0119] Preparation of Comparative Example 2

[0120] AH-8 was compounded into the external aqueous phase portion at a ratio of 0.1%, and after sufficient stirring, the oil phase portion was added to the external aqueous phase portion and emulsified to prepare the O / W type emulsified composition of Comparative Example 2. It should be noted that the components and compounding amounts of Comparative Example 2 are the same as those of Example 1 and Comparative Example 1, which is equivalent to the formulation in which the components of the innermost aqueous phase in Example 1 and Comparative Example 1 are compounded into the external aqueous phase.

[0121] Cutaneous Permeation Test of Peptide Acetyl Hexapeptide-8 (AH-8)

[0122] The stratum corneum permeability of AH-8 contained in the prepared compositions of Example 1 and Comparative Examples 1 to 2 was evaluated by the Diffusion Cell Array method. The Diffusion Cell Array method is based on the method described in a well-known literature (Uchida, T., Nishioka, K., Motoki, A., Yakumaru, M., Sano, T., Todo, H., & Sugibayashi, K. (2016). Effect of Esters on the Permeation of Chemicals with Different Polarities through Synthetic Artificial Membranes Using a High-Throughput Diffusion Cell Array. Chemical & pharmaceutical bulletin, 64(11), 1597-1606.), and was carried out using a Diffusion Cell Array equipped with multiple diffusion cells (effective permeation area of 0.785 cm 2 ). In addition, as the permeation membrane, human skin (manufactured by BIOPREDIC International) with a thickness of 400 μm or more was used. The human skin was firmly fixed to the Diffusion Cell Array using a cell clamp so that air did not enter between the receiving cell and the supply cell. Then, the receiving cell was filled with PBS and hydrated for 1 hour. During this period, the Diffusion Cell Array with the human skin fixed was placed in a temperature regulator to adjust the temperature so that the skin surface temperature was 30 °C. At the same time, the PBS in the receiving cell was stirred with a stirrer at about 100 rpm.

[0123] Next, the compositions of Example 1 and Comparative Examples 1 to 2 were each applied at 10 μL / cm 2The formulation was uniformly applied to human skin fixed on a Diffusion Cell Array at a ratio for 60 seconds. Assuming actual use, each formulation example was applied to the skin in a limited open application manner. After application, the PBS in the receiving cell was stirred with a stir bar at about 100 rpm for 4 hours. After stirring, the human skin was removed from the Diffusion Cell Array. The foaming soap solution was applied to a cotton swab, and the removed human skin was wiped 5 times with the cotton swab, then wiped 5 times with purified water, and finally the moisture on the skin surface was absorbed.

[0124] By tape stripping, the stratum corneum of the parts coated with Example 1 and Comparative Examples 1-2 was collected 10 times (10 layers). Ten tapes of 10 layers were sequentially placed 2 tapes of 2 layers into 1 vial from the upper layer, immersed in 500 μL of an extraction solvent (a mixed solvent containing water and methanol in a ratio of 97:3), and ultrasonic vibration was performed for 15 minutes to extract the drug from the tape. Using LC-QTOF-MS, the amount of the drug in the collected extract was quantified, and the stratum corneum permeation amounts of 2 layers were calculated respectively and added together to obtain the value of the stratum corneum permeation amount of 10 layers. The compositions of Example 1 and Comparative Examples 1-2 were applied to 4 places on the same skin respectively, and the average value of the stratum corneum permeation amounts of 10 layers at each of the 4 places was used as the total stratum corneum permeation amount of each formulation example. The results are shown in Table 6.

[0125] Table 6

[0126] Table 6: Example 1 and Comparative Examples 1-2

[0127]

[0128] ※: The stratum corneum permeation amount is the average value, and the unit is μg / mL.

[0129] For each stratum corneum permeation amount, it was shown that in any one of the 1-2 layers, 3-4 layers, 5-6 layers, 7-8 layers, and 9-10 layers, the stratum corneum permeation amount of AH-8 in the composition of Example 1 was higher than that of AH-8 in the compositions of Comparative Examples 1-2. In addition, regarding the total stratum corneum permeation amount, statistical processing was performed using the corresponding Student's t-test. The results showed that the total stratum corneum permeation amount of AH-8 in the composition of Example 1 was significantly higher than that of AH-8 in the compositions of Comparative Examples 1-2. The above results indicate that the W / O / W type emulsified composition of the present invention has good percutaneous permeability of water-soluble drugs.

[0130] Next, the compositions of Example 2 and Comparative Example 3 shown in Table 7 were prepared according to the following steps.

[0131] Preparation of Example 2

[0132] The water-soluble 1-(2-hydroxyethyl)-2-imidazolidinone (HEI) was compounded at 1.5% and dissolved while stirring thoroughly to prepare the innermost aqueous phase portion by a conventional method. The prepared innermost aqueous phase portion was added to the oil phase portion and stirred to prepare the W / O portion. The prepared W / O portion was further added to the outer aqueous phase portion and stirred for emulsification to prepare the W / O / W type emulsified composition of Example 2. The mass of HEI added to the outer aqueous phase portion and the oil phase portion was 0%.

[0133] Preparation of Comparative Example 3

[0134] The innermost aqueous phase portion was prepared by a conventional method. The prepared innermost aqueous phase portion was added to the oil phase portion and stirred to prepare the W / O portion. HEI was compounded at 1.5% into the outer aqueous phase portion, and the prepared W / O portion was further added to the outer aqueous phase portion and stirred for emulsification to prepare the W / O / W type emulsified composition of Comparative Example 3. The mass of HEI added to the innermost aqueous phase portion and the oil phase portion was 0%. It should be noted that the components and their compounding amounts of Comparative Example 3 were the same as those of Example 2.

[0135] Cutaneous Permeation Test of 1-(2-Hydroxyethyl)-2-imidazolidinone (HEI)

[0136] The stratum corneum permeability of HEI contained in the prepared compositions of Example 2 and Comparative Example 3 was evaluated by the same method as the stratum corneum penetration test of the above-mentioned peptide acetyl hexapeptide-8 (AH-8). The results are shown in Table 7.

[0137] Table 7

[0138] Table 7: Example 2 and Comparative Example 3

[0139]

[0140] ※: The stratum corneum penetration amount is the average value, and the unit is μg / mL.

[0141] Regarding each stratum corneum penetration amount, it was shown that in any layer of the 1st - 2nd layer, 3rd - 4th layer, 5th - 6th layer, 7th - 8th layer, and 9th - 10th layer, the stratum corneum penetration amount of HEI in the composition of Example 2 was higher than that of HEI in the composition of Comparative Example 3. In addition, regarding the total stratum corneum penetration amount, it was also shown that the total stratum corneum penetration amount of HEI in the composition of Example 2 was higher than that of HEI in the composition of Comparative Example 3. The above results indicate that the W / O / W type emulsified composition of the present invention has good transdermal permeability of water-soluble medicaments.

Claims

1. A W / O / W emulsified composition comprising: Internal water phase, an oil phase in which the inner water phase is dispersed, and an external water phase in which the oil phase is dispersed, The composition comprises a water-soluble agent. At least 99% of the total amount of the water-soluble agent is contained in the internal aqueous phase, The inner aqueous phase contains an osmotic pressure regulator, wherein the osmotic pressure regulator generates an osmotic pressure between the inner aqueous phase and the outer aqueous phase. The composition comprises, as a surfactant for emulsifying the internal aqueous phase in the oil phase, at least one selected from the group consisting of polyglycerol fatty acid esters having an average polymerization degree of glycerol of 2 to 9 and polyethylene glycol dipolyhydroxystearate, The external aqueous phase contains a thickener having an alkyl group.

2. The composition according to claim 1, wherein The water-soluble drug is a cyclic carboxamide derivative or a salt thereof represented by the following formula (I), In the formula, n is an integer from 1 to 3, R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms which may be substituted by a hydroxyl group, and X is -CH2- or -N(R 2 )-, R 2 It refers to a hydrocarbon group having 1 to 6 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group.

3. The composition according to claim 2, wherein The cyclic carboxamide derivative is 1-(2-hydroxyethyl)-2-imidazolidinone.

4. The composition according to claim 1, wherein The water-soluble drug is a peptide consisting of the amino acid sequence shown in sequence number 1 or the amino acid sequence shown in sequence number 2, or a salt thereof.

5. The composition according to claim 4, wherein The amino acids are D-amino acids or L-amino acids.

6. The composition according to claim 4, wherein The N-terminal amino acid is acetylated.

7. The composition according to claim 4, wherein The C-terminal amino acid is amidated.

8. The composition according to claim 4, wherein The peptide is acetyl hexapeptide-8.

9. The composition according to claim 1, wherein The osmotic pressure regulator is one or more selected from the group consisting of sodium L-glutamate, maltitol and trehalose.

10. The composition according to claim 1, wherein The osmotic pressure regulator is trehalose.

11. The composition according to claim 1, wherein The osmotic pressure regulator is contained in an amount of 0.1 to 0.5% by weight relative to the weight of the composition.

12. The composition according to claim 1, wherein As a surfactant for emulsifying the inner aqueous phase in the oil phase, a polyglycerol fatty acid ester having an average polymerization degree of glycerol of 2 to 9 is included, and the polyglycerol fatty acid ester is one or more selected from the group consisting of polyglycerol oleate, polyglycerol isostearate, polyglycerol diisostearate, polyglycerol dipolyhydroxystearate and polyglycerol polyricinoleate.

13. The composition according to claim 1, wherein The surfactant for emulsifying the internal aqueous phase in the oil phase includes one or more polyglyceryl fatty acid esters selected from the group consisting of polyglyceryl-4 oleate, polyglyceryl-6 oleate, polyglyceryl-2 isostearate, polyglyceryl-6 polyricinoleate, polyglyceryl-2 diisostearate and polyglyceryl-2 dipolyhydroxystearate.

14. The composition according to claim 1, wherein The oil phase contains one or more oil components selected from the group consisting of polar oils having an IOB value of 0.1 to 0.

80.

15. The composition according to claim 14, wherein The oil may be one or more selected from the group consisting of castor seed oil, bis-diglyceryl polyacyladipate-2, and dipentaerythritol hexahydroxystearate.

16. The composition according to claim 14, wherein The amount of the oil component blended with respect to the composition is 3 to 20% by weight.

17. The composition according to claim 1, wherein The thickener having an alkyl group is at least one selected from the group consisting of an alkyl-modified carboxyvinyl polymer, ammonium acryloyldimethyltaurate / beheneth-25 methacrylate crosspolymer, and acrylic acid (esters) / steareth-20 methacrylate copolymer.

18. The composition according to any one of claims 1 to 17, which is a cosmetic composition.

19. A method for improving biomembrane permeability of a water-soluble drug, comprising the step of applying the composition according to any one of claims 1 to 17 to a biomembrane.

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