Oil-in-water emulsion

Abstract

To provide a pharmaceutical technique that enables a diphenhydramine-containing emulsion composition to express excellent emulsion stability while viscosity is imparted thereto.SOLUTION: An oil-in-water emulsion composition contains (A) diphenhydramine and / or a salt thereof and (B) carboxymethyl cellulose and / or a salt thereof with a pH of 8.5 or less. Such an oil-in-water emulsion composition can express excellent emulsion stability.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an oil-in-water emulsion composition having a predetermined pH, which contains diphenhydramine and / or a salt thereof and a thickener, and which has excellent emulsion stability. [Background technology]

[0002] Diphenhydramines such as diphenhydramine hydrochloride are known to be capable of suppressing the action of histamine, which causes allergic symptoms such as skin itching, and are used as antihistamines by being incorporated into pharmaceuticals or quasi-drugs, either for internal or external use.

[0003] For example, Patent Document 1 describes a method for producing diphenhydramine-containing tablets, which comprises granulating a composition containing diphenhydramine or a salt thereof and an excipient, adding a disintegrant containing carboxymethylcellulose calcium in powder form to the granules, and compressing the resulting mixture into tablets. Patent Document 2 describes an aqueous ophthalmic composition containing (A) at least one compound selected from diphenhydramine, chlorpheniramine, and salts thereof, (B) at least one compound selected from boric acid and salts thereof, and (C) at least four compounds selected from the group consisting of tetrahydrozoline hydrochloride, naphazoline hydrochloride, neostigmine methylsulfate, epsilon-aminocaproic acid, berberine sulfate, allantoin, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, sodium flavin adenine dinucleotide, cyanocobalamin, pyridoxine hydrochloride, panthenol, retinol palmitate, tocopherol acetate, potassium aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and sodium hyaluronate.

[0004] In addition, when diphenhydramines are incorporated into topical preparations, they may be incorporated into emulsion compositions that are advantageous in terms of functionality and the expression of effects due to the active ingredients. For example, Patent Document 3 describes that a water-in-oil emulsion composition containing (A) a liquid oily substance, (B) a dextrin fatty acid ester, (C) a fatty acid ester in which two or more hydroxyl groups of polyglycerin are esterified with a fatty acid, and (D) a higher alcohol and / or a higher fatty acid is stable, and that diphenhydramine or the like may be used as the component (A). Patent Document 4 also describes that an emulsion-type pharmaceutical composition containing at least one selected from the group consisting of (a) a salicylic acid ester and (b) a terpene, (c) an antihistamine in the form of a salt, (d) a polyethylene glycol fatty acid ester, (e) a sorbitan fatty acid ester, and (f) a surfactant with an HLB of 10 to 13, and (g) a thickener is stable, and that diphenhydramine hydrochloride or the like may be used as the component (c). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2007-291045 A [Patent Document 2] JP 2013-227343 A [Patent Document 3] JP 2014-047158 A [Patent Document 4] JP 2015-187085 A Summary of the Invention [Problem to be solved by the invention]

[0006] The emulsion compositions of Patent Documents 3 and 4 have achieved a certain degree of emulsion stability. However, the emulsion composition of Patent Document 3 can only be used in water-in-oil formulations, and the emulsion composition of Patent Document 4 has significant limitations in terms of formulation. For this reason, there are an increasing number of cases where the conventional emulsification technology cannot accommodate the diversification of formulations of emulsion compositions containing diphenhydramines. Therefore, there is a demand for the development of a new formulation technology that can achieve excellent emulsion stability in emulsion compositions containing diphenhydramines.

[0007] The present inventors have investigated formulations of emulsion compositions containing diphenhydramines, and have found that when diphenhydramines are added to an emulsion composition, the pH increases. However, when the pH is lowered so that the composition can be used as an external preparation, the emulsion stability is severely deteriorated. The inventors have found that this severe deterioration in emulsion stability occurs when a thickener, which is essential for imparting viscosity, is added.

[0008] An object of the present invention is to provide a formulation technique that can provide excellent emulsion stability while imparting viscosity to an emulsion composition containing a diphenhydramine. [Means for solving the problem]

[0009] The present inventors have conducted extensive research and found that, among various thickeners, carboxymethylcellulose and / or its salts exhibit a unique effect of improving emulsion stability in emulsion compositions containing diphenhydramines and having a pH of 8.5 or less. The present invention was completed through further research based on this finding.

[0010] That is, the present invention provides the following aspects. Item 1. An oil-in-water emulsion composition comprising (A) diphenhydramine and / or a salt thereof, and (B) carboxymethylcellulose and / or a salt thereof, and having a pH of 8.5 or less. Item 2. The oil-in-water emulsion composition according to Item 1, further comprising (C) ufenamate. Item 3. The oil-in-water emulsion composition according to Item 1 or 2, wherein the oil phase content is 3 to 30 wt %. Item 4. The oil-in-water emulsion composition according to any one of Items 1 to 3, wherein the pH is 4.8 to 5.5. Item 5. The oil-in-water emulsion composition according to any one of Items 1 to 4, wherein the content of the component (A) is 0.01 to 5% by weight. Item 6. The oil-in-water emulsion composition according to any one of Items 1 to 5, wherein the blending amount of the component (B) is 0.1 to 7% by weight. Item 7. (A) A method for improving emulsion stability in an oil-in-water emulsion composition containing diphenhydramine and / or a salt thereof and having a pH of 8.5 or less, comprising: A method for improving emulsion stability, comprising blending (B) carboxymethylcellulose and / or a salt thereof together with the component (A) into an oil-in-water emulsion composition. Effect of the Invention

[0011] According to the present invention, there is provided a formulation technique that can impart viscosity to an emulsion composition containing diphenhydramines while still exhibiting excellent emulsion stability. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] definition In this specification, "emulsion stability" refers to a property that suppresses non-uniformity or separation after an oil-in-water emulsion composition is allowed to stand at room temperature for a certain period of time. The method for determining "emulsion stability" is not particularly limited, and can be determined by visually observing the appearance of the oil-in-water emulsion composition. More specifically, it can be determined by the method described in "<Emulsion Stability>" in the Examples. In this specification, "method for improving emulsion stability" refers to a method for improving the "emulsion stability" of an oil-in-water emulsion composition.

[0013] The "oil phase" in the oil-in-water emulsion composition of the present invention means a phase containing an oily component and an oily base.

[0014] The oil phase content in the oil-in-water emulsion composition of the present invention means the total amount of the oily component and the oily base.

[0015] 1. Oil-in-water emulsion composition The oil-in-water emulsion composition of the present invention is characterized by comprising (A) diphenhydramine and / or a salt thereof (hereinafter also referred to as "component (A)") and (B) carboxymethylcellulose and / or a salt thereof (hereinafter also referred to as "component (B)"), and having a pH of 8.5 or less. The oil-in-water emulsion composition of the present invention will be described in detail below.

[0016] (A) Diphenhydramine and / or its salts The oil-in-water emulsion composition of the present invention contains diphenhydramine and / or a salt thereof as component (A). Diphenhydramine is a known drug known to have an antihistamine effect.

[0017] The salt of diphenhydramine is not particularly limited as long as it is pharma- ceutically acceptable, and specific examples thereof include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyl disulfonate, tannate, lauryl sulfate, sulfate, etc. These salts may be used alone or in combination of two or more.

[0018] In the oil-in-water emulsion composition of the present invention, one kind of diphenhydramine and its salts may be selected and used, or two or more kinds of diphenhydramine and its salts may be used in combination.

[0019] In the oil-in-water emulsion composition of the present invention, diphenhydramine and its salts are preferred.

[0020] The content of component (A) in the oil-in-water emulsion composition of the present invention may be appropriately set depending on the medicinal effect to be imparted, and may be, for example, a total amount of 0.01 to 5% by weight.

[0021] The more the amount of the (A) component is blended in the emulsion composition, the more rapid the pH rises, and the more marked the deterioration of emulsion stability after pH adjustment, but the incoming composition of the present invention has excellent emulsion stability, and is therefore highly useful in that it can effectively improve emulsion stability even when the (A) component is included in a relatively large amount. From the viewpoint of enhancing the usefulness of the present invention, examples of suitable contents of the (A) component are preferably 0.1 to 5% by weight, more preferably 0.3 to 5% by weight, even more preferably 0.6 to 5% by weight, and even more preferably 0.8 to 5% by weight, and 1.0 to 3% by weight.

[0022] From the viewpoint of further improving emulsion stability, the content of component (A) is preferably 0.01 to 3 weight %, more preferably 0.01 to 2 weight %, even more preferably 0.01 to 1.5 weight %, and even more preferably 0.01 to 1.2 weight %.

[0023] (B) Carboxymethylcellulose and / or its salt The oil-in-water emulsion composition of the present invention contains carboxymethylcellulose and / or a salt thereof as component (B). Carboxymethylcellulose is a component known as a thickener. Component (B) imparts viscosity to the oil-in-water emulsion composition, and unlike other general thickeners that significantly deteriorate emulsion stability in oil-in-water emulsion compositions containing diphenhydramines at pH 8.5 or less, component (B) exhibits a unique effect of improving emulsion stability.

[0024] The salt of carboxymethylcellulose is not particularly limited as long as it is pharma- ceutically acceptable, and specifically includes alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as magnesium salt and calcium salt. These salts may be used alone or in combination of two or more. Among these salts, sodium salt is preferred from the viewpoint of further improving emulsion stability.

[0025] The viscosity of component (B) is, for example, 10 mPa·s to 6000 mPa·s as the viscosity of a 1 wt % aqueous solution at 25° C. From the viewpoint of further improving emulsion stability, the viscosity of component (B) is preferably 100 mPa·s to 5000 mPa·s, more preferably 300 mPa·s to 4000 mPa·s, even more preferably 600 mPa·s to 3000 mPa·s, even more preferably 800 mPa·s to 2500 mPa·s, and even more preferably 1000 mPa·s to 2000 mPa·s.

[0026] The degree of etherification of the (B) component is, for example, 0.1 to 3.0. From the viewpoint of further increasing emulsion stability, the degree of etherification of the (B) component is preferably 0.3 to 2.0, more preferably 0.5 to 1.5, even more preferably 0.6 to 1, and even more preferably 0.7 to 0.9.

[0027] As for the component (B), commercially available products can be used. For example, the Cellogen (registered trademark) series PR-S (viscosity of a 2% by weight aqueous solution at 25°C is 20 mPa·s to 40 mPa·s, degree of etherification is 0.70 to 0.85), P-715A (viscosity of a 2% by weight aqueous solution at 25°C is 80 mPa·s to 140 mPa·s, degree of etherification is 0.60 to 0.70), F-SC (viscosity of a 2% by weight aqueous solution at 25°C is 300 mPa·s to 400 mPa·s, degree of etherification is 0.70 to 0.85), etc., sold by Daiichi Kogyo Seiyaku Co., Ltd. Examples of usable adhesives include the CMC Daicel series sold by Daicel Chemical Industries, Ltd., and the Sunrose F series sold by Nippon Paper Chemicals Co., Ltd., as well as AG Gum M (viscosity of a 2 wt% aqueous solution at 25°C is 900 mPa·s to 1500 mPa·s, degree of etherification 0.70 to 0.85), AG Gum M (viscosity of a 2 wt% aqueous solution at 25°C is 1000 mPa·s to 2000 mPa·s, degree of etherification 0.70 to 0.85), and P-815C (viscosity of a 1 wt% aqueous solution at 25°C is 1000 mPa·s to 2000 mPa·s, degree of etherification 0.70 to 0.85).

[0028] In the oil-in-water emulsion composition of the present invention, one type may be selected from carboxymethylcellulose and salts thereof and used, or two or more types may be used in combination.

[0029] The content of the (B) component in the oil-in-water emulsion composition of the present invention may be appropriately set depending on the emulsion stability to be imparted, and may be, for example, a total amount of 0.1 to 7% by weight. From the viewpoint of further increasing the emulsion stability, the content of the (B) component is preferably 0.3 to 5% by weight, more preferably 0.5 to 3% by weight, even more preferably 1 to 2% by weight, and even more preferably 1.2 to 1.8% by weight.

[0030] In the oil-in-water emulsion composition of the present invention, the ratio of the (B) component to the (A) component is determined depending on the respective contents of the (A) and (B) components, but may be, for example, 0.1 to 20 parts by weight as the amount of the (B) component per 1 part by weight of the (A) component. From the viewpoint of further increasing the emulsion stability, the amount of the (B) component per 1 part by weight of the (A) component is preferably 0.3 to 15 parts by weight, more preferably 0.5 to 5 parts by weight, even more preferably 0.7 to 3 parts by weight, even more preferably 1.0 to 2 parts by weight, and particularly preferably 1.2 to 1.8 parts by weight.

[0031] (C) Ufenamart The oil-in-water emulsion composition of the present invention may contain ufenamate as component (C). Component (C) further deteriorates emulsion stability in an emulsion composition containing diphenhydramines and having a pH of 8.5 or less, but the composition for external use on skin of the present invention has excellent emulsion stability, and therefore can effectively exhibit excellent emulsion stability even when component (C) is added.

[0032] Ufenamate, also known as butyl flufenamate, is a known lipid-soluble nonsteroidal anti-inflammatory drug.

[0033] In the oil-in-water emulsion composition of the present invention, the content of component (C) is appropriately set depending on the medicinal effect to be imparted, and can be, for example, 0.1 to 20% by weight, preferably 0.5 to 10% by weight, more preferably 2 to 10% by weight, even more preferably 3 to 7% by weight, and particularly preferably 4 to 6% by weight.

[0034] In the oil-in-water emulsion composition of the present invention, the ratio of component (C) to component (A) is determined depending on the respective contents of components (A) and (C), and may be, for example, 0.5 to 50 parts by weight of component (C) per part by weight of component (A). From the viewpoint of further improving emulsion stability, the content of component (C) per part by weight of component (A) is preferably 1 to 20 parts by weight, more preferably 3 to 10 parts by weight, even more preferably 4 to 8 parts by weight, and particularly preferably 4 to 7 parts by weight.

[0035] In the oil-in-water emulsion composition of the present invention, the ratio of component (C) to component (B) is determined depending on the respective contents of components (B) and (C), but may be, for example, 0.5 to 30 parts by weight of component (C) per part by weight of component (B). From the viewpoint of further improving emulsion stability, the amount of component (C) per part by weight of component (B) is preferably 1 to 15 parts by weight, more preferably 1.5 to 10 parts by weight, even more preferably 2 to 8 parts by weight, and particularly preferably 2.5 to 6 parts by weight.

[0036] Oil-based The oil-in-water emulsion composition of the present invention contains a base component of the oil phase. The oil base is not particularly limited as long as it is pharma- ceutically or cosmetically acceptable, and examples thereof include oils (medium-chain fatty acid triglyceride, olive oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil, lard, squalane, fish oil, etc.), mineral oils (liquid paraffin, paraffin, gelling hydrocarbon, petrolatum, etc.), waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oils (isopropyl myristate, isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate ... isopropyl, cetyl palmitate, ethyl oleate, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oils (dimethylpolysiloxane, cyclic silicone, etc.), etc.

[0037] These oils may be used alone or in combination of two or more.

[0038] Among these oily bases, from the viewpoint of obtaining better emulsion stability, preferred are oils, higher alcohols, and silicone oils, and more preferred are medium-chain fatty acid triglycerides, squalane, stearyl alcohol (especially those in the form of a polyoxyethylene arachyl ether-stearyl alcohol mixture), and dimethylpolysiloxane.

[0039] The oil phase content in the oil-in-water emulsion composition of the present invention (i.e., the total amount of the oily component and the oily base) is not particularly limited as long as it can be emulsified into an oil-in-water type, and can be, for example, 3 to 30% by weight.

[0040] The oil-in-water emulsion composition of the present invention has excellent emulsion stability, and is therefore highly useful in that it can effectively improve emulsion stability even in a composition with a low oil phase content, which is inherently difficult to stabilize. In addition, the lower the oil phase content, the better the feeling of use. From the viewpoint of enhancing the usefulness and / or feeling of use of the present invention, suitable examples of the oil phase content in the oil-in-water emulsion composition of the present invention include 3 to 25% by weight, preferably 3 to 20% by weight, more preferably 3 to 15% by weight, even more preferably 3 to 12% by weight, even more preferably 3 to 10% by weight, even more preferably 3 to 9% by weight, and particularly preferably 3 to 7.5% by weight.

[0041] From the viewpoint of further enhancing the emulsion stability of the oil-in-water emulsion composition of the present invention, the oil phase blending ratio is preferably 4 to 30% by weight, more preferably 5 to 30% by weight, and even more preferably 6 to 30% by weight.

[0042] water The oil-in-water emulsion composition of the present invention contains water as a base component of the aqueous phase. The content of water in the oil-in-water emulsion composition of the present invention is not particularly limited as long as it can be emulsified into an oil-in-water emulsion, and may be, for example, 60 to 95% by weight.

[0043] The oil-in-water emulsion composition of the present invention has excellent emulsion stability of oil-in-water type, and is therefore highly useful in that it can effectively improve emulsion stability even in compositions with a large amount of water, which is inherently difficult to stabilize as an emulsion. In addition, the more water, the better the feeling of use. From the viewpoint of enhancing the usefulness and / or feeling of use of the present invention, suitable examples of the water content in the oil-in-water emulsion composition of the present invention include 64 to 95% by weight, preferably 73 to 95% by weight, more preferably 75 to 95% by weight, even more preferably 78 to 95% by weight, and even more preferably 80 to 95% by weight.

[0044] From the viewpoint of further enhancing the emulsion stability of the oil-in-water emulsion composition of the present invention, the water content is preferably 60 to 90% by weight, more preferably 60 to 85% by weight, and even more preferably 60 to 83% by weight.

[0045] Surfactants The oil-in-water emulsion composition of the present invention contains a surfactant for emulsification. The surfactant is not particularly limited as long as it is pharma- ceutical or cosmetically acceptable, and examples thereof include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. Among these surfactants, nonionic surfactants are preferred from the viewpoint of obtaining better emulsion stability.

[0046] Specific examples of nonionic surfactants include polyoxyethylene hydrogenated castor oil; sorbitan fatty acid esters (e.g., sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, diglycerol sorbitan penta-2-ethylhexyl acid, diglycerol sorbitan tetra-2-ethylhexyl acid, etc.); glycerin fatty acid esters (e.g., monocottonseed oil fatty acid glyceryl, monoerucate glyceryl, sesquioleate glyceryl monostearate (glycerin stearate), α,α'-oleic acid pyroglutamic acid glyceryl, monostearate glycerin malic acid, etc.); propylene glycol fatty acid esters (e.g., propylene glycol monostearate, etc.); glycerin alkyl ether; steareth-2; polyoxyethylene sorbitan fatty acid esters sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tetraoleate, etc.; polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan pentaoleate, polyoxyethylene sorbitan monostearate, etc.); polyoxyethylene glycerin fatty acid esters (e.g., polyoxyethylene glycerin monostearate, polyoxyethylene glycerin monoisostearate, polyoxyethylene glycerin triisostearate, etc.); polyoxyethylene fatty acid esters (e.g., polyoxyethylene monooleate, polyoxyethylene monostearate (polyoxyl stearate), polyoxyethylene distearate, polyoxyethylene monodioleate, ethylene glycol distearate, etc.);Polyoxyethylene alkyl or arachidyl ethers (e.g., polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene behenyl ether, polyoxyethylene 2-octyldodecyl ether, polyoxyethylene arachidyl ether, polyoxyethylene cholestanol ether, etc.) and their phosphoric acids or phosphates (e.g., polyoxyethylene cetyl ether sodium phosphate, etc.); Pluronic (registered trademark) types (e.g., Pluronic (registered trademark), etc.); polyoxyethylene-polyoxypropylene alkyl ethers (e.g., polyoxyethylene-polyoxypropylene cetyl ether, polyoxyethylene-polyoxypropylene-2-decyltetradecyl ether, polyoxyethylene-polyoxypropylene monobutyl ether, polyoxyethylene-polyoxypropylene hydrogenated lanolin, polyoxyethylene-polyoxypropylene glycerin ether, etc.); steareth-21, etc.;

[0047] These surfactants may be used alone or in combination of two or more.

[0048] Among these nonionic surfactants, from the viewpoint of obtaining better emulsion stability, preferred are polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl or arachyl ethers, and their phosphoric acids or phosphates, and more preferred are polyoxyethylene hydrogenated castor oil, polyoxyethylene behenyl ether, and sodium polyoxyethylene cetyl ether phosphate.

[0049] The HLB value of the surfactant is, for example, 8 to 19.5. From the viewpoint of obtaining better emulsion stability, the HLB value of the surfactant is preferably 9 to 19, more preferably 10 to 18. The HLB value (hydrophilic-lipophilic balance) indicates the molecular weight of the hydrophilic group portion in the total molecular weight of the surfactant, and is calculated by the Griffin formula.

[0050] In the oil-in-water emulsion composition of the present invention, the content of the surfactant may be appropriately set depending on the type of surfactant used, etc., and may be, for example, 0.5 to 7 wt %, preferably 1 to 6.5 wt %, more preferably 2 to 6 wt %, even more preferably 3 to 5.5 wt %, and even more preferably 4 to 5 wt %.

[0051] Other Ingredients The oil-in-water emulsion composition of the present invention may contain, in addition to the above-mentioned components, other commonly used additives as necessary. Examples of such additives include polyhydric alcohols, thickeners (other than the above component (B)), biocompatible polymers, pH regulators, buffers, solubilizers, chelating agents, preservatives, antioxidants, stabilizers, fragrances, colorants, etc.

[0052] The polyhydric alcohol is not particularly limited as long as it is pharma- ceutically or cosmetically acceptable, and examples thereof include dihydric alcohols such as propylene glycol, 1,3-butylene glycol (1,3-BG), ethylene glycol, isoprene glycol, diethylene glycol, and dipropylene glycol; trihydric alcohols such as glycerin; and polyethylene glycols such as macrogol 4000 and macrogol 6000. These polyhydric alcohols may be used alone or in combination of two or more. Among these polyhydric alcohols, from the viewpoint of obtaining better emulsion stability, dihydric alcohols and trihydric alcohols are preferred, and 1,3-butylene glycol (BG) and glycerin are more preferred. Biocompatible polymers include homopolymers of 2-methacryloyloxyethyl phosphorylcholine or copolymers with alkyl methacrylates, and preferably copolymers of 2-methacryloyloxyethyl phosphorylcholine and butyl methacrylate.

[0053] The pH adjuster is not particularly limited, but may be an inorganic acid or an organic acid, and specifically may be phosphoric acid, hydrochloric acid, citric acid, sodium citrate, malic acid, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc. These pH adjusters may be used alone or in combination of two or more. Among these pH adjusters, from the viewpoint of further improving the emulsion stability of the oil-in-water emulsion composition, preferably phosphoric acid, hydrochloric acid, citric acid, sodium citrate, malic acid, succinic acid, or tartaric acid, more preferably phosphoric acid, hydrochloric acid, citric acid, sodium citrate, or malic acid, even more preferably phosphoric acid, hydrochloric acid, citric acid, or malic acid, and particularly preferably citric acid.

[0054] Furthermore, the oil-in-water emulsion composition of the present invention may contain, in addition to the above-mentioned components, a medicinal ingredient capable of exerting a pharmaceutical or cosmetic physiological function, if necessary. Examples of such medicinal ingredients include steroids (dexamethasone, dexamethasone hydrochloride, dexamethasone acetate, hydrocortisone hydrochloride, prednisolone valerate, prednisolone acetate, etc.), antihistamines (diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), local anesthetics (lidocaine, dibucaine, procaine, tetracaine, bupivacaine, mepivacaine, chloroprocaine, proparacaine, meprylcaine, or salts thereof), alkyl benzoates (e.g., ethyl aminobenzoate, diethylaminoethyl p-butylaminobenzoate hydrochloride), orthocaine, oxethazaine, oxypolyethyleneoxydecane, Scopolia extract, percaminpase, tesitdesitin, etc.), anti-inflammatory agents (allantoin, Salicylic acid, glycol salicylate, methyl salicylate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), bactericides (benzalkonium chloride, dequalinium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, ammonia water, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents (crotamiton, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (vanillylamide nonylate, benzyl nicotinate, capsaicin, chili pepper extract, etc.), vitamins (vitamins A, B, C, D, E, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, hyaluronic acid, etc.), etc. These medicinal ingredients may be used alone or in combination of two or more. Furthermore, when these medicinal ingredients are contained in the emulsion composition containing the oil-in-water emulsion stabilizer of the present invention, the content thereof may be appropriately determined depending on the type of the medicinal ingredient used, the expected effect, etc.

[0055] pH The pH of the oil-in-water emulsion composition of the present invention is not particularly limited, but is limited to not more than 8.5. From the viewpoint of obtaining a superior emulsion stability of the oil-in-water emulsion composition, the pH is preferably 3.0 to 8.5, more preferably 3.5 to 8.0, even more preferably 3.5 to 7.0, still more preferably 3.5 to 6.0, and particularly preferably 4.8 to 5.5. Formulation

[0056] The formulation of the oil-in-water emulsion composition of the present invention is not particularly limited, and examples thereof include emulsions, creams, lotions, etc., and preferably creams.

[0057] Specific examples of the oil-in-water emulsion composition of the present invention include medicines, quasi-drugs, cosmetics, etc. Among these formulations, medicines and quasi-drugs are preferred.

[0058] The oil-in-water emulsion composition of the present invention is preferably an external preparation, more preferably an external preparation for skin.

[0059] 2. Method for improving emulsion stability As described above, carboxymethylcellulose and / or a salt thereof improves emulsion stability in an oil-in-water emulsion composition containing diphenhydramine and having a pH of 8.5 or less. Therefore, the present invention also provides a method for improving emulsion stability in an oil-in-water emulsion composition containing diphenhydramine and / or a salt thereof and having a pH of 8.5 or less.

[0060] The method for improving emulsion stability of the present invention is a method for improving emulsion stability in an oil-in-water emulsion composition containing (A) diphenhydramine and / or a salt thereof and having a pH of 8.5 or less, characterized in that (B) carboxymethylcellulose and / or a salt thereof is blended with the oil-in-water emulsion composition together with the component (A). In the method for improving emulsion stability of the present invention, the types and blending amounts of the components used, the formulation form of the method for improving emulsion stability, etc. are as described in the above section "1. Method for improving emulsion stability". EXAMPLES

[0061] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these.

[0062] Test Example Oil-in-water emulsion compositions (skin topical preparations) were prepared having the compositions shown in Tables 1 to 3. Specifically, the oil-in-water emulsion compositions were prepared by gradually adding a mixture of an oil phase and a polyhydric alcohol heated to 60°C to 80°C to an aqueous phase at about 25°C while thoroughly stirring.

[0063] Details of each component used in the preparation of the oil-in-water emulsion composition are shown below. Arachides-20 Stearyl Alcohol: Polyoxyethylene arachidyl ether-stearyl alcohol mixture, WAX230 (Nikko Chemicals) Medium-chain triglyceride: Triester F-810 (Nikko Chemicals) Polyoxyethylene behenyl ether: NIKKOL BB-30 (Nippon Surfactant Industry Co., Ltd.), HLB 18.0 Polyoxyethylene hydrogenated castor oil 20: NIKKOL HCO-20 (Nippon Surfactant Industry Co., Ltd.), HLB 10.5 Triceteth-5 phosphate: Sodium polyoxyethylene cetyl ether phosphate, NIKKOL TCP-5 (Nippon Surfactant Industry Co., Ltd.), HLB 10.0 Sodium carboxymethylcellulose: P-815C (Dai-ichi Kogyo Seiyaku), viscosity of 1% by weight aqueous solution at 25°C: 1000 mPa·s to 2000 mPa·s, degree of etherification: 0.70 to 0.85

[0064] The obtained oil-in-water emulsion compositions were subjected to the following evaluations.

[0065] <Emulsification stability> The oil-in-water emulsion composition was placed in a glass bottle (No. 8 vial) and allowed to stand at room temperature for one day. After standing, the appearance of the oil-in-water emulsion composition was visually observed, and the emulsion stability was evaluated based on the following criteria. The results are shown in Tables 1 to 3. ○: No heterogeneity or separation observed ×: Non-uniformity is observed ××: The product becomes non-uniform immediately after preparation, and separation is observed after standing.

[0066] <Viscosity> Apply 0.05 g of an oil-in-water emulsion composition (with emulsion stability evaluation of ○) to the skin (skin on the back of the hand) in a 1 cm 2 The skin was then tilted 30° from a horizontal position, and the viscosity was evaluated based on the presence or absence of dripping (according to the following criteria) immediately after the tilt. The results are shown in Tables 1 to 3. ○: No dripping occurs and desired viscosity is imparted ×: Dripping occurs and desired viscosity is not imparted

[0067] <Feeling of use> A trained panelist applied each oil-in-water emulsion composition (with an emulsion stability rating of ○) to the inside of the forearm and evaluated the feel after absorption into the skin based on the following criteria. The results are shown in Tables 1 to 3. ◎: No oily feeling. 〇: Almost no oily feeling. △: Feels oily. ×: Feels quite oily. [Table 1]

[0068] [Table 2]

[0069] [Table 3]

[0070] As seen in the comparison between Reference Example 1 and Reference Example 2, the pH was increased by adding diphenhydramine to the oil-in-water emulsion composition, and as seen in Comparative Example 1 and Comparative Example 2, the emulsion stability was extremely deteriorated when the pH was lowered. As seen in the comparison between Comparative Example 2 and Comparative Example 3, the extreme deterioration of emulsion stability in Comparative Example 2 and the like was caused by the incorporation of hydroxypropyl cellulose as a thickener. In other words, it was found that the emulsion stability of an oil-in-water emulsion composition containing diphenhydramine and hydroxypropyl cellulose and having a lowered pH was deteriorated. In addition, as seen in the comparison between Comparative Example 4 and Comparative Example 5, the emulsion stability was further deteriorated by further adding ufenamate. On the other hand, as seen in Example 1 and Example 2, the emulsion stability was significantly improved when sodium carboxymethylcellulose was used as a thickener.

[0071] Furthermore, as shown in Comparative Examples 7 to 16, when a thickener other than sodium carboxymethylcellulose was used, the emulsion stability was extremely poor as in Comparative Example 2, whereas the emulsion stability was significantly improved when sodium carboxymethylcellulose was used as in Example 3. Similarly, the oil-in-water emulsion compositions of Examples 3 to 10 were also found to have excellent emulsion stability.

[0072] Prescription Examples Oil-in-water emulsion compositions (external skin preparations) were prepared according to the formulations shown in Table 4. Each oil-in-water emulsion composition was imparted with the desired viscosity and exhibited excellent emulsion stability.

[0073] [Table 4]

Claims

1. An oil-in-water emulsion composition comprising (A) diphenhydramine and / or a salt thereof, (B) carboxymethylcellulose and / or a salt thereof, and (C) ufenamate, and having a pH of 8.5 or less.

2. 2. The oil-in-water emulsion composition according to claim 1, wherein the oil phase content is 3 to 30% by weight.

3. 3. The oil-in-water emulsion composition according to claim 1, having a pH of 4.8 to 5.

5.

4. The oil-in-water emulsion composition according to any one of claims 1 to 3, wherein the content of the component (A) is 0.01 to 5% by weight.

5. The oil-in-water emulsion composition according to any one of claims 1 to 4, wherein the blending amount of the component (B) is 0.1 to 7% by weight.

6. A method for improving emulsion stability in an oil-in-water emulsion composition having a pH of 8.5 or less, comprising: (A) diphenhydramine and / or a salt thereof; and (C) ufenamate, the method comprising the steps of: A method for improving emulsion stability, comprising blending (B) carboxymethylcellulose and / or a salt thereof together with the component (A) and the component (C) into an oil-in-water emulsion composition.

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