Aqueous formulation

Abstract

To provide a stable aqueous preparation containing EPC-K, and a method for stabilizing an aqueous preparation containing EPC-K.SOLUTION: An aqueous preparation contains (a) dl-α-tocopherol-2-L-ascorbic acid phosphoric acid diester potassium salt, and (b) at least any one selected from the group consisting of polyoxyethylene alkyl phenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester. Further, a method for stabilizing an aqueous preparation includes a step of preparing an aqueous preparation containing (a) dl-α-tocopherol-2-L-ascorbic acid phosphoric acid diester potassium salt, and (b) at least any one selected from the group consisting of polyoxyethylene alkyl phenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention generally relates to aqueous formulations, and particularly to an aqueous formulation containing dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt (EPC-K).

Background Art

[0002] Dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt (hereinafter sometimes referred to as "EPC-K") is a compound in which vitamin C and vitamin E are ester-bonded via phosphate, and has antioxidant, anti-inflammatory, and moisturizing effects, and is used in cosmetics such as hair tonics (Miyako Oba et al., Journal of Pharmacy, 114(7), 514-522 (1994) (Non-Patent Document 1)). Further, applications to oral compositions such as mouthwashes, quasi-drugs, and pharmaceuticals such as eye drops and injections are also expected.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] An object of this invention is to provide a stable aqueous formulation containing EPC-K. Another object of the present invention is to provide a method for stabilizing an aqueous formulation containing EPC-K.

Means for Solving the Problems

[0005] The inventors conducted diligent research to solve the above problems. As a result, they found that it is possible to stabilize EPC-K by adding at least one of polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester to an aqueous formulation containing EPC-K. Based on the above findings, the present invention is configured as follows.

[0006] [1] An aqueous formulation comprising (a) dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt and (b) at least one selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters.

[0007] [2] The aqueous formulation according to [1] above, wherein the polyoxyethylene alkylphenyl ether comprises at least one of polyoxyethylene octylphenyl ether and polyoxyethylene nonylphenyl ether.

[0008] [3] The aqueous formulation according to either [1] or [2] above, wherein the polyoxyethylene alkyl ether comprises at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, and polyoxyethylene stearyl ether.

[0009] [4] The aqueous formulation according to any one of [1] to [3] above, wherein the polyoxyethylene fatty acid ester comprises at least one selected from the group consisting of polyoxyethylene laurate, polyoxyethylene palmitate, and polyoxyethylene stearate.

[0010] [5](b) an aqueous formulation according to any one of [1] to [4] above, comprising 0.1 w / v% or more of at least one selected from the group consisting of polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester.

[0011] [6] An aqueous formulation according to any one of [1] to [5] above, comprising 0.05 w / v% to 0.2 w / v% of dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt.

[0012] [7] An aqueous formulation according to any one of [1] to [6] above, comprising 0.01 w / v% to 10 w / v% of polyoxyethylene alkylphenyl ether.

[0013] [8] An aqueous formulation according to any one of [1] to [7] above, containing 0.05 w / v% to 0.1 w / v% of dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt and 0.01 w / v% to 5.0 w / v% of polyoxyethylene alkylphenyl ether.

[0014] [9] An aqueous formulation according to any one of [1] to [7] above, containing 0.2 w / v% to 1.0 w / v% of dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt and 0.1 w / v% to 10 w / v% of polyoxyethylene alkylphenyl ether.

[0015]

[10] An aqueous formulation according to any one of [1] to [9] above, comprising 0.1 w / v% to 4.0 w / v% of polyoxyethylene alkyl ether.

[0016]

[11] An aqueous formulation according to any one of [1] to

[10] above, wherein the weight ratio of dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt to polyoxyethylene alkylphenyl ether is 1:1 to 1:50.

[0017]

[12] An aqueous formulation according to any one of [1] to

[11] above, wherein the weight ratio of dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt to polyoxyethylene alkyl ether is 1:0.5 to 1:20.

[0018]

[13] (b) an aqueous formulation according to any one of [1] to

[12] above, wherein at least one polyoxyethylene selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters has a chain length of 10 or less.

[0019]

[14] (b) an aqueous formulation according to any one of [1] to

[13] above, wherein at least one HLB selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters is greater than 12.

[0020]

[15] A cosmetic composition containing the aqueous preparation described in any one of [1] to

[14] above.

[0021]

[16] An oral composition containing the aqueous formulation described in any one of [1] to

[14] above.

[0022]

[17] A pharmaceutical composition containing the aqueous preparation described in any one of [1] to

[14] above.

[0023]

[18] A method for stabilizing an aqueous formulation, comprising the step of preparing an aqueous formulation comprising (a) dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt and (b) at least one selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters.

[0024]

[19] The polyoxyethylene alkyl phenyl ether is at least one of polyoxyethylene octyl phenyl ether and polyoxyethylene nonyl phenyl ether, and is the stabilization method described in

[18] above.

[0025]

[20] The polyoxyethylene alkyl ether is at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, and polyoxyethylene stearyl ether, and is the stabilization method described in

[18] or

[19] above.

[0026]

[21] The polyoxyethylene fatty acid ester is at least one selected from the group consisting of polyoxyethylene laurate, polyoxyethylene palmitate, and polyoxyethylene stearate, and is the stabilization method described in any one of

[18] to

[20] above.

[0027]

[22] (b) The stabilization method described in any one of

[18] to

[21] above, which contains at least one selected from the group consisting of polyoxyethylene alkyl phenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester at 0.1 w / v% or more.

[0028]

[23] The stabilization method described in any one of

[18] to

[22] above, which contains dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt at 0.05 w / v% to 0.2 w / v%.

[0029]

[24] The stabilization method described in any one of

[18] to

[23] above, which contains polyoxyethylene alkyl phenyl ether at 0.01 w / v% to 10 w / v%.

[0030]

[25] A stabilization method according to any one of

[18] to

[24] above, comprising 0.05 w / v% to 0.1 w / v% of dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt and 0.01 w / v% to 5.0 w / v% of polyoxyethylene alkylphenyl ether.

[0031]

[26] A stabilization method according to any one of

[18] to

[24] above, comprising 0.2 w / v% to 1.0 w / v% of dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt and 0.1 w / v% to 10 w / v% of polyoxyethylene alkylphenyl ether.

[0032]

[27] A stabilization method according to any one of

[18] to

[26] above, comprising 0.1 w / v% to 4.0 w / v% of polyoxyethylene alkyl ether.

[0033]

[28] The stabilization method according to any one of

[18] to

[27] above, wherein the weight ratio of dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt to polyoxyethylene alkylphenyl ether is 1:1 to 1:50.

[0034]

[29] The stabilization method according to any one of

[18] to

[28] above, wherein the weight ratio of dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt to polyoxyethylene alkyl ether is 1:0.5 to 1:20.

[0035]

[30] (b) The stabilization method according to any one of

[18] to

[29] above, wherein at least one polyoxyethylene selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters has a chain length of 10 or less.

[0036]

[31] (b) The stabilization method according to any one of

[18] to

[30] above, wherein at least one HLB selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters is greater than 12. [Effects of the Invention]

[0037] As described above, the present invention can provide a stable aqueous formulation containing EPC-K. Furthermore, it can provide a method for stabilizing an aqueous formulation containing EPC-K. [Modes for carrying out the invention]

[0038] Embodiments of the present invention will be described below.

[0039] The aqueous formulation of the present invention comprises (a) dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt (EPC-K) and (b) at least one selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters.

[0040] The present invention also relates to a method for stabilizing an aqueous formulation containing EPC-K. The method for stabilizing an aqueous formulation of the present invention comprises the steps of preparing an aqueous formulation comprising (a) EPC-K and (b) at least one selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters.

[0041] EPC-K is easily decomposed in aqueous solutions. For example, Non-Patent Literature 1 states that EPC-K was stable in aqueous solutions containing EPC-K at ethanol concentrations in the range of 30-70%. When EPC-K is used as a topical skin preparation such as a hair growth agent, a high alcohol concentration in the preparation may cause allergic symptoms, rashes, skin irritation, or a burning sensation. Also, when EPC-K is used as eye drops, a high alcohol concentration in the preparation may cause pain or discomfort due to increased osmotic pressure or irritation from the alcohol itself. However, since the aqueous preparation of the present invention does not require the stabilization of EPC-K by alcohol, it can contain no alcohol or only a low concentration of alcohol. The aqueous preparation of the present invention is advantageous because it is a preparation with reduced irritation to biological tissues such as skin.

[0042] In aqueous formulations, EPC-K may be in any form as long as at least a portion of it is dissolved in water, for example, it may be in the form of an aqueous solution, emulsion (lotion), or suspension. Furthermore, aqueous formulations may be used for any purpose, for example, by being included in cosmetic compositions, oral compositions, or pharmaceutical compositions. Aqueous formulations may also be included in cosmetics, pharmaceuticals, or quasi-drugs. In this specification, a quasi-drug is a product intended for the prevention of disease or disability, the alleviation of daily discomfort, or hygiene management. For example, in Japan, a quasi-drug refers to a product containing ingredients effective for the effects and efficacy approved by the Ministry of Health, Labour and Welfare. In this specification, a quasi-drug may be used for any purpose, and may be a cosmetic composition, an oral composition, or a pharmaceutical composition. Aqueous formulations may be in the form of, for example, topical skin preparations, mouthwashes, transdermal preparations, eye drops, nasal drops, oral preparations, or injections. Aqueous formulations may also be mixed with paste-like compositions.

[0043] The EPC-K content in aqueous formulations varies depending on the application, but is preferably 0.001 w / v% or more, more preferably 0.01 w / v% or more, and even more preferably 0.05 w / v% or more. Furthermore, the EPC-K content in aqueous formulations is preferably 5.0 w / v% or less, more preferably 2.0 w / v% or less, and even more preferably 0.2 w / v% or less.

[0044] The alkyl chain of the polyoxyethylene alkylphenyl ether is not limited, but preferably has 7 or more carbon atoms, more preferably 8 or more. The number of carbon atoms in the alkyl group is preferably 30 or less. The polyoxyethylene chain length of the polyoxyethylene alkylphenyl ether is not limited, but is preferably shorter, and the average number of moles of ethylene oxide added is preferably 40 or less, more preferably 25 or less, and even more preferably 10 or less. The average number of moles of ethylene oxide added is also 1 or more. As the polyoxyethylene alkylphenyl ether, it is preferable to use at least one of polyoxyethylene octylphenyl ether and polyoxyethylene nonylphenyl ether. Commercially available polyoxyethylene octylphenyl ethers can be used, such as Triton X-100 or Triton X-405.

[0045] The alkyl chain of the polyoxyethylene alkyl ether is not limited, but preferably has 18 or fewer carbon atoms, more preferably 16 or fewer, and even more preferably 13 or fewer. The alkyl group also has 1 or more carbon atoms. The polyoxyethylene chain length of the polyoxyethylene alkyl ether is not limited, but shorter is preferable, and the average number of moles of ethylene oxide added is preferably 40 or less, more preferably 25 or less, and even more preferably 10 or less. The average number of moles of ethylene oxide added is also 1 or more. As the polyoxyethylene alkyl ether, for example, at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, and polyoxyethylene stearyl ether can be used, and polyoxyethylene lauryl ether or polyoxyethylene cetyl ether is preferred. As the polyoxyethylene lauryl ether, a commercially available product can be used; for example, NIKKOL BL-9EX can be used.

[0046] The alkyl chain of the polyoxyethylene fatty acid ester is not limited, but preferably has 20 or fewer carbon atoms, more preferably 18 or fewer. The alkyl group also has 1 or more carbon atoms, preferably 10 or more, and more preferably 12 or more. The polyoxyethylene chain length of the polyoxyethylene alkyl ether is not limited, but shorter is preferable, and the average number of moles of ethylene oxide added is preferably 40 or less, more preferably 25 or less. The average number of moles of ethylene oxide added is also preferably 1 or more, more preferably 10 or more. As the polyoxyethylene fatty acid ester, for example, at least one selected from the group consisting of polyoxyethylene laurate, polyoxyethylene palmitate, and polyoxyethylene stearate can be used, and it is preferable to use polyoxyethylene stearate or polyoxyethylene laurate. As the polyoxyethylene stearate, commercially available products can be used, for example, polyethylene glycol monostearate (palmitate and stearate mixture) n=25: Tokyo Chemical Industry Co., Ltd. can be used. Commercially available polyoxyethylene laurate esters can also be used; for example, polyethylene glycol monolaurate (n=10: Tokyo Chemical Industry Co., Ltd.) can be used.

[0047] The aqueous formulation contains at least one selected from the group consisting of polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester, preferably in an amount of 0.1 w / v% or more, more preferably more than 0.1 w / v%, even more preferably 0.5 w / v% or more, preferably 5 w / v% or less, and more preferably 2 w / v% or less.

[0048] In aqueous formulations, polyoxyethylene alkylphenyl ether is preferably contained in an amount of 0.01 w / v% to 10 w / v%. In aqueous formulations, if EPC-K is contained in an amount of 0.05 w / v% to 0.1 w / v%, polyoxyethylene alkylphenyl ether is preferably contained in an amount of 0.01 w / v% to 5 w / v%, and more preferably in an amount of 0.1 to 2.5 w / v%. In aqueous formulations, if EPC-K is contained in an amount of 0.2 w / v% to 1.0 w / v%, polyoxyethylene alkylphenyl ether is preferably contained in an amount of 0.1 w / v% to 10 w / v%, more preferably in an amount of 0.5 w / v% to 10 w / v%, even more preferably in an amount of 1.0 w / v% to 10 w / v%, and particularly preferably in an amount of 2.0 w / v% to 10 w / v%. In aqueous formulations, the weight ratio of EPC-K to polyoxyethylene alkylphenyl ether (EPC-K content: polyoxyethylene alkylphenyl ether content) is preferably 1:1 to 1:50, and more preferably 1:2.5 to 1:50.

[0049] In aqueous formulations, the polyoxyethylene alkyl ether is preferably contained in an amount of 0.1 w / v% to 4.0 w / v%, and more preferably in an amount of 0.5 w / v% to 4.0 w / v%. In aqueous formulations, the weight ratio of EPC-K to polyoxyethylene alkyl ether (EPC-K content: polyoxyethylene alkyl ether content) is preferably 1:0.5 to 1:20, and more preferably 1:1 to 1:20.

[0050] In aqueous formulations, it is preferable that polyoxyethylene fatty acid esters be contained in an amount of 0.1 w / v% or more.

[0051] In aqueous formulations, it is preferable that at least one selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters has an HLB greater than 12.

[0052] In this way, a stable aqueous formulation containing EPC-K can be provided. In the aqueous formulation according to the present invention, EPC-K is stabilized even without alcohol, but alcohol may be optionally included. Alcohols include ethanol and polyols such as butylene glycol, dipropylene glycol, concentrated glycerin, pentylene glycol, propanediol, and isopentyldiol. The alcohol content in the aqueous formulation is preferably 40 w / v% or less, more preferably 30 w / v% or less, even more preferably 20 w / v%, and particularly preferably 5 w / v% or less. A lower alcohol content is preferable because it reduces irritation and improves the feel of use. If the aqueous formulation contains two or more types of alcohol, the alcohol content refers to the total amount of the two or more types of alcohol.

[0053] In this specification, "stabilizing EPC-K" means that, after storing an aqueous formulation containing EPC-K at a constant temperature for a certain period of time, the EPC-K content in the aqueous formulation containing at least one selected from the group consisting of polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester does not decrease compared to an aqueous formulation that does not contain any of these. In the aqueous formulations of this specification, the EPC-K content decreases due to the decomposition of EPC-K. In other words, "stabilization" of EPC-K in an aqueous formulation can be rephrased as "suppression of the decrease in EPC-K content" or "improvement of the remaining rate" of EPC-K in the aqueous formulation. In this specification, the "remaining rate" of EPC-K in an aqueous solution means, as described in the examples, the percentage of the EPC-K content in the aqueous formulation after storage at a constant temperature for a certain period of time relative to the EPC-K content in the aqueous formulation before storage.

[0054] In this specification, "stabilization" of EPC-K in an aqueous formulation means that the EPC-K content in the aqueous formulation is stable before and after storage at a constant temperature for a certain period of time (i.e., the difference in content is small). More specifically, it is preferable that the EPC-K retention rate in the aqueous formulation is maintained at 92% or more, more preferably 95% or more, after storage at 60°C for 4 weeks, or that the EPC-K retention rate in the aqueous formulation is maintained at 92% or more, preferably 94% or more, more preferably 95% or more, after storage at 40°C for 2 months. Alternatively, it is preferable that the aqueous formulation of this specification maintains an EPC-K retention rate of 85% or more, preferably 90% or more, more preferably 92% or more, after storage at 40°C for 6 months. The EPC-K content in the aqueous formulation can be measured by the method described in the examples below.

[0055] Furthermore, aqueous formulations may also contain additives commonly used in aqueous formulations, if necessary. Examples of such additives include buffers, isotonic agents, solubilizers, viscous bases, oily bases, chelating agents, cooling agents, pH adjusters, preservatives, antioxidants, and stabilizers.

[0056] Examples of buffering agents include phosphate buffers, borate buffers, citrate buffers, tartaric acid buffers, acetate buffers, Tris buffers, and amino acids.

[0057] Examples of isotonic agents include sugars such as sorbitol, glucose, and mannitol; polyhydric alcohols such as glycerin and propylene glycol; salts such as sodium chloride; and boric acid.

[0058] Examples of solubilizers include glycerin, polyhydric alcohols such as macrogol, and so on.

[0059] Examples of viscous bases include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, and carboxyvinyl polymer; and celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose.

[0060] Examples of oily bases include castor oil, soybean oil, corn oil, and camellia oil.

[0061] Examples of chelating agents include sodium edetate and citric acid.

[0062] Examples of cooling agents include l-menthol, borneol, camphor, and eucalyptus oil.

[0063] Examples of pH adjusting agents include alkalis such as sodium hydroxide and potassium hydroxide; and acids such as acetic acid, citric acid, hydrochloric acid, phosphoric acid, and tartaric acid.

[0064] Examples of preservatives include sorbic acid, potassium sorbate, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorohexidine gluconate, boric acid, dehydroacetic acid, sodium dehydroacetate, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, and sodium chlorite.

[0065] Examples of antioxidants include tetrasodium etidronate, disodium edetate, tetrasodium edetate, vitamin C, vitamin E, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, potassium sulfite, potassium pyrosulfite, sulfur dioxide, chlorogenic acid, catechin, and rosemary extract.

[0066] Examples of stabilizers include polyvinylpyrrolidone, sodium sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrins, dextran, ascorbic acid, sodium edetate, taurine, and tocopherol.

[0067] The aqueous formulation may contain other surfactants in addition to polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester, as long as they do not impair the effects of the present invention or its safety for living organisms.

[0068] The pH of the aqueous formulation is not particularly limited, as long as it is within an acceptable range depending on the purpose of the aqueous formulation, but a range of 5.5 to 7.0 is preferred. Similarly, the osmotic pressure of the aqueous formulation is not particularly limited, as long as it is within an acceptable range depending on the purpose. For example, when the aqueous formulation is used as eye drops, the osmotic pressure ratio to Japanese Pharmacopoeia physiological saline solution is about 0.5 to 3, preferably about 0.9 to 1.1.

[0069] Furthermore, we will explain the use of aqueous formulations as cosmetic compositions and oral compositions.

[0070] The cosmetic composition of the present invention includes compositions for use on the skin, hair, or scalp. For example, it can be suitably used in topical skin preparations and hair cosmetics such as hair growth agents, hair growth lotions, hair growth gels, hair growth tonics, hair growth sprays, hair growth tonic sprays, hair tonics, hair creams, hair treatments, antiperspirants, skin lotions, shampoos, and hair dyes. Furthermore, the cosmetic composition may contain other active ingredients other than EPC-K, moisturizers, etc., insofar as it does not impair the effects of the present invention or its safety for living organisms.

[0071] The cosmetic composition may further contain active pharmaceutical ingredients. Examples of active pharmaceutical ingredients include minoxidil, finasteride, or carpronium chloride.

[0072] The cosmetic composition may further contain active ingredients used in quasi-drugs. Examples of active ingredients used in quasi-drugs include, but are not limited to, cell activators, blood circulation promoters, anti-androgen agents, sebum secretion inhibitors, immunosuppressants, antihistamines, antiseptics, local irritants, keratolytic agents, anti-inflammatory agents, and anti-apoptotic agents. Specifically, for example, carpronium chloride, cantharis tincture, tocopherol (vitamin E) or its derivatives, tocopherol acetate, capsicum tincture, swertia japonica extract, garlic extract, benzyl nicotinate, vitamin A or its derivatives, vitamin B1 or its derivatives, vitamin B2 or its derivatives, vitamin B6 or its derivatives, dialkylmonoamine derivatives, biotin, calcium pantothenate, pantothenyl alcohol, methionine, calendula, carrot extract, porphyrin compounds, minerals, pentadecanoic acid glyceride, cystine, serine, leucine, tryptophan, amino acid extract, St. John's wort extract, scutellaria baicalensis, clove extract, cuacara extract, duke extract, eugenyl glucoside, hop extract, iso One or more of the following can be used in combination: propylmethylphenol, biosol, photosensitizer 101, photosensitizer 102, salicylic acid, benzalkonium chloride, benzethonium chloride, chlorhexidine, hinokitiol, phenol, resorcinol, sulfur, pyridoxine, lecithin, diethylstilbestrol, thioxolone, diphenhydramine hydrochloride, hydrocortisone acetate, azulene, glycyrrhizin / glycyrrhetin, dipotassium glycyrrhizate, prednisolone, chondroitin sulfate, hyaluronic acid, pyrrolidone carboxylic acid, propylene glycol, soluble collagen, glycerin, mini sasanishiki extract, allantoin, hydrogenated bisabolol, l-limonene, bisabolol, l-menthol, delamid, and others. The cosmetic composition may further contain additives, such as saw palmetto, zinc, capsaicin, isoflavones, and L-lysine.

[0073] The cosmetic composition may also contain moisturizers. Moisturizers include pyrrolidone carboxylic acid, hyaluronic acid, ginseng extract, mandarin orange extract, yuzu extract, marshmallow extract, burnet extract, hawthorn extract, ginkgo leaf extract, kelp extract, rice bran extract, rice bran sphingoglycolipid, cocoa butter, mallow extract, sodium pyrrolidone carboxylate, calendula extract, royal jelly extract, lemon extract, silk extract, orange extract, acerola extract, placenta extract, collagen, and ro Examples of ingredients include prune extract, Belamcanda chinensis extract, Rehmannia glutinosa extract (root extract), Cinchona extract, Pine extract, Lamium album flower extract, Equisetum arvense extract, Fucus vesiculosus extract, Chimaphila japonica leaf extract, Zostera margaritacea extract, Aloe vera extract, Hypericum perforatum extract, Seaweed extract, Chitofilmer, Plant oils (for moisturizing), Cherimoya fruit extract, Cucumis fruit extract, Hydrolyzed okra seed extract, Amla, Shikakai, and Lotus extract (Nelumbo nucifera stamen extract).

[0074] The aqueous formulation can be used as an oral composition. The oral composition is suitably used as a mouthwash, liquid toothpaste, oral freshener, etc. The aqueous formulation may also be mixed with paste-like substances such as toothpaste. Furthermore, the oral composition may contain other active ingredients other than EPC-K, sweeteners, colorants, fragrances, humectants, solvents, thickeners, pH adjusters, solubilizers, cleaning agents, tooth coating agents, preservatives, etc., as long as the effects of the present invention and safety for living organisms are not impaired.

[0075] Oral compositions may contain additional active ingredients found in quasi-drugs. Examples of active ingredients in quasi-drugs include disinfectants, fluorine-containing compounds (e.g., sodium fluoride), anti-inflammatory agents such as tranexamic acid and ε-aminocaproic acid, enzymes such as dextranase, vitamins (e.g., pyridoxine hydrochloride (vitamin B6) and tocopherol (vitamin E)), dipotassium glycyrrhizinate, zeolite, allantoin, and methyl salicylate. Examples of disinfectants include cationic disinfectants such as cetylpyridinium chloride, benzethonium chloride, and benzalkonium chloride, nonionic disinfectants such as isopropylmethylphenol, β-glycyrrhetinic acid, and sodium lauroyl sarcosinate.

[0076] Examples of sweeteners include sodium saccharin and stevioside. Examples of colorants include highly safe water-soluble dyes such as Blue No. 1, Green No. 3, Yellow No. 4, and Red No. 105. Examples of fragrances include natural essential oils such as peppermint oil, spearmint oil, eucalyptus oil, wintergreen oil, clove oil, thyme oil, sage oil, cardamom oil, rosemary oil, marjoram oil, lemon oil, nutmeg oil, lavender oil, and paraclete oil, as well as fragrance components contained in the above natural essential oils such as l-menthol, l-carvone, cinnamic aldehyde, orange oil, anethole, 1,8-cineole, methyl salicylate, eugenol, thymol, linalool, limonene, menthone, menthyl acetate, citral, camphor, borneol, pinene, and spiranthol, as well as ethyl acetate, ethyl butyrate, isoamyl acetate, and hexanal. Fragrance components such as hexenal, methyl anthranilate, ethyl methylphenyl glycidate, benzaldehyde, vanillin, ethyl vanillin, furaneol, maltol, ethyl maltol, gamma / deltadecalactone, gamma / deltadecalactone, N-ethyl-p-menthane-3-carboxamide, menthyl lactate, and ethylene glycol-l-menthyl carbonate, as well as blended flavors such as apple, banana, strawberry, blueberry, melon, peach, pineapple, grape, muscat, wine, cherry, squash, coffee, brandy, and yogurt, which are made by combining several fragrance components and natural essential oils. Examples of humectants include concentrated glycerin, horsetail extract, hawthorn extract, witch hazel extract, betaine, kelp extract, and sodium hyaluronate; examples of solvents include ethanol; examples of thickeners include xanthan gum and hydroxyethylcellulose; examples of pH adjusters include sodium bicarbonate, sodium hydroxide, sodium citrate, and citric acid; examples of solubilizers include POE hydrogenated castor oil; examples of cleaning agents include alkyl carboxymethyl hydroxyethyl imidazolinium betaine, disodium edetate, and lauryl dimethyl betaine; examples of tooth coating agents include white shellac; and examples of preservatives include phenoxyethanol and parabens.

[0077] Next, a method for producing the aqueous formulation of the present invention will be described. The aqueous formulation can be prepared using known methods. For example, an aqueous formulation can be obtained by adding EPC-K, at least one selected from the group consisting of polyoxyethylene alkylphenyl ethers, polyoxyethylene alkyl ethers, and polyoxyethylene fatty acid esters, and other additives to water. The components of the aqueous formulation can be added in any order. [Examples]

[0078] Examples of the present invention are described below. Unless otherwise specified, the content (%) of each component is given in w / v%.

[0079] [Test Example 1] Samples of aqueous formulations for each example and comparative example were prepared using the formulations shown in Table 1. In Example 1, polyoxyethylene (9) lauryl ether (NIKKOL BL-9EX, HLB=14.5), which has a polyoxyethylene chain length of 9, was used as the polyoxyethylene alkyl ether. In Example 2, polyoxyethylene (10) octylphenyl ether (Triton X-100, HLB=13.5), which has a polyoxyethylene chain length of 10, was used as the polyoxyethylene alkylphenyl ether. EPC-K was EPC (Senju) (Senju Pharmaceutical Co., Ltd.). The surfactants used in Comparative Examples 1-6 were polysorbate 80 (HLB=15), polyoxyethylene hydrogenated castor oil 60 (HLB=14), polyoxyl monostearate 40 (HLB=17.5), tyroxapole (HLB=12.9), and poloxamer 407 (HLB=18-23).

[0080] [Table 1]

[0081] The obtained samples were placed in 5 mL colorless glass ampoules and stored at 60°C for 4 weeks, and at 40°C for 2 months and 6 months.

[0082] After storage, the EPC-K content was measured. For the 0.2% EPC-K solution, 2 mL of each sample was accurately measured, and the diluent (50% acetonitrile solution) was added to make exactly 20 mL. 2 mL of this solution was accurately measured, and the diluent was added to make exactly 20 mL to prepare the sample solution. For the 0.1% EPC-K solution, 1 mL of each sample was accurately measured, and the diluent was added to make exactly 50 mL to prepare the sample solution. For the 0.05% EPC-K solution, 1 mL of each sample was accurately measured, and the diluent was added to make exactly 25 mL to prepare the sample solution. Separately, 10 mg of EPC-K was precisely measured, and the diluent was added to make exactly 100 mL to prepare the standard solution. 2 mL of this solution was accurately measured, and the diluent was added to make exactly 10 mL to prepare the standard solution. The following tests were conducted using liquid chromatography to determine the EPC-K content at the start of storage and after storage. The percentage of the EPC-K content after storage relative to the EPC-K content at the start of storage was then calculated and expressed as the residual rate (%).

[0083] The test conditions for the liquid chromatography method were as follows: Detector: Ultraviolet absorbance photometer (measurement wavelength: 225 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm is packed with 5 μm octadecylsilylated silica gel for liquid chromatography. (Capcell pak C18 MG, 5 μm, 4.6 mm × 250 mm, Osaka Soda) Column temperature: Constant temperature around 40°C Mobile phase: 1.2 g of crystalline sodium dihydrogen phosphate and 0.9 g of sodium chloride were dissolved in 150 mL of water, and 1500 mL of methanol and 1350 mL of acetonitrile were added. Phosphoric acid was added to this solution to adjust the pH to 4.0. Flow rate: 1.0mL / min Inflow volume: 20μL

[0084] The results are shown in Table 2.

[0085] [Table 2]

[0086] When stored at 60°C, Comparative Example 2 showed a significantly lower remaining EPC-K content compared to Comparative Example 1. Comparative Examples 3-6 showed a slight stabilization effect compared to Comparative Example 1, but the remaining EPC-K content was only about 90%, which was insufficient. On the other hand, Examples 1 and 2 both showed an EPC-K remaining content of 94% or more, indicating improved stability.

[0087] Furthermore, when stored at 40°C, the remaining EPC-K content of Comparative Examples 1, 4, 5, and 6 was almost the same, and no stabilization effect was observed. On the other hand, the decrease in EPC-K content was suppressed in Examples 1 and 2, and a significant stabilization effect was observed.

[0088] [Test Example 2] Aqueous formulations for each example and comparative example were prepared using the formulations shown in Tables 3 to 5. In Examples 3 to 8, polyoxyethylene (9) lauryl ether (NIKKOL BL-9EX: Fujifilm Wako Pure Chemical Industries, HLB=14.5), which has a polyoxyethylene chain length of 9, was used as the polyoxyethylene alkyl ether, and the content was varied. Note that Example 5 has the same formulation as Example 1. In Examples 9 to 22, polyoxyethylene (10) octylphenyl ether (Triton X-100: Nacalai Tesque, HLB=13.5), which has a polyoxyethylene chain length of 10, was used as the polyoxyethylene alkylphenyl ether, and the content was varied. Note that Example 12 has the same formulation as Example 2.

[0089] [Table 3]

[0090] [Table 4]

[0091] [Table 5]

[0092] The obtained samples were stored using the same method as in Test Example 1, and the EPC-K content was measured to determine the remaining EPC-K percentage after storage. The results are shown in Tables 6-8.

[0093] [Table 6]

[0094] [Table 7]

[0095] [Table 8]

[0096] As shown in Tables 6-8, compared to Comparative Examples 1 and 7, all of the examples showed a higher residual rate of EPC-K when stored at 60°C, indicating improved stability. Therefore, it was found that the stability of EPC-K in aqueous formulations was improved when the content of polyoxyethylene alkyl ether and polyoxyethylene alkylphenyl ether was 0.1 w / v% or higher.

[0097] [Test Example 3] Samples of aqueous formulations for each example and comparative example were prepared according to the formulations in Table 9. In Example 23, polyoxyethylene(9) lauryl ether (NIKKOL BL-9EX: Fujifilm Wako Pure Chemical Industries, HLB=14.5), which has a polyoxyethylene chain length of 9, was used as the polyoxyethylene alkyl ether. In Example 24, polyoxyethylene(10) octylphenyl ether (Triton X-100: Nacalai Tesque, HLB=13.5), which has a polyoxyethylene chain length of 10, was used as the polyoxyethylene alkylphenyl ether. In Example 25, polyoxyethylene(23) lauryl ether (Fujifilm Wako Pure Chemical Industries, HLB=15.7), which has a polyoxyethylene chain length of 23, was used as the polyoxyethylene alkyl ether. In Example 26, polyoxyethylene (40) octylphenyl ether (Triton X-405: Nacalai Tesque, HLB=17.9), which has a polyoxyethylene chain length of 40, was used as the polyoxyethylene alkylphenyl ether. Note that Example 23 and Example 24 use the same formulation as Example 1 and Example 2, respectively.

[0098] [Table 9]

[0099] The obtained samples were stored using the same method as in Test Example 1, and the EPC-K content was measured to determine the remaining EPC-K percentage after storage. The results are shown in Table 10.

[0100] [Table 10]

[0101] As shown in Table 10, in both cases of storage at 60°C for 4 weeks and storage at 40°C for 2 months, all of Examples 23-26 showed a higher retention rate of EPC-K after storage compared to Comparative Example 1. Furthermore, in Examples 23 and 24, the retention rate of EPC-K after storage was even higher compared to Examples 25 and 26. Thus, it was found that the stability of EPC-K can be improved when the polyoxyethylene chain of the polyoxyethylene alkylphenyl ether or polyoxyethylene alkyl ether is 10 or less.

[0102] [Test Example 4] Samples of aqueous formulations for each example and comparative example were prepared according to the formulations in Table 11. In Example 27, polyoxyethylene(20) cetyl ether (Fujifilm Wako Pure Chemical Industries, HLB=17), with a polyoxyethylene chain length of 20, was used as the polyoxyethylene alkyl ether. In Example 28, polyoxyethylene(20) stearyl ether (Fujifilm Wako Pure Chemical Industries, HLB=18), with a polyoxyethylene chain length of 20, was used as the polyoxyethylene alkyl ether. In Example 29, polyoxyethylene(20) nonylphenyl ether (Fujifilm Wako Pure Chemical Industries, HLB=16.2), with a polyoxyethylene chain length of 20, was used as the polyoxyethylene alkylphenyl ether. In Example 30, polyoxyethylene(25) stearate ester (Polyethylene Glycol monostearate (palmitate and stearate mixture) n=25: Tokyo Chemical Industry Co., Ltd., HLB=15), with a polyoxyethylene chain length of 25, was used as the polyoxyethylene fatty acid ester. In Example 31, polyoxyethylene(10) laurate ester (Polyethylene Glycol monolaurate n=10: Tokyo Chemical Industry Co., Ltd., HLB=12.5), which has a polyoxyethylene chain length of 10, was used as the polyoxyethylene fatty acid ester. The surfactant used in Comparative Example 8 was polyoxyethylene(20) oleyl ether (HLB=17), which has a polyoxyethylene chain length of 20.

[0103] [Table 11]

[0104] The obtained samples were stored using the same method as in Test Example 1, and the EPC-K content was measured to determine the remaining EPC-K percentage after storage. The results are shown in Table 12.

[0105] [Table 12]

[0106] As shown in Table 12, both when stored at 60°C for 4 weeks and when stored at 40°C for 2 months, Examples 27-31 showed a higher retention rate of EPC-K after storage compared to Comparative Examples 1 and 8. Furthermore, Example 29 showed an even higher retention rate of EPC-K after storage compared to Examples 27, 28, 30, and 31.

[0107] As described above, by adding at least one selected from the group consisting of polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester to EPC-K, the degradation of EPC-K was significantly suppressed during storage at 60°C and 40°C compared to EPC-K without the addition of at least one selected from the group consisting of polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester. A stabilizing effect was obtained with the addition of at least one selected from the group consisting of polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester at a concentration of 0.1 w / v% or more. Furthermore, it was found that the stabilizing effect was higher when the polyethylene chain length of at least one selected from the group consisting of polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl ether, and polyoxyethylene fatty acid ester was 10 or less than when the polyethylene chain length was longer.

[0108] The polyoxyethylene alkylphenyl ethers and polyoxyethylene alkyl ethers used in the examples were both used at concentrations above the critical micelle concentration (0.016% for Triton X100 and approximately 0.26% for NIKKOL BL-9EX). Therefore, it is considered that the surfactants formed micelles in the aqueous formulations of the examples, thereby stabilizing EPC-K. Furthermore, the aqueous formulations of the examples did not appear viscous to the naked eye.

[0109] The embodiments and examples disclosed herein should be considered in all respects to be illustrative and not restrictive. The scope of the present invention is indicated by the claims rather than the embodiments and examples herein, and includes all modifications and variations within the meaning and scope equivalent to the claims.

Claims

1. (a) dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt, (b) comprising any one selected from the group consisting of polyoxyethylene alkylphenyl ethers having a polyoxyethylene chain length of 25 or less, polyoxyethylene alkyl ethers having a polyoxyethylene chain length of 25 or less, and polyoxyethylene fatty acid esters having a polyoxyethylene chain length of 25 or less, The above (a) contains 0.001 w / v% or more and 0.2 w / v% or less, It must satisfy one of the following conditions selected from (i) to (iii): (i) When (b) is a polyoxyethylene alkylphenyl ether having a polyoxyethylene chain length of 25 or less, and the weight ratio of (a) to (b) is 1:1 to 1:50, (ii) When (b) is a polyoxyethylene alkyl ether having a polyoxyethylene chain length of 25 or less, and the weight ratio of (a) to (b) is 1:0.5 to 1:20, (iii) The case in which (b) is a polyoxyethylene fatty acid ester having a polyoxyethylene chain length of 25 or less, and contains 0.1 w / v% or more of (b), Furthermore, the concentration of (b) is greater than or equal to the critical micelle concentration and less than or equal to 5 w / v%, An aqueous formulation containing 5% w / v% or less of propanediol, or containing no propanediol at all.

2. The aqueous formulation according to claim 1, in the case of (i) or (ii), comprising 0.1 w / v% or more of (b).

3. The aqueous formulation according to claim 1, in the case of (i) above, wherein the formulation contains 0.01 w / v% to 10 w / v% of (b).

4. The aqueous formulation according to claim 1 or claim 2, in the case of (ii) above, wherein the aqueous formulation contains 0.1 w / v% to 4.0 w / v% of (b).

5. The aqueous formulation according to any one of claims 1 to 3, wherein the polyoxyethylene alkylphenyl ether comprises at least one of polyoxyethylene octylphenyl ether and polyoxyethylene nonylphenyl ether.

6. The aqueous formulation according to claim 1, claim 2, or claim 4, wherein the polyoxyethylene alkyl ether comprises at least one selected from the group consisting of polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, and polyoxyethylene stearyl ether.

7. The aqueous formulation according to claim 1, wherein the polyoxyethylene fatty acid ester comprises at least one selected from the group consisting of polyoxyethylene laurate, polyoxyethylene palmitate, and polyoxyethylene stearate.

8. The aqueous formulation according to any one of claims 1 to 7, wherein (b) is one selected from the group consisting of polyoxyethylene alkylphenyl ether having a polyoxyethylene chain length of 10 or less, polyoxyethylene alkyl ether having a polyoxyethylene chain length of 10 or less, and polyoxyethylene fatty acid ester having a polyoxyethylene chain length of 10 or less.

9. (b) The aqueous formulation according to any one of claims 1 to 8, wherein the HLB is greater than 12.

10. A cosmetic composition containing the aqueous formulation described in any one of claims 1 to 9.

11. An oral composition containing the aqueous formulation described in any one of claims 1 to 9.

12. A pharmaceutical composition containing the aqueous formulation described in any one of claims 1 to 9.

13. (a) dl-α-tocopherol-2-L-ascorbic acid phosphate diester potassium salt, (b) A step of preparing an aqueous formulation comprising one selected from the group consisting of a polyoxyethylene alkylphenyl ether having a polyoxyethylene chain length of 25 or less, a polyoxyethylene alkyl ether having a polyoxyethylene chain length of 25 or less, and a polyoxyethylene fatty acid ester having a polyoxyethylene chain length of 25 or less, The above (a) contains 0.001 w / v% or more and 0.2 w / v% or less, It must satisfy one of the following conditions selected from (i) to (iii): (i) When (b) is a polyoxyethylene alkylphenyl ether having a polyoxyethylene chain length of 25 or less, and the weight ratio of (a) to (b) is 1:1 to 1:50, (ii) When (b) is a polyoxyethylene alkyl ether having a polyoxyethylene chain length of 25 or less, and the weight ratio of (a) to (b) is 1:0.5 to 1:20, (iii) The case in which (b) is a polyoxyethylene fatty acid ester having a polyoxyethylene chain length of 25 or less, and contains 0.1 w / v% or more of (b), Furthermore, the concentration of (b) is greater than or equal to the critical micelle concentration and less than or equal to 5 w / v%, A method for stabilizing an aqueous formulation having a propanediol content of 5 w / v% or less, or not containing propanediol.

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