W / o / w emulsion composition

Abstract

To provide a W / O / W emulsion composition having good percutaneous permeability of a water-soluble drug.SOLUTION: There is provided a W / O / W 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, wherein the composition comprises a water-soluble drug, at least 99% of the total amount of the water-soluble drug is contained in the inner aqueous phase, the inner aqueous phase contains an osmotic pressure regulator in which the osmotic pressure regulator generates an osmotic pressure between the inner aqueous phase and the outer aqueous phase, the inner aqueous phase contains, as a surfactant emulsifying the inner aqueous phase into the oil phase, one or more selected from the group consisting of a polyglycerol fatty acid ester having an average degree of polymerization of glycerol of 2 to 9 and a polyethylene glycol dipolyhydroxystearate and the outer aqueous phase contains a thickening agent having an alkyl group.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a W / O / W type emulsion composition.

Background Art

[0002] Skin external use compositions such as ointments, emulsions, creams, lotions, gels, etc. contain various water-soluble drugs such as antioxidants, blood circulation promoters, whitening agents, moisturizing agents, vitamins, etc. When these water-soluble drugs are applied to the skin in the skin external use composition, they penetrate into the skin while dissolved in water. However, when the moisture in the base evaporates and crystallizes on the skin surface, the penetration into the skin stops, resulting in a problem that the absorption into the skin is low and sufficient effects cannot be exerted.

[0003] In order to enhance the permeability of water-soluble drugs in skin external use compositions to the skin, various research and developments have been made conventionally. For example, attempts have been made to form micelles in the composition (Patent Document 1), to blend specific components capable of enhancing the permeability of water-soluble drugs in the composition (Patent Document 2), etc.

[0004] However, these methods are not applicable to all skin external use compositions. When formulating water-soluble drugs with an oily base or the like, the usability deteriorates, and there is also a problem that the percutaneous absorption of the water-soluble drug itself cannot be sufficiently enhanced because the water-soluble drug does not directly contact the skin.

[0005] Therefore, the development of a skin external use composition having excellent percutaneous permeability of water-soluble drugs is still required at present.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Summary of the Invention

[0007] The inventors have found that a water-soluble drug in a W / O / W type emulsion composition containing a specific emulsifier and having at least 99% of the water-soluble drug in the internal aqueous phase exhibits excellent percutaneous permeability. The present invention is based on this finding.

[0008] Therefore, the present invention provides a W / O / W type emulsion composition in which the percutaneous permeability of the water-soluble drug is good.

[0009] According to the present invention, the following inventions are provided. (1) An internal aqueous phase, an oil phase in which the internal aqueous phase is dispersed, an external aqueous phase in which the oil phase is dispersed, A W / O / W type emulsion composition comprising: the composition contains a water-soluble drug, at least 99% of the total amount of the water-soluble drug is contained in the internal aqueous phase, the internal aqueous phase contains an osmotic pressure adjuster, where the osmotic pressure adjuster generates an osmotic pressure between the internal aqueous phase and the external aqueous phase, as the surfactant for emulsifying the internal 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 glycerin of 2 to 9 and polyethylene glycol dipolyhydroxystearate the external aqueous phase contains a thickener having an alkyl group. (2) The water-soluble drug is represented by the following formula (I): [Chemical formula] a cyclic carboxamide derivative represented by [wherein, n is an integer of 1 to 3, R 1 is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, X is a group represented by -CH2- or -N(R 2 )-, and R 2 means a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group.] or a salt thereof The composition according to (1). (3) The composition according to (2), wherein the cyclic carboxamide derivative is 1-(2-hydroxyethyl)-2-imidazolidinone. (4) The composition according to (1), wherein the water-soluble drug is a peptide consisting 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. (5) The composition according to (4), wherein the amino acid is D-amino acid or L-amino acid. (6) The composition according to (4) or (5), wherein the N-terminal amino acid is acetylated. (7) The composition according to any one of (4) to (6), wherein the C-terminal amino acid is amidated. (8) The composition according to any one of (4) to (7), wherein the peptide is acetyl hexapeptide-8. (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. (10) The composition according to any one of (1) to (9), wherein the osmotic pressure regulator is trehalose. (11) The composition according to any one of (1) to (10), wherein the blending amount of the osmotic pressure regulator in the composition is 0.1 to 0.5% by weight. (12) As the surfactant for emulsifying the inner aqueous phase into the oil phase, the composition according to any one of (1) to (11) contains one or more polyglycerol fatty acid esters selected from the group consisting of polyglyceryl oleate, polyglyceryl isostearate, polyglyceryl diisostearate, polyglyceryl dipolyhydroxystearate, and polyglyceryl polyricinoleate, wherein the average degree of polymerization of glycerin is 2 to 9. (13) The composition according to any one of (1) to (12), comprising at least one polyglycerol fatty acid ester 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 as a surfactant for emulsifying the inner aqueous phase into the oil phase. (14) The composition according to any one of (1) to (13), wherein the oil phase contains at least one oil selected from the group consisting of polar oils having an IOB value of 0.1 to 0.80. (15) The composition according to (14), wherein the oil is at least one selected from the group consisting of castor oil, bis-diglyceryl polyacyl adipate-2, and dipentaerythrityl hexahydroxystearate. (16) The composition according to (14) or (15), wherein the blending amount of the oil in the composition is 3 to 20% by weight. (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 alkyl-modified carboxyvinyl polymer, (acryloyldimethyltaurine ammonium / methacrylic acid behenes-25) cross-polymer, and (acrylates / methacrylic acid stearles-20) copolymer. (18) The composition according to any one of (1) to (17), which is a cosmetic composition. (19) A method for improving the transdermal permeability of a water-soluble drug, comprising the step of applying the composition according to any one of (1) to (18) to a biological membrane.

[0010] According to the present invention, there is provided a W / O / W type emulsion composition having good transdermal permeability of a water-soluble drug. Further, according to the present invention, there is also provided a W / O / W type emulsion composition showing excellent stability. Detailed description of the invention

[0011] According to one aspect of the present invention, there is provided 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. This composition contains a water-soluble drug, and at least 99% of the total amount of this water-soluble drug is contained in the inner aqueous phase, preferably at least 99.9% of the total amount is contained in the inner aqueous phase. Thereby, an effect of enhancing the transdermal permeability of the water-soluble drug can be expected. Further, the inner aqueous phase in this composition contains an osmotic pressure regulator, and this osmotic pressure regulator generates an osmotic pressure between the inner aqueous phase and the outer aqueous phase, causing water to migrate from the outer aqueous phase to the inner aqueous phase. Thereby, a high internal phase (oil phase + inner aqueous phase) ratio can be obtained with a relatively small amount of oil phase, and a moist feeling can be obtained while having a high viscosity, and an effect of obtaining a unique phase inversion feeling accompanying the release of the inner aqueous phase when applied to the skin can be expected. This composition contains at least one selected from the group consisting of polyglycerol fatty acid esters having an average degree of polymerization of glycerin of 2 to 9 and polyethylene glycol dipolyhydroxystearate as a surfactant for emulsifying the inner aqueous phase in the oil phase. Further, the outer aqueous phase in this composition contains a thickener having an alkyl group.

[0012] The W / O / W type emulsion composition of the present invention has a structure in which a W / O type emulsion is dispersed in an outer aqueous phase.

[0013] In the W / O type emulsion forming the inner phase in the present invention, an osmotic pressure regulator is contained in the innermost aqueous 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 with respect to the total amount of the emulsion composition is preferably 0.01 to 1% by weight, and more preferably 0.01 to 0.5% by weight.

[0014] In the present invention, the inner aqueous phase and the oil phase are emulsified with one or more surfactants selected from the group consisting of polyglycerol fatty acid esters having an average degree of polymerization of glycerin of 2 to 9 and polyethylene glycol dipolyhydroxystearate to form a W / O type emulsion.

[0015] The water-soluble drug in the present invention is not particularly limited as long as it is a compound that dissolves in water, and it may be either a low-molecular compound or a high-molecular compound.

[0016] According to one embodiment of the present invention, the W / O / W type emulsified composition of the present invention contains, as a water-soluble drug, the following formula (I):

Chemical formula

[0017] The "hydrocarbon group" of the cyclic carboxamide derivative represented by the above formula (I) in the present invention is not particularly limited, and may be, for example, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, haloalkyl, alkoxyalkyl, alkoxycarbonylalkyl, etc., and preferably alkyl.

[0018] "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.

[0019] According to one preferred embodiment of the present invention, the W / O / W type emulsion composition of the present invention comprises, as a water-soluble drug, 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. More preferably, the water-soluble drug comprises one or more selected from the group consisting of 2-imidazolidinone (not a salt), 1-(2-hydroxyethyl)-2-imidazolidinone (not a salt), and 1-(2-hydroxyethyl)-2-pyrrolidone (not a salt). According to one more preferred embodiment of the present invention, the W / O / W type emulsion composition of the present invention comprises, as a water-soluble drug, 1-(2-hydroxyethyl)-2-imidazolidinone (HEI) or a salt thereof, and more preferably, comprises 1-(2-hydroxyethyl)-2-imidazolidinone (not a salt) as the water-soluble drug.

[0020] The salt of the cyclic carboxamide derivative in the present invention is not particularly limited as long as it is acceptable in cosmetics, pharmaceuticals, etc. Examples of inorganic salts include hydrochloride, sulfate, phosphate, hydrobromide, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, etc. Examples of organic salts include acetate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, p-toluenesulfonate, triethanolamine salt, diethanolamine salt, amino acid salt, etc.

[0021] The W / O / W type emulsion composition of the present invention may contain only one kind of the cyclic carboxamide derivative represented by the above formula (I) or a salt thereof as a water-soluble drug, or may contain two or more kinds of the cyclic carboxamide derivatives represented by the above formula (I) or salts thereof in any combination and ratio.

[0022] The content of the cyclic carboxamide derivative represented by the above formula (I) or a salt thereof in the W / O / W type emulsion composition of the present invention can be appropriately selected according to its use, and is preferably 0.1 to 10% by mass based on the total amount of the W / O / W type emulsion composition. When using two or more of the cyclic carboxamide derivatives represented by the above formula (I) or salts thereof, the total amount thereof may satisfy the above range.

[0023] According to another embodiment of the present invention, the W / O / W type emulsion composition of the present invention comprises a peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 (EEMQRR) or a peptide functionally equivalent thereto or a salt thereof as a water-soluble drug, and preferably comprises a peptide (not a salt) consisting of the amino acid sequence shown in SEQ ID NO: 1 or a peptide (not a salt) functionally equivalent thereto as a water-soluble drug. In the present invention, "functionally equivalent" means that the target peptide has at least one of the biological activities of the peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 (for example, the ability to at least partially suppress neuronal exocytosis, etc.).

[0024] The salt of the peptide in the present invention is not particularly limited as long as it is acceptable in cosmetics, pharmaceuticals, etc., and includes salts formed by adding salts customarily used to form metal salts or free acids or bases. The salt of the peptide in the present invention can be obtained from organic or inorganic acids or bases by reacting the appropriate acid or base with the peptide of the present invention by a method well known to those skilled in the art.

[0025] The amino acids constituting the structural unit of the above peptide in the present invention may have a D-configuration or an L-configuration. Also, the amino acid at the amino terminus of the above peptide in the present invention may have an acetylated terminal amino group, and the amino acid at the carboxyl terminus may have an amidated terminal carboxyl group.

[0026] According to one preferred embodiment of the present invention, the W / O / W type emulsion composition of the present invention comprises a peptide consisting 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 drug or a salt thereof, and more preferably, comprises a peptide (not a salt) consisting of the amino acid sequence shown in SEQ ID NO: 1 or the amino acid sequence shown in SEQ ID NO: 2 as a water-soluble drug. According to one more preferred embodiment of the present invention, the W / O / W type emulsion composition of the present invention comprises a peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 (acetyl hexapeptide-8 (AH-8)) as a water-soluble drug or a salt thereof, and more preferably, comprises AH-8 (not a salt) as a water-soluble drug.

[0027] The content of the above peptide or its salt in the W / O / W type emulsion 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 emulsion composition. When two or more of the above peptides or their salts are used, the total amount thereof should satisfy the above range.

[0028] If there are commercially available water-soluble drugs in the present invention, they may be used.

[0029] According to one embodiment of the present invention, the W / O / W type emulsion composition of the present invention contains one or more polyglycerol fatty acid esters having an average degree of polymerization of glycerin of 2 to 9 as a surfactant for emulsifying the internal aqueous phase into the oil phase. The polyglycerol fatty acid ester having an average degree of polymerization of glycerin of 2 to 9 in the present invention is preferably one or more polyglycerol fatty acid esters selected from the group consisting of polyglyceryl oleate, polyglyceryl isostearate, polyglyceryl diisostearate, polyglyceryl dipolyhydroxystearate, and polyglyceryl polyricinoleate, each having an average degree of polymerization of glycerin of 2 to 9, and more preferably one or more polyglycerol 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.

[0030] According to another embodiment of the present invention, the W / O / W type emulsion composition of the present invention contains one or more polyethylene glycol dipolyhydroxystearates as a surfactant for emulsifying the internal aqueous phase into the oil phase.

[0031] According to one preferred embodiment of the present invention, the W / O / W type emulsion composition of the present invention contains one or more polyglycerol fatty acid esters having an average degree of polymerization of glycerin of 2 to 9 as a surfactant for emulsifying the internal aqueous phase into the oil phase.

[0032] For the surfactant selected from the group consisting of one or more polyglycerol fatty acid esters having an average degree of polymerization of glycerin of 2 to 9 and polyethylene glycol dipolyhydroxystearate in the W / O / W type emulsion composition of the present invention, if there are commercially available products, they may be used.

[0033] In the W / O / W type emulsion composition of the present invention, the blending amount of one or more surfactants selected from the group consisting of polyglycerin fatty acid esters having an average degree of polymerization of glycerin of 2 to 9 and polyethylene glycol dipolyhydroxystearate is not limited, but is preferably 0.5 to 2% by weight.

[0034] According to one preferred embodiment of the present invention, the W / O / W type emulsion composition of the present invention contains one or more oil components selected from the group consisting of polar oils having an IOB value of 0.1 to 0.80. Such oil components are those commonly used in cosmetics, pharmaceuticals, foods, etc., and preferably, pentaerythrityl tetraethylhexanoate, glyceryl diisostearate, di(phytosteryl / octyldodecyl) lauroyl glutamate, bisdiglyceryl polyacyl adipate-2, dipentaerythrityl hexahydroxystearate, and castor oil. More preferably, it is one or more selected from the group consisting of castor oil, bisdiglyceryl polyacyl adipate-2, and dipentaerythrityl hexahydroxystearate. The IOB value is an abbreviation for Inorganic / Organic Balance, which represents the ratio of the inorganic value to the organic value and is an index indicating the degree of polarity of an organic compound. Specifically, the IOB value is expressed as "IOB value = inorganic value / organic value". Here, for each of the "inorganic value" and "organic value", for example, the "organic value" is 20 for one carbon atom in the molecule, and the "inorganic value" is 100 for one hydroxyl group. The "inorganic value" and "organic value" corresponding to various atoms or functional groups are set, and the IOB value of the organic compound can be calculated by integrating the "inorganic value" and "organic value" of all atoms and functional groups in the organic compound (see, for example, Fujita, "Chemical Region", Vol. 11, No. 10, pp. 719-725, 1957).

[0035] In the W / O / W type emulsion composition of the present invention, 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 with respect to the total amount of the composition is not particularly limited, but is preferably 3 to 20% by weight, more preferably 5 to 10% by weight. The W / O / W type emulsion composition of the present invention may usually further contain an oil component used in cosmetics, pharmaceuticals, foods, etc. Such oil components are not particularly limited, but examples 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, and the like.

[0036] Examples of the hydrocarbon oil in the present invention include liquid paraffin, squalane, squalene, pristane, paraffin, isoparaffin, hydrogenated polyisobutene, olefin oligomer, volatile hydrocarbon oil (for example, isododecane, isohexadecane, undecane, tridecane, etc.).

[0037] 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, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene glycol di(2-ethylhexanoate), dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, glycerin di(2-heptylundecanoate), trimethylolpropane tri(2-ethylhexanoate), trimethylolpropane triisostearate, glycerin triisostearate, pentaerythrityl tetra(2-ethylhexanoate), glyceryl tri(2-ethylhexanoate) (triethylhexanoin), cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, glycerin trimyristate, glyceride tri(2-heptylundecanoate), methyl ester of castor oil fatty acid, oleyl oleate, cetostearyl alcohol, acetoglyceride, 2-heptylundecyl palmitate, diisobutyl adipate, 2-octyldodecyl N-lauroyl-L-glutamate, di(2-heptylundecyl) adipate, ethyl laurate, di(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, triethyl citrate and other triester oils, etc.

[0038] Examples of the silicone oil in the present invention include linear polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, methylhydrogenpolysiloxane, and cyclic polysiloxanes such as decamethylpolysiloxane, dodecamethylpolysiloxane, tetramethyltetrahydrogenpolysiloxane, etc.

[0039] Examples of the higher alcohols having 12 to 22 carbon atoms in the present invention include oleyl alcohol, 2-decyltetradecynol, 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.

[0040] Examples of the fats and oils in the present invention include cocoa butter, avocado oil, camellia oil, macadamia nut oil, corn oil, olive oil, rapeseed oil, sesame oil, persic oil, wheat germ oil, sasanqua oil, castor oil, linseed oil, safflower oil, cottonseed oil, eno oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, sinagiri oil, Japanese cedar oil, jojoba oil, germ oil, triglyceride, glyceryl trioctanoate, glyceryl triisopalmitate, etc.

[0041] 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 is contained in the outer aqueous phase to disperse the oil phase (W / O emulsion) in 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 emulsion composition. The thickener having an alkyl group in the present invention is preferably, but not limited to, one or more selected from the group consisting of an alkyl-modified carboxyvinyl polymer, (acryloyldimethyltaurine ammonium / beheneth-25 methacrylate) crosspolymer, and (acrylates / steareth-20 methacrylate) copolymer.

[0042] The alkyl-modified carboxyvinyl polymer in the present invention is preferably an (acrylates / alkyl acrylate (C10-30)) cross-polymer and acts as an emulsifier and a thickener. The alkyl-modified carboxyvinyl polymer in the present invention preferably has a molecular weight of about 500,000 to 3,000,000, although it is not limited thereto. As the alkyl-modified carboxyvinyl polymer in the present invention, if there is a commercially available product, it may be used. For example, "CARBOPOL 1342", "PEMULEN TR-1", "PEMULEN TR-2" (all manufactured by Lubrizol) etc. may be used.

[0043] The W / O / W type emulsion composition of the present invention may preferably contain a polyol in the outer aqueous phase in order to improve freeze resistance. Examples of such polyols include glycerin, 1,3-butylene glycol, dipropylene glycol and the like. Further, the blending amount of such a polyol is preferably 5 to 25% by weight based on the total amount of the emulsion composition.

[0044] The W / O / W type emulsion composition of the present invention may further contain optional additive components usually formulated in cosmetics and the like, as long as the effects of the present invention are not impaired. Examples of such additive components include thickeners such as cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl hydroxypropyl 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, mucoitin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, guar gum, dextran, kerato sulfate, locust bean gum, succinoglucan, carroninic acid, chitin, chitosan, carboxymethyl chitin, agar; lower alcohols such as ethanol; antioxidants such as butylhydroxytoluene, tocopherol, phytic acid; antibacterial agents such as benzoic acid, salicylic acid, sorbic acid, alkyl paraoxybenzoates, hexachlorophene; benzoic acid-based ultraviolet absorbers such as para-aminobenzoic acid (hereinafter abbreviated as "PABA"), PABA monoglycerin ester, N,N-dipropoxy PABA ethyl ester, N,N-diethoxy PABA ethyl ester, 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 homomenthyl-N-acetylanthranilate; salicylic acid-based ultraviolet absorbers such as amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanolphenyl salicylate;Octyl cinnamate, ethyl-4-isopropyl cinnamate, methyl-2,5-diisopropyl cinnamate, ethyl-2,4-diisopropyl cinnamate, methyl-2,4-diisopropyl cinnamate, propyl-p-methoxy cinnamate, isopropyl-p-methoxy cinnamate, isoamyl-p-methoxy cinnamate, octyl-p-methoxy cinnamate (2-ethylhexyl-p-methoxy cinnamate), 2-ethoxyethyl-p-methoxy cinnamate, cyclohexyl-p-methoxy cinnamate, ethyl-α-cyano-β-phenyl cinnamate, 2-ethylhexyl-α-cyano-β-phenyl cinnamate, glycerol mono-2-ethylhexanoyl-diparamethoxy cinnamate and other cinnamic acid-based ultraviolet absorbers; silicone-based cinnamic acid ultraviolet absorbers such as [3-bis(trimethylsiloxy)methylsilyl-1-methylpropyl]-3,4,5-trimethoxy cinnamate, [3-bis(trimethylsiloxy)methylsilyl-3-methylpropyl]-3,4,5-trimethoxy cinnamate, [3-bis(trimethylsiloxy)methylsilylpropyl]-3,4,5-trimethoxy cinnamate, [3-bis(trimethylsiloxy)methylsilylbutyl]-3,4,5-trimethoxy cinnamate, [3-tris(trimethylsiloxy)silylbutyl]-3,4,5-trimethoxy cinnamate, [3-tris(trimethylsiloxy)silylbutyl]-3,4,5-trimethoxy cinnamate, [3-tris(trimethylsiloxy)silyl-1-methylpropyl]-3,4-dimethoxy cinnamate; benzophenone-based ultraviolet 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, 2-ethylhexyl-4'-phenyl-benzophenone-2-carboxylate, 2-hydroxy-4-n-octoxybenzophenone, 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'-t-octylphenyl)benzotriazole, 2-(2'-hydroxy-5'-methylphenyl)benzotriazole, dibenzalazine, dianisoylmethane, 4-methoxy-4'-t-butyldibenzoylmethane, 5-(3,3'-dimethyl-2-norbornylidene)-3-pentan-2-one; organic acids such as acyl sarcosinic acid (e.g., sodium lauroyl sarcosinate), glutathione, citric acid, malic acid, tartaric acid, lactic acid; vitamins B 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, etc., vitamin E such as α-tocopherol, β-tocopherol, γ-tocopherol, vitamin E acetate, etc., vitamin D, vitamin H, pantothenic acid, pantethine, nicotinamide, benzyl nicotinate, etc.;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)aminomethylcyclohexanecarboxylic acid hydrochloride, etc.), ester forms of tranexamic acid and hydroquinone (e.g., 4'-hydroxyphenyl ester of trans-4-aminomethylcyclohexanecarboxylic acid, etc.), ester forms of tranexamic acid and gentisic acid (e.g., 2-(trans-4-aminomethylcyclohexylcarbonyloxy)-5-hydroxybenzoic acid and its salts, etc.), amide forms of tranexamic acid (e.g., methylamide of trans-4-aminomethylcyclohexanecarboxylic acid and its salts, trans-4-(p-methoxybenzoyl)aminomethylcyclohexanecarboxylic acid and its salts, trans-4-guanidinomethylcyclohexanecarboxylic acid and its salts, etc.)], hinokitiol, bisabolol, eucalyptone, thymol, inositol, saponins such as sikasaponin, carrot saponin, hechimasaponin, mukurozisaponin, etc., pantothenyl ethyl ether, ethinyl estradiol, tranexamic acid, arbutin, cephalanthin, placenta extract and other various drugs; extracts of plants such as gishigishi, clara, kouhone, orange, sage, sawtoothwort, zeniao, assembly, thyme, toki, tohii, birch, sugina, hechima, maronier, yukinoshita, arnica, lily, mugwort, peony, aloe, pittosporum, sawara, etc.; pigments; porous and / or water-absorbent powders (e.g., starches obtained from corn, potato, etc., anhydrous silicic acid, talc, kaolin, magnesium aluminum silicate, calcium alginate, etc.);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, lauryl amine oxide, etc.; anionic surfactants such as sodium palmitate, sodium laurate, sodium laurylate, potassium lauryl sulfate, alkyl sulfate triethanolamine ether, rosin oil, linear dodecyl benzene sulfonic acid, polyoxyethylene hydrogenated castor oil maleate, acyl methyl taurine, etc.; amphoteric surfactants; neutralizing agents; preservatives; fragrances; pigments, etc.

[0045] The method for producing the W / O / W type emulsion composition of the present invention is not particularly limited and can be produced by a conventional method. For example, a W / O type emulsion produced by stirring and mixing using an emulsifier such as a homomixer or a disper is prepared, and this is mixed and emulsified with an external aqueous phase containing a thickener having an alkyl group to obtain the composition.

[0046] The composition of the present invention may also be a cosmetic composition. The cosmetic composition in the present invention means a composition used for the purpose of applying makeup.

[0047] According to one aspect of the present invention, there is provided a method for improving the biofilm permeability of a water-soluble drug, which includes the step of applying the W / O / W type emulsion composition of the present invention to a biofilm.

[0048] The method for improving the biofilm permeability of the water-soluble drug of the present invention may be carried out either in vivo or in vitro.

[0049] The targets to which the method for improving the biofilm permeability of the water-soluble drug of the present invention is applied are not particularly limited. For example, 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 can be mentioned. As the target to which the method for improving the biofilm permeability of the water-soluble drug of the present invention is applied, preferably, it is a human.

[0050] The biological membrane in the present invention is not particularly limited. For example, biological membranes in the skin, biological membranes in mucous membranes (for example, oral mucosa, ocular mucosa, nasal mucosa, vaginal mucosa, rectal mucosa, etc.) can be mentioned, and preferably, it is a biological membrane in the skin. Therefore, according to one preferred embodiment of the present invention, there is provided a method for improving the skin permeability of a water-soluble drug, which includes the step of applying the W / O / W type emulsion composition of the present invention to the skin.

Examples

[0051] 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 shown in weight%.

[0052] Using four types of oil components with different polarities (hydrogenated polydecene, cetyl ethylhexanoate, pentaerythrityl tetraethylhexanoate, castor oil), a W / O / W type emulsion composition as shown in Table 1 below was prepared. The W / O / W type emulsion composition was obtained by adding an aqueous phase containing an osmotic pressure regulator to an oil phase containing a surfactant, performing W / O emulsification using a homomixer, and then adding this W / O emulsion to the external aqueous phase and dispersing it. For each sample, the viscosity the next day was measured at 10 rpm using a VISCOMETER TVB-15 (manufactured by Toki Sangyo Co., Ltd.) with rotor No. 7 at a sample temperature of 30°C. Also, the viscosity of each sample after storage at 50°C for 4 weeks or in a frozen state for 4 weeks was measured. When the viscosity after the change over time was greater than 80% of the viscosity the next day, it was evaluated as A, when the viscosity after the change over time was between 30% and 80% of the viscosity the next day, it was evaluated as B, and when the viscosity after the change over time was less than 30% of the viscosity the next day, it was evaluated as C. The results are shown in Table 1.

Table 1

[0053] From the results in Table 1, it was found that the W / O / W type emulsion compositions of Formulation Examples 1 to 4 showed little change in viscosity over time and also exhibited good freeze stability.

[0054] Next, using highly polar oil components or combinations thereof, W / O / W type emulsion compositions as shown in Table 2 below were prepared. The change in viscosity over time and freeze stability were evaluated according to the same method and evaluation criteria as above. The results are shown in Table 2.

Table 2

[0055] From the results in Table 2, it was also found that the W / O / W type emulsion compositions of Formulation Examples 5 to 8 showed little change in viscosity over time and also exhibited good freeze stability.

[0056] Next, using other surfactants, W / O / W type emulsion compositions as shown in Table 3 below were prepared. The change in viscosity over time and freeze stability were evaluated according to the same method and evaluation criteria as above. The results are shown in Table 3.

Table 3

[0057] From the results in Table 3, it was also found that the W / O / W type emulsion compositions of Formulation Examples 9 to 11 showed little change in viscosity over time and also exhibited good freeze stability.

[0058] Next, using various osmotic pressure regulators (trehalose, sodium glutamate, maltitol), W / O / W type emulsion compositions as shown in Table 4 below were prepared. The change in viscosity over time and freeze stability were evaluated according to the same method and evaluation criteria as above. The results are shown in Table 4.

Table 4

[0059] From the results in Table 4, it was found that the W / O / W type emulsion compositions of Formulation Examples 12 to 15 also showed little change in viscosity over time and exhibited good stability.

[0060] From the above results, it was found that the W / O / W type emulsion compositions of Formulation Examples 1 to 15 showed good stability, such as being able to suppress the decrease in viscosity when stored at 50°C.

[0061] Other formulations Formulation Examples 16 to 19 of other W / O / W type emulsion compositions are shown in Table 5.

Table 5

[0062] Next, the compositions of Example 1 and Comparative Examples 1 to 2 as shown in Table 6 were prepared by the following procedure.

[0063] Preparation of Example 1 Water-soluble peptide acetyl hexapeptide-8 (AH-8) was blended to be 0.1%, dissolved with sufficient stirring, and the innermost aqueous phase part was prepared by a conventional method. While stirring, the prepared innermost aqueous phase part was added to the oil phase part to prepare the W / O part. While stirring and emulsifying, the prepared W / O part was further added to the outer aqueous phase part to prepare the W / O / W type emulsion composition of Example 1. The mass of AH-8 added to the outer aqueous phase part and the oil phase part was 0%.

[0064] Preparation of Comparative Example 1 The innermost aqueous phase part was prepared by a conventional method. While stirring, the prepared innermost aqueous phase part was added to the oil phase part to prepare the W / O part. AH-8 was blended to be 0.1% in the outer aqueous phase part, and while stirring and emulsifying, the prepared W / O part was further added to the outer aqueous phase part to prepare the W / O / W type emulsion composition of Comparative Example 1. The mass of AH-8 added to the innermost aqueous phase part and the oil phase part was 0%. The components and their blending amounts of Comparative Example 1 are the same as those of Example 1.

[0065] Preparation of Comparative Example 2 AH-8 was added to the external aqueous phase part to a concentration of 0.1% and stirred well. Then, while adding the oil phase part to the external aqueous phase part, emulsification was carried out to prepare the O / W type emulsion composition of Comparative Example 2. The components and their blending amounts in Comparative Example 2 were the same as those in Example 1 and Comparative Example 1, and corresponded to a formulation in which the components of the innermost aqueous phase in Example 1 and Comparative Example 1 were blended in the external aqueous phase.

[0066] Stratum corneum penetration test of peptide acetyl hexapeptide-8 (AH-8) The stratum corneum permeability of AH-8 contained in the adjusted compositions of Example 1 and Comparative Examples 1 to 2 was evaluated by the Diffusion Cell Array method. The Diffusion Cell Array method was carried out according to the method described in a 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.) to be 0.785 cm 2Performed using a Diffusion Cell Array in which a plurality of diffusion cells having an effective penetration area were arranged. As the permeation membrane, human skin (manufactured by BIOPREDIC International) having a thickness of 400 μm or more was used. Using a cell clamp, the human skin was firmly fixed to the Diffusion Cell Array so that no air entered between the receiver cell and the donor cell. Then, PBS was filled into the receiver cell and hydrated for 1 hour. During that time, the Diffusion Cell Array with the fixed human skin was set in a temperature controller, and the temperature was adjusted so that the skin surface temperature became 30 °C. At the same time, the PBS in the receiver cell was stirred with a stir bar at about 100 rpm.

[0067] Next, the compositions of Example 1 and Comparative Examples 1 to 2 were each applied to the human skin fixed to the Diffusion Cell Array at a rate of 10 μL / cm 2 for 60 seconds so as to be uniform. The application of each formulation to the skin was carried out by finite open application assuming actual use. After application, the PBS in the receiver cell was stirred with a stir bar at about 100 rpm for 4 hours. After stirring, the human skin was taken out from the Diffusion Cell Array. Foamed soap solution was taken on a cotton swab, and the taken-out human skin was wiped with the cotton swab 5 times, then wiped with purified water 5 times, and finally the moisture on the skin surface was absorbed.

[0068] The stratum corneum of the sites where Examples 1 and Comparative Examples 1 to 2 were each applied 10 times (equivalent to 10 layers) by tape stripping was collected. Among the 10 tapes for 10 layers, 2 tapes for 2 layers were put into one vial in order from the upper layer, and ultrasonic vibration was carried out for 15 minutes while immersing them in 500 μL of an extraction solvent (a mixed solvent containing water and methanol at a ratio of 97:3) to extract the drug from the tape. Using LC-QTOF-MS, the amount of the drug in the collected extract was quantified, the stratum corneum penetration amount for 2 layers was calculated respectively, and the value of the stratum corneum penetration amount for 10 layers was obtained by summing them up. The compositions of Example 1 and Comparative Examples 1 to 2 were each applied to 4 locations on the same skin, and the average value of the stratum corneum penetration amount for 10 layers at each of the 4 locations was taken as the total stratum corneum penetration amount of each formulation example. The results are shown in Table 6.

[0069]

Table 6

[0070] Regarding each stratum corneum penetration amount, in any of the layers of 1 - 2 layers, 3 - 4 layers, 5 - 6 layers, 7 - 8 layers, and 9 - 10 layers, it was shown that the stratum corneum penetration amount of AH - 8 in the composition of Example 1 was higher than that of AH - 8 in the compositions of Comparative Examples 1 to 2. Also, regarding the total stratum corneum penetration amount, when statistical processing was performed by the corresponding Student's t - test, it was shown that the total stratum corneum penetration 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 to 2. From the above results, it was shown that the W / O / W type emulsion composition of the present invention has good percutaneous permeability for water - soluble drugs.

[0071] Next, the compositions of Example 2 and Comparative Example 3 as shown in Table 7 were prepared by the following procedure.

[0072] Preparation of Example 2 Water-soluble 1-(2-hydroxyethyl)-2-imidazolidinone (HEI) was formulated to be 1.5% and dissolved while stirring well to prepare the innermost aqueous phase part by a conventional method. While stirring, the prepared innermost aqueous phase part was added to the oil phase part to prepare a W / O part. While stirring and emulsifying, the prepared W / O part was further added to the outer aqueous phase part to prepare the W / O / W type emulsion composition of Example 2. The mass of HEI added to the outer aqueous phase part and the oil phase part was 0%.

[0073] Preparation of Comparative Example 3 The innermost aqueous phase part was prepared by a conventional method. While stirring, the prepared innermost aqueous phase part was added to the oil phase part to prepare a W / O part. HEI was formulated to be 1.5% in the outer aqueous phase part, and while stirring and emulsifying, the prepared W / O part was further added to the outer aqueous phase part to prepare the W / O / W type emulsion composition of Comparative Example 3. The mass of HEI added to the innermost aqueous phase part and the oil phase part was 0%. Note that the components and their blending amounts of Comparative Example 3 are the same as those of Example 2.

[0074] Stratum corneum penetration test of 1-(2-hydroxyethyl)-2-imidazolidinone (HEI) The stratum corneum permeability of HEI contained in the adjusted 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.

[0075]

Table 7

[0076] Regarding the stratum corneum penetration amount of each layer, in any of the layers of 1-2 layers, 3-4 layers, 5-6 layers, 7-8 layers, and 9-10 layers, the stratum corneum penetration amount of HEI in the composition of Example 2 was shown to be higher than that of HEI in the composition of Comparative Example 3. Also, regarding the total stratum corneum penetration amount, the total stratum corneum penetration amount of HEI in the composition of Example 2 was shown to be higher than that of HEI in the composition of Comparative Example 3. From the above results, it was shown that the W / O / W type emulsion composition of the present invention has good percutaneous permeability of water-soluble drugs.

Claims

1. An internal aqueous phase, an oil phase in which the internal aqueous phase is dispersed, an external aqueous phase in which the oil phase is dispersed, A W / O / W type emulsion composition comprising: The composition comprises a water-soluble drug, At least 99% of the total amount of the water-soluble drug is contained in the internal aqueous phase, The internal aqueous phase contains an osmotic pressure regulator, where the osmotic pressure regulator generates an osmotic pressure between the internal aqueous phase and the external aqueous phase, As a surfactant for emulsifying the internal aqueous phase in the oil phase, it contains one or more selected from the group consisting of polyglycerol fatty acid esters with an average degree of polymerization of glycerin of 2 to 9 and polyethylene glycol dipolyhydroxystearate The external aqueous phase contains a thickener having an alkyl group, the composition.

2. The water-soluble drug is represented by the following formula (I): 【Chemical 1】 A cyclic carboxamide derivative represented by [In the formula, n is an integer of 1 to 3, and R １ is a hydrocarbon group having 1 to 6 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group, and X is -CH ２ - or a group represented by -N(R ２ ), and R ２ means a hydrocarbon group having 1 to 6 carbon atoms which may be substituted with a hydrogen atom or a hydroxyl group.] or a salt thereof The composition according to claim 1.

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 SEQ ID NO: 1 or the amino acid sequence shown in SEQ ID NO: 2 or a salt thereof.

5. The composition according to claim 4, wherein the amino acid is D-amino acid or L-amino acid.

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

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

8. The composition according to claim 4, wherein the peptide is acetylhexapeptide-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 blending amount of the osmotic pressure regulator in the composition is 0.1 to 0.5% by weight.

12. The composition according to claim 1, comprising at least one polyglycerol fatty acid ester selected from the group consisting of polyglyceryl oleate, polyglyceryl isostearate, polyglyceryl diisostearate, polyglyceryl dipolyhydroxystearate, and polyglyceryl polyricinoleate, wherein the average degree of polymerization of glycerin is 2 to 9, as a surfactant for emulsifying the inner aqueous phase in the oil phase.

13. The composition according to claim 1, comprising at least one polyglycerol fatty acid ester 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, as a surfactant for emulsifying the inner aqueous phase in the oil phase.

14. The composition according to claim 1, wherein the oil phase comprises at least one oil 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 is at least one selected from the group consisting of castor oil, bis-diglyceryl polyacyl adipate-2, and dipentaerythrityl hexahydroxystearate.

16. The composition according to claim 14, wherein the blending amount of the oil in 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 alkyl-modified carboxyvinyl polymer, (acryloyldimethyltaurine ammonium / methacrylic acid behenes-25) crosspolymer, and (acrylates / methacrylic acid steares-20) copolymer.

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

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

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