Composition comprising fat-soluble vitamin or derivative thereof and temperature-responsive ionic liquid

Abstract

To provide a composition in which a fat-soluble vitamin or its derivative, broadly used in pharmaceuticals, quasi-drugs, or cosmetics, is solubilized.SOLUTION: Provided is a composition comprising a fat-soluble vitamin or its derivative and a temperature-responsive ionic liquid.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a composition comprising a fat-soluble vitamin or a derivative thereof and a temperature-responsive ionic liquid. [Background technology]

[0002] Pharmaceuticals, quasi-drugs and cosmetics are formulated from a base and active ingredients, optionally mixed with additives to impart functionality.

[0003] Taking into consideration the stability and absorbability of the active ingredient, the active ingredient is used in the form of a neutral molecule or its salt, but for example, in the case of a fat-soluble compound, there are issues such as the inability to incorporate it into an aqueous formulation at a high concentration, and the instability of the active ingredient in the formulation. For example, fat-soluble vitamins such as retinol are active ingredients incorporated into quasi-drugs and cosmetics, but because they are fat-soluble and insoluble in water, they are considered to be difficult to incorporate into an aqueous formulation as an active ingredient alone.

[0004] In recent years, ionic liquids have emerged as compounds exhibiting characteristic solubility, and their use as solubilizing agents for active ingredients such as pharmaceuticals has been reported. For example, Patent Document 1 describes that etodolac, which is a fat-soluble carboxylic acid and insoluble in water, can be solubilized in water by using an ionic liquid. Non-Patent Document 1 describes that some water-soluble proteins can be dissolved in an ionic liquid by using a sulfonic acid-based temperature-responsive ionic liquid. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2021 / 070893 [Non-patent literature]

[0006] [Non-Patent Document 1] AUST.J. CHEM. 2012, 65, 1548-1553. Summary of the Invention [Problem to be solved by the invention]

[0007] Patent Document 1 merely discloses that specific active ingredients such as etodolac can be solubilized. Non-Patent Document 1 writes that whether or not a protein dissolves in an ionic liquid depends on the protein, and merely discloses that the solubility of a specific protein can be improved.

[0008] Therefore, an object of the present invention is to provide a composition in which a fat-soluble vitamin or a derivative thereof, which is widely used as a medicine, a quasi-drug, or a cosmetic, is solubilized. [Means for solving the problem]

[0009] The present inventors have conducted extensive research to solve the above problems and have discovered the following inventions (1) to (7). (1) A composition comprising a fat-soluble vitamin or a derivative thereof and a temperature-responsive ionic liquid. (2) The composition according to claim 1, wherein the fat-soluble vitamin or derivative thereof is selected from the group consisting of retinol, retinal and retinoid acid. (3) The composition according to (1) or (2), wherein the temperature responsive ionic liquid contains an anion represented by the following general formula (I) or general formula (II): [ka] (In formula (II), R 1 represents a hydrogen atom or an acyl group, R 2 represents an alkyl group which may be substituted with a halogen atom, a halogen atom, a sulfo group, an aryl group, or an alkoxy group. (4) The composition according to any one of (1) to (3), wherein the ratio of the concentration (mg / mL) of the fat-soluble vitamin or its derivative to the concentration (wt%) of the temperature-responsive ionic liquid is within the range of 1:1.1 to 1:50. (5) A temperature-responsive ionic liquid for use as a solubilizer for fat-soluble vitamins or their derivatives. (6) A temperature-responsive ionic liquid for use as a stabilizer for fat-soluble vitamins or their derivatives. (7) A method for solubilizing a fat-soluble vitamin or a derivative thereof, comprising: a mixing step of mixing a fat-soluble vitamin or a derivative thereof, a temperature-responsive ionic liquid, and water to prepare a mixed solution; a separation step of separating the mixed solution into layers; and a homogenization step of remixing the solution obtained in the separation step to make it homogenous. Effect of the Invention

[0010] According to the present invention, there is provided a composition in which a fat-soluble vitamin or a derivative thereof for use in a drug, quasi-drug, or cosmetic is solubilized. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The composition of the present invention is characterized by comprising a fat-soluble vitamin or a derivative thereof and a temperature-responsive ionic liquid.

[0012] Fat-soluble vitamins are vitamins that are fat-soluble, specifically vitamin A (retinol), vitamin D, vitamin E, and vitamin K. Derivatives of fat-soluble vitamins include vitamin A derivatives such as retinal and retinoic acid, as well as esters of various fat-soluble vitamins.

[0013] The fat-soluble vitamin or a derivative thereof is preferably retinol, retinal or retinoic acid, more preferably retinol.

[0014] The temperature-responsive ionic liquid is an ionic liquid composed of a cation and an anion and exhibits temperature responsiveness. Although there is no particular limitation on the melting point of the temperature-responsive ionic liquid, it is preferable that the melting point is 100° C. or less.

[0015] Here, temperature responsiveness refers to a property of changing shape and / or properties in response to a change in temperature (heat). Examples of the temperature responsiveness of an ionic liquid include volumetric changes such as expansion and contraction, and changes in hydrophobicity such as the lower critical solution temperature (hereinafter referred to as "LCST") and upper critical solution temperature (hereinafter referred to as "UCST").

[0016] The temperature-responsive ionic liquid of the present invention preferably has an LCST in order to enhance the permeability of drugs. The LCST means a temperature at which the hydrophobicity of the temperature-responsive ionic liquid increases and the solubility in water decreases when the temperature of the temperature-responsive ionic liquid is increased. In this case, when the temperature-responsive ionic liquid contains water, it does not matter whether the temperature-responsive ionic liquid is compatible with water at a temperature lower than the LCST. This is because the temperature-responsive ionic liquid has a property of containing a certain amount of water even at a temperature lower than the LCST, and therefore, even if the ionic liquid is phase-separated from water at a temperature lower than the LCST, when heated to a temperature higher than the LCST, the hydrophobicity of the temperature-responsive ionic liquid increases.

[0017] Whether or not the ionic liquid has an LCST (hereinafter also referred to as "LCST-type temperature-responsive ionic liquid") can be confirmed by measuring the absorbance of wavelengths in the visible light region while gradually increasing the temperature, and by checking whether or not the phenomenon of turbidity due to an increase in hydrophobicity occurs at a certain temperature, and the absorbance increases. The specific procedure is as follows. First, a mixture of ionic liquid and water is prepared, mixed well, and then the solution is placed in a measurement cell. After leaving the solution at 4°C until it becomes transparent, the temperature is raised from 4°C to 95°C at a rate of 0.5°C / min., and the change in absorbance at 450 nm is measured, thereby confirming whether or not the measured ionic liquid is an LCST-type temperature-responsive ionic liquid. In addition, the LCST value can be obtained by analyzing the obtained data on the absorbance change using the differential method of a Tm (nucleic acid melting temperature) analysis program.

[0018] By utilizing the property of the temperature-responsive ionic liquid that changes to hydrophobicity with temperature change, fat-soluble vitamins or derivatives thereof can be efficiently dissolved even when heated to about human body temperature. Therefore, the LCST of the temperature-responsive ionic liquid is preferably 40°C or less, more preferably 35°C or less, and even more preferably 30°C or less. On the other hand, from the viewpoint of handling, the lower limit is preferably 0°C or more, more preferably 5°C or more, even more preferably 10°C or more, and most preferably 15°C or more. The upper limit and the lower limit can be combined arbitrarily.

[0019] Whether a liquid is a temperature-responsive ionic liquid having a UCST (hereinafter also referred to as a "temperature-responsive ionic liquid of UCST type") can be confirmed by measuring the absorbance of wavelengths in the visible light region while gradually increasing the temperature, and by observing whether or not a phenomenon occurs in which the solution becomes transparent due to an increase in hydrophilicity at a certain temperature and the absorbance decreases. Specifically, whether or not a liquid is a temperature-responsive ionic liquid of UCST type can be confirmed by measuring the change in absorbance using the same method as the above-mentioned method for confirming a temperature-responsive ionic liquid of LCST type. In addition, the UCST value can be obtained by analyzing the obtained data on the change in absorbance using the differential method of a Tm (nucleic acid melting temperature) analysis program.

[0020] The cations and anions in the temperature-responsive ionic liquid may be selected in any combination as long as the combination exhibits temperature responsiveness. For example, the two may be combined in equimolar amounts.

[0021] Specific examples of the cation constituting the temperature-responsive ionic liquid include those having a nitrogen atom as the ion center, those having a phosphorus atom as the ion center, those having a sulfur atom as the ion center, and those having a nitrogen atom and a sulfur atom as the ion center, but are not limited thereto.

[0022] Specific examples of the cation having a nitrogen atom as the ion center include imidazolium ion, ammonium ion, pyridinium ion, quinolinium ion, pyrrolidinium ion, piperidinium ion, piperazinium ion, morpholinium ion, pyridazinium ion, pyrimidinium ion, pyrazinium ion, pyrazolium ion, thiazolium ion, oxazolium ion, triazolium ion, guanidium ion, 4-aza-1-azonia-bicyclo-[2,2,2]octanium ion, etc. In addition, these cations may have a substituent such as an alkyl group at any position, and the number of the substituents may be multiple.

[0023] The cation having a nitrogen atom as the ion center is preferably an imidazolium ion, an ammonium ion, a pyridinium ion, a pyrrolidinium ion or a piperidinium ion.

[0024] Specific examples of imidazolium ions include 1-methylimidazolium ion, 1-ethylimidazolium ion, 1-propylimidazolium ion, 1-butylimidazolium ion, 1-butyl-3-methylimidazolium ion, 1-ethyl-3-methylimidazolium ion, 1-allyl-3-methylimidazolium ion, 1,3-diallylimidazolium ion, 1-benzyl-3-methylimidazolium ion, 1-methyl-3-octylimidazolium ion, 1-ethyl-2,3-dimethylimidazolium ion, 1-butyl-2,3-dimethylimidazolium ion, 1,2-dimethyl-3-propylimidazolium ion, and 1-cyanopropyl-3-methylimidazolium. ion, 1,3-biscyanomethylimidazolium ion, 1,3-bis(3-cyanopropyl)imidazolium ion, 1-(2-hydroxyethyl)-3-methylimidazolium ion, 1-methoxyethyl-3-methylimidazolium ion, 1-[2-(2-methoxyethoxy)-ethyl]-3-methylimidazolium ion, 1,3-diethoxyimidazolium ion, 1,3-dimethoxyimidazolium ion, 1,3-dihydroxyimidazolium ion, 1-methyl-3-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctylimidazolium ion, or 1-methyl-3-[(triethoxysilyl)propyl]imidazolium ion.

[0025] Specific examples of ammonium ions include tetraalkylammonium ions such as tetramethylammonium ion, tetraethylammonium ion, tetrapropylammonium ion, tetrabutylammonium ion, tetrahexylammonium ion, and trihexyltetradecylammonium ion; (2-hydroxyethyl)trimethylammonium ion, N,N-diethyl-N-(2-methoxyethyl)-N-methylammonium ion, tris(2-hydroxyethyl)methylammonium ion, trimethyl(1H,1H,2H,2H-heptadecafluorodecyl)ammonium ion, trimethyl-(4-vinylbenzyl)ammonium ion, tributyl-(4-vinylbenzyl)ammonium ion, 2-(methacryloyloxy)ethyltrimethylammonium ion, benzyldimethyl(octyl)ammonium ion, and N,N-dimethyl-N-(2-phenoxyethyl)-1-dodecylammonium ion.

[0026] Specific examples of pyridinium ions include a 1-ethylpyridinium ion, a 1-butylpyridinium ion, a 1-(3-hydroxypropyl)pyridinium ion, a 1-ethyl-3-methylpyridinium ion, a 1-butyl-3-methylpyridinium ion, a 1-butyl-4-methylpyridinium ion, and a 1-(3-cyanopropyl)pyridinium ion.

[0027] Specific examples of pyrrolidinium ions include 1-methyl-1-propylpyrrolidinium ion, 1-butyl-1-methylpyrrolidinium ion, 1-(2-hydroxyethyl)-1-methylpyrrolidinium ion, and 1-ethyl-1-methylpyrrolidinium ion.

[0028] Specific examples of piperidinium ions include 1-methyl-1-propylpiperidinium ion, 1-butyl-1-methylpiperidinium ion, 1-(2-hydroxyethyl)-1-methylpiperidinium ion, and 1-ethyl-1-methylpiperidinium ion.

[0029] A cation having a phosphorus atom as the ionic center is generally called a phosphonium ion, and specific examples of the phosphonium ion include tetraalkylphosphonium ions such as tetrapropylphosphonium ion, tetrabutylphosphonium ion, tetrahexylphosphonium ion, trihexyltetradecylphosphonium ion, triphenylmethylphosphonium ion, triisobutylmethylphosphonium ion, triethylmethylphosphonium ion, tributylmethylphosphonium ion, and tributylhexadecylphosphonium ion; (2-cyanoethyl)triethylphosphonium ion, (3-chloropropyl)trioctylphosphonium ion, tributyl(4-vinylbenzyl)phosphonium ion, and 3-(triphenylphosphonio)propane-1-sulfonate ion.

[0030] A cation having a sulfur atom as the ionic center is generally called a sulfonium ion, and specific examples of the sulfonium ion include a triethylsulfonium ion, a tributylsulfonium ion, a 1-ethyltetrahydrothiophenium ion, and a 1-butyltetrahydrothiophenium ion.

[0031] From the viewpoint of having appropriate fat solubility and achieving both temperature responsiveness and solubility of fat-soluble vitamins or derivatives thereof, specific examples of cations constituting the temperature responsive ionic liquid include ammonium ions and phosphonium ions, and more preferably, tetraalkylammonium ions and tetraalkylphosphonium ions.

[0032] In one embodiment of the tetraalkylammonium ion, the total number of carbon atoms in the four alkyl groups is 13 or more and 35 or less (for example, a tetrabutylammonium ion, a tetrapentylammonium ion, a tetrahexylammonium ion, a tetraheptylammonium ion, a tetraoctylammonium ion, or a trioctylmethylammonium ion).

[0033] Also, one embodiment of the tetraalkylphosphonium ion includes a tetraalkylphosphonium ion in which the total number of carbon atoms in the four alkyl groups is 13 or more and 35 or less (for example, a tetrabutylphosphonium ion, a tetrapentylphosphonium ion, a tetraoctylphosphonium ion, a tributylhexylphosphonium ion, a tributylheptylphosphonium ion, a tributyloctylphosphonium ion, a tributyldodecylphosphonium ion, a tributyltridecylphosphonium ion, a tributylpentadecylphosphonium ion, a tributylhexadecylphosphonium ion, or a trihexyltetradecylphosphonium ion).

[0034] In the above-listed tetraalkylammonium ions or tetraalkylphosphonium ions, the four alkyl groups may be the same or different.

[0035] Specific examples of anions constituting the temperature-responsive ionic liquid include, but are not limited to, halide ions, imide ions such as bis(trifluoromethylsulfonyl)imide, carboxylate ions, sulfonate ions, phosphate ions, phosphonate ions, phosphinate ions, amino acid ions, etc. Furthermore, these anions may have a substituent, typically an alkyl group or an aryl group, at any position, and the number of substituents may be multiple.

[0036] The anion constituting the temperature responsive ionic liquid preferably contains at least one type selected from the group consisting of aromatic carboxylate ions and aromatic sulfonate ions.

[0037] Specific examples of aromatic carboxylate ions include benzoate ion, optionally substituted alkylated benzoate ions (e.g., toluate ion, trifluoromethylbenzoate ion), halogenated benzoate ions (e.g., fluorobenzoate ion, chlorobenzoate ion, bromobenzoate ion, or iodobenzoate ion), acylated benzoate ions (e.g., formylbenzoate ion or acetylbenzoate ion), alkoxylated benzoates (e.g., methoxybenzoate ion, ethoxybenzoate ion), hydroxybenzoate ion, aminobenzoate ion, sulfobenzoate ion, or substituted or unsubstituted polycyclic aromatic carboxylate ions (e.g., naphthalenecarboxylate ion or anthracenecarboxylate ion).

[0038] As long as the combination results in a temperature-responsive ionic liquid, the position of the substituent on the aromatic carboxylate ion may be any position, and there is no particular limitation on the number or type of the substituent. When a hydroxyl group, an amino group, or the like is contained as a substituent, the hydroxyl group, the amino group, or the like may be further substituted with an acyl group, or the like.

[0039] Examples of aromatic sulfonate ions include a benzenesulfonate ion, an optionally substituted alkylated benzenesulfonate ion (for example, a toluenesulfonate ion, a xylenesulfonate ion, or a trichloromethylbenzenesulfonate ion), a halogenated benzenesulfonate ion (for example, a fluorobenzenesulfonate ion, a chlorobenzenesulfonate ion, a bromobenzenesulfonate ion, or an iodobenzenesulfonate ion), an alkoxylated benzenesulfonate ion (for example, a methoxybenzenesulfonate ion, an ethoxybenzenesulfonate ion), a hydroxybenzenesulfonate ion, or an aminobenzenesulfonate ion.

[0040] As long as the combination results in a temperature-responsive ionic liquid, the position of the substituent on the aromatic sulfonate ion may be any position, and there is no particular limitation on the number or type of the substituent. When a hydroxyl group, an amino group, or the like is contained as a substituent, the hydroxyl group, the amino group, or the like may be further substituted with an acyl group, or the like.

[0041] A preferred example of the anion constituting the temperature-responsive ionic liquid is an anion derived from salicylic acid or a salicylic acid derivative. Specific examples of the salicylic acid derivative include a compound having a substituent on the benzene ring of salicylic acid and a compound having a substituent on the phenolic hydroxyl group.

[0042] In one embodiment, the anion constituting the temperature responsive ionic liquid is, for example, an anion represented by the following general formula (I) or general formula (II). [ka] (In formula (II), R 1 represents a hydrogen atom or an acyl group, R 2 represents an alkyl group which may be substituted with a halogen atom, a halogen atom, a sulfo group, an aryl group, or an alkoxy group.

[0043] Specific examples of the temperature-responsive ionic liquid used in the composition of the present invention include a temperature-responsive ionic liquid containing an ammonium ion (e.g., a tetraalkylammonium ion) and an aromatic carboxylate ion (e.g., an anion derived from salicylic acid or a salicylic acid derivative), a temperature-responsive ionic liquid containing an ammonium ion (e.g., a tetraalkylammonium ion) and an aromatic sulfonate ion, a temperature-responsive ionic liquid containing a phosphonium ion (e.g., a tetraalkylphosphonium ion) and an aromatic carboxylate ion (e.g., an anion derived from salicylic acid or a salicylic acid derivative), or a temperature-responsive ionic liquid containing a phosphonium ion (e.g., a tetraalkylphosphonium ion) and an aromatic sulfonate ion.

[0044] More specifically, examples of the temperature-responsive ionic liquid include tetrabutylammonium salicylate, tetrabutylammonium 4-(trifluoromethyl)salicylate, tetrabutylphosphonium salicylate, tetrabutylphosphonium 4-(trifluoromethyl)salicylate, tetrabutylphosphonium acetylsalicylate, tetrabutylphosphonium 5-bromosalicylate, tetrabutylphosphonium 4-chlorosalicylate, tetrabutylphosphonium 5-chlorosalicylate, tetrabutylphosphonium 5-iodosalicylate, and tetrabutylphosphonium acetylsalicylate. Examples of the phosphonium salt include 3-methylsalicylate, 4-methylsalicylate, 5-sulfosalicylate, 4-methoxysalicylate, 4-fluorosalicylate, 6-fluorosalicylate, 4-methoxysalicylate, 4-fluorosalicylate, 6-fluorosalicylate, and 3-phenylsalicylate.

[0045] In the composition of the present invention, the ratio of the concentration (mg / mL) of the fat-soluble vitamin or its derivative to the concentration (wt%) of the temperature-responsive ionic liquid is preferably greater than 1:1.1. More preferably, it is 1:2 or more, even more preferably 1:3 or more, and most preferably 1:4 or more. By setting it within this range, a composition in which the fat-soluble vitamin or its derivative and water are uniformly mixed can be obtained. There is no particular upper limit, but from the viewpoint of handling, it is preferably 1:50 or less, more preferably 1:20 or less, and even more preferably 1:10 or less.

[0046] The composition of the present invention contains a fat-soluble vitamin or a derivative thereof, and therefore can be suitably used as a pharmaceutical composition, a quasi-drug, or a cosmetic.

[0047] The composition of the present invention can be used by mixing with other ingredients, solvents, etc. that are generally used in pharmaceutical compositions, quasi-drugs, or cosmetics, and the intended efficacy and feel during use can be imparted by blending them.

[0048] The composition of the present invention can be used as a skin external composition. Since one embodiment of the composition of the present invention is a composition in which a fat-soluble vitamin or a derivative thereof is dissolved in water, it can be suitably used as a water-based skin external preparation such as a lotion.

[0049] The temperature-responsive ionic liquid used in the composition of the present invention can be used as a solubilizing agent for fat-soluble vitamins or derivatives thereof. By using the temperature-responsive ionic liquid, as described below, fat-soluble vitamins or derivatives thereof can be easily dissolved in water or a mixed solvent of water and another solvent by simply changing the temperature.

[0050] The temperature-responsive ionic liquid used in the composition of the present invention can be used as a stabilizer for fat-soluble vitamins or derivatives thereof. By using a temperature-responsive ionic liquid, the stability of fat-soluble vitamins or derivatives thereof that are unstable to heat or light can be improved at room temperature without shading the vitamins.

[0051] The present invention provides a method for dissolving a fat-soluble vitamin or a derivative thereof, which comprises a mixing step of mixing a fat-soluble vitamin or a derivative thereof, a temperature-responsive ionic liquid, and water to prepare a mixed solution, a separation step of separating the mixed solution into layers, and a homogenization step of remixing the solution obtained in the separation step to homogenize it.

[0052] The solution obtained during the mixing step in which the fat-soluble vitamin or a derivative thereof, the temperature-responsive ionic liquid, and water are mixed in the mixing step may be homogeneous, or may be in a state in which the fat-soluble vitamin or a derivative thereof is partially dissolved, dispersed, or suspended.

[0053] The method of layer separation in the separation step is not particularly limited as long as it is a method that causes layer separation of a solution obtained by mixing a fat-soluble vitamin or a derivative thereof, a temperature-responsive ionic liquid, and water, but a method using heating or cooling is preferred from the viewpoint of ease of operation.

[0054] The homogenization method in the homogenization step is not particularly limited as long as it is a method that homogenizes the solution obtained by mixing the fat-soluble vitamin or a derivative thereof, the temperature-responsive ionic liquid, and water. However, from the viewpoint of ease of operation, a method in which the homogenization is performed by mixing with a vortex mixer or ultrasonic waves after heating or cooling is preferred.

[0055] Furthermore, in the dissolution method, by blending other ingredients after the homogenization step, it is possible to produce a pharmaceutical composition, quasi-drug, or cosmetic in which the fat-soluble vitamin or a derivative thereof is blended in an aqueous solvent.

[0056] In addition, in the dissolution method, by blending other ingredients with a mixture of fat-soluble vitamins or derivatives thereof and temperature-responsive ionic liquid obtained by a homogenization step followed by a removal step of removing water under reduced pressure, it is possible to produce a pharmaceutical composition, quasi-drug, or cosmetic in which the fat-soluble vitamins or derivatives thereof are dissolved at a high concentration.

[0057] The fat-soluble vitamin or derivative thereof is preferably retinol, retinal or retinoic acid, more preferably retinol. The reason why retinol is preferred is that it is easily solubilized in water by using a temperature-responsive ionic liquid. EXAMPLES

[0058] The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. In addition, for compounds used in the synthesis of the compounds in the examples and comparative examples for which no synthesis method is described, commercially available compounds were used. In addition, unless otherwise specified, commercially available reagents were used in the reaction without purification. First, the measurement methods and test methods are shown below. % indicates weight % unless otherwise specified.

[0059] (Synthesis Example 1) Synthesis of temperature-responsive ionic liquid: As a cationic component, 6.91 g (10 mmol) of a 40% aqueous solution of tetrabutylphosphonium hydroxide and 1.38 g (10 mmol) of salicylic acid were weighed as an anionic component and charged into a glass vial. The mixture was stirred at room temperature for 2 hours, and the reaction was terminated after confirming that the salicylic acid had completely dissolved, thereby quantitatively obtaining a mixed solution of tetrabutylphosphonium salicylate and water (hereinafter referred to as "Sample 1"). In the following examples and comparative examples, Sample 1 was used as is or after dilution.

[0060] (Example 1) Retinol dissolution test (part 1) 2.06 mg of all-trans-retinol was weighed into a glass screw bottle, and 2.06 mL of a 10% temperature-responsive ionic liquid aqueous solution was added so that the retinol concentration was 1 mg / mL, to prepare a retinol solution, which was then mixed with a vortex mixer (mixing process). The retinol solution was then heated in a thermostatic bath at 38°C. Heating was continued for 2.5 hours, with mixing with a vortex mixer several times during the process, until the retinol was completely dissolved (separation process).

[0061] The glass screw bottle was removed from the thermostatic bath and placed in a refrigerator at 4°C for 15 minutes, then mixed again with a vortex mixer to obtain a solution in which retinol was uniformly dissolved (homogenization process). The resulting solution was left at room temperature, unshaded from light, for two months, and when visually inspected, no precipitate was found, and the yellow color derived from retinol was maintained. This demonstrated that retinol, which is normally unstable and insoluble in water, can be dissolved in water while maintaining its stability.

[0062] (Example 2) Retinol dissolution test (part 2) 3.94 mg of all-trans-retinol was weighed into a glass screw bottle, and 394 μL of a 48% temperature-responsive ionic liquid aqueous solution was added to prepare a retinol solution so that the retinol concentration was 10 mg / mL, and mixed with a vortex mixer (mixing process). The retinol solution was then heated in a thermostatic bath at 38°C. Heating was continued for 1 hour, with mixing with a vortex mixer several times during the process, until the retinol was completely dissolved (layer separation process).

[0063] The glass screw bottle was removed from the thermostatic bath and placed in a refrigerator at 4°C for 15 minutes, then mixed again with a vortex mixer to obtain a solution in which retinol was uniformly dissolved (homogenization process). The resulting solution was left at room temperature, unshaded from light, for two months, and when visually inspected, no precipitate was found, and the yellow color derived from retinol was maintained. This demonstrated that retinol, which is normally unstable and insoluble in water, can be dissolved in water while maintaining its stability.

[0064] (Example 3) Retinol dissolution test (part 3) 3.94 mg of all-trans-retinol was weighed into a glass screw bottle, and 394 μL of a 10% temperature-responsive ionic liquid aqueous solution was added to prepare a retinol solution with a retinol concentration of 10 mg / mL, and mixed with a vortex mixer. The retinol solution was then heated in a thermostatic bath at 38°C. Heating was continued for 2.5 hours while mixing with a vortex mixer several times during the process.

[0065] The glass screw bottle was removed from the thermostatic bath and placed in a refrigerator at 4°C for 15 minutes, then mixed again with a vortex mixer to obtain a solution containing retinol. The solution obtained was left at room temperature for 2 months without being shaded and visually inspected. Although there was no precipitate and retinol was dissolved in the ionic liquid layer, the solution separated into two layers and a homogeneous solution was not obtained. However, the solution obtained was left at room temperature for 2 months without being shaded and visually inspected. Although the ionic liquid layer remained separated from the water, the yellow color derived from the retinol dissolved in the ionic liquid layer was maintained.

[0066] (Comparative Example 1) Retinol dissolution test (part 4) 0.53 mg of all-trans-retinol was weighed into a glass screw bottle, and 530 μL of ethanol was added to prepare a retinol solution so that the retinol concentration became 1 mg / mL. The solution was mixed using a vortex mixer to obtain a retinol solution.

[0067] The resulting solution was left at room temperature, exposed to light, for two months and the results were visually inspected. Although no precipitate was found, the yellow solution had turned colorless and transparent, suggesting that the retinol had decomposed.

[0068] (Comparative Example 2) Cholesterol dissolution test A dissolution test was conducted using cholesterol, which is not a fat-soluble vitamin, as the active ingredient. 7.4 mg of cholesterol was weighed out into a glass screw bottle, and a cholesterol solution was prepared by adding 740 μL of a 10% temperature-responsive ionic liquid aqueous solution so that the cholesterol concentration was 10 mg / mL, and mixing was performed using a vortex mixer. The retinol solution was then heated in a thermostatic bath at 38°C. Heating was continued for 2.5 hours while mixing several times with a vortex mixer during the process. Even when the solution was heated using the temperature-responsive ionic liquid, cholesterol did not dissolve, so a homogeneous solution similar to that of retinol could not be created.

[0069] The ratio of the active ingredient concentration (mg / mL) to the temperature-responsive ionic liquid concentration (wt %) in the above Examples 1 to 3 and Comparative Examples 1 and 2, the results of solubility evaluation of the active ingredient, the uniformity of the solution, and the evaluation results of the color and stability of the solution after 2 months are shown in the following Table 1. The solubility and stability were evaluated according to the following criteria. (Evaluation of solubility of active ingredients) 〇: The solid content of the active ingredient has dissolved to the point where it is invisible to the naked eye. ×: The solid content of the active ingredient is visible to the naked eye and has not dissolved. (Evaluation of the stability of the active ingredient) ○: Upon visual inspection, the yellow color from the active ingredient retinol remains. ×: Upon visual inspection, the yellow color derived from the active ingredient, retinol, has disappeared.

[0070] [Table 1]

[0071] As shown in Table 1, when the retinol concentration (mg / mL) and the temperature-responsive ionic liquid concentration (wt%) are in the range of 1:1.1 to 1:10, a composition in which retinol is uniformly dissolved can be obtained, and the stability of retinol is improved, which is particularly preferable. On the other hand, when retinol is dissolved in ethanol, the solution becomes colorless and transparent after two months, suggesting that retinol is decomposed. From this, it is considered that a composition in which retinol is uniformly dissolved can be obtained by the presence of a temperature-responsive ionic liquid at a certain concentration or higher relative to the concentration of retinol, which is a fat-soluble vitamin, and therefore a composition in which retinol is uniformly dissolved can be obtained even when the retinol concentration (mg / mL) and the temperature-responsive ionic liquid concentration (wt%) are in the range of 1:10 or more, for example, 1:50.

[0072] Furthermore, even when a temperature-responsive ionic liquid was used, cholesterol, which is also a fat-soluble alcohol, could not be dissolved, demonstrating that the temperature-responsive ionic liquid used in the present invention is particularly effective as a solubilizing agent for retinol. [Industrial Applicability]

[0073] The composition of the present invention is a composition in which a fat-soluble vitamin or a derivative thereof is solubilized in water, and therefore can be used in medicines such as external preparations, quasi-drugs, cosmetics, and the like.

Claims

1. A composition comprising a fat-soluble vitamin or a derivative thereof and a temperature-responsive ionic liquid.

2. 2. The composition of claim 1, wherein the fat-soluble vitamin or derivative thereof is selected from the group consisting of retinol, retinal, and retinoid acid.

3. The composition according to claim 1 or 2, wherein the temperature responsive ionic liquid comprises an anion represented by the following general formula (I) or general formula (II): 【Chemistry 1】 (In formula (II), R １ represents a hydrogen atom or an acyl group; R ２ represents an alkyl group which may be substituted with a halogen atom, a halogen atom, a sulfo group, an aryl group, or an alkoxy group.

4. The composition according to any one of claims 1 to 3, wherein the ratio of the concentration (mg / mL) of the fat-soluble vitamin or its derivative to the concentration (wt%) of the temperature-responsive ionic liquid is within the range of 1:1.1 to 1:

50.

5. A temperature-responsive ionic liquid for use as a solubilizer for fat-soluble vitamins or their derivatives.

6. A temperature-responsive ionic liquid for use as a stabilizer for fat-soluble vitamins or their derivatives.

7. A method for solubilizing a fat-soluble vitamin or a derivative thereof, comprising: a mixing step of mixing a fat-soluble vitamin or a derivative thereof, a temperature-responsive ionic liquid, and water to prepare a mixed solution; a separation step of separating the mixed solution into layers; and a homogenization step of remixing the solution obtained in the separation step to make it homogenous.

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