Oil-in-water type emulsion composition

Abstract

To provide an oil-in-water type emulsion composition excellent in dispersion stability.SOLUTION: The oil-in-water emulsion composition of the present invention comprises (A) ufenamate, (B) polyoxyethylene hydrogenated castor oil, and (C) polyoxyethylene alkyl ether acid or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an oil-in-water emulsion composition. [Background technology]

[0002] An oil-in-water emulsion composition is a composition in which oil droplet particles are emulsified in an aqueous phase component, and is used in a variety of pharmaceutical formulations. In addition, oil-in-water emulsion compositions have an excellent feel on the skin when used, and are therefore widely used in the fields of topical medicines and cosmetics.

[0003] Ufenamate is a nonsteroidal anti-inflammatory agent that is incorporated into pharmaceutical or quasi-drug topical skin preparations for use. Ufenamate is a poorly water-soluble drug and is formulated as an aqueous liquid composition, an emulsion composition, or a gel composition. For example, an oil-in-water emulsion composition containing ufenamate and diphenhydramine has been proposed as a topical skin composition with a high antipruritic effect (see, for example, Patent Documents 1 and 2).

[0004] Furthermore, an oil-in-water emulsion composition containing ufenamate, glycyrrhetinic acid, and diphenhydramine has been disclosed as a topical skin composition for improving skin darkening (see, for example, Patent Document 3), and a gel ointment containing ufenamate, a nonionic surfactant, and an auxiliary agent such as glycyrrhetinic acid has been disclosed as a safe gel ointment that is excellent in stability for poorly water-soluble drugs and is non-irritating (see, for example, Patent Document 4). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 2020-33310 [Patent Document 2] Japanese Patent Application Publication No. 2020-33311 [Patent Document 3] Japanese Patent Application Publication No. 2019-99501 [Patent Document 4] Japanese Patent Application Laid-Open No. 2003-321347 Summary of the Invention [Problem to be solved by the invention]

[0006] Patent Documents 1 and 2 examine the efficacy of oil-in-water emulsion compositions using ufenamate and diphenhydramine as active ingredients, but do not examine the dispersion stability of the oil-in-water emulsion compositions. Oil-in-water emulsion compositions are generally thermodynamically unstable, and there is a demand for composition formulations with excellent dispersion stability.

[0007] Patent Document 3 discloses a formulation for an oil-in-water emulsion composition for topical use that uses ufenamate as one of the active ingredients and polyoxyethylene (50) hydrogenated castor oil, polyethylene glycol monostearate, and glyceryl monostearate as surfactants; however, the dispersion stability is insufficient due to the large diameter of the oil droplets dispersed in the aqueous phase.

[0008] Patent Document 4 proposes a gel ointment formulation that uses ufenamate as one of the active ingredients, polyoxyethylene (40) hydrogenated castor oil as a surfactant, and carboxyvinyl polymer as a gelling agent. However, gel ointments have the problem of low skin permeability for poorly water-soluble drugs.

[0009] The present invention provides an oil-in-water emulsion composition having excellent dispersion stability. [Means for solving the problem]

[0010] As a result of extensive research into the above-mentioned problems, the present inventors have discovered that in a formulation that combines, as surfactants, polyoxyethylene hydrogenated castor oil, which has excellent solubilizing power and low skin irritation, with polyoxyethylene alkyl ether acid or its salt, which has high emulsifying properties due to electric charge repulsion, by adding ufenamate, which is generally added as an active ingredient, the average particle size of oil droplets can be reduced and dispersion stability dramatically improved, thereby completing the present invention.

[0011] That is, the oil-in-water emulsion composition of the present invention contains (A) ufenamate, (B) polyoxyethylene hydrogenated castor oil, and (C) polyoxyethylene alkyl ether acid or a salt thereof. Furthermore, the oil-in-water emulsion composition of the present invention, in the above invention, contains (D) a poorly water-soluble drug. In addition, in the oil-in-water emulsion composition of the present invention, the poorly water-soluble drug (D) is diphenhydramine. In addition, in the oil-in-water emulsion composition of the present invention, the mass ratio of the oil phase component to the surfactant component containing (B) polyoxyethylene hydrogenated castor oil and (C) polyoxyethylene alkyl ether acid or a salt thereof is 1:1 to 2.5:1. Furthermore, in the oil-in-water emulsion composition of the present invention, the mass ratio of (B) polyoxyethylene hydrogenated castor oil to (C) polyoxyethylene alkyl ether acid or a salt thereof is 1:1 to 10:1. Furthermore, the oil-in-water emulsion composition of the present invention is used for antipruritic purposes in the above invention. Furthermore, in the oil-in-water emulsion composition of the present invention, the mass ratio of (A) ufenamate to (D) the poorly water-soluble drug is 1:1 to 5:1. In the oil-in-water emulsion composition of the present invention, the polyoxyethylene hydrogenated castor oil (B) has an average number of moles of polyoxyethylene added of 10 to 40. Furthermore, in the oil-in-water emulsion composition of the present invention, in the above invention, (C) the polyoxyethylene alkyl ether acid or a salt thereof is selected from polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl ether acetic acid, polyoxyethylene alkyl ether sulfate, or a salt thereof. Furthermore, the oil-in-water emulsion composition of the present invention is an emulsion in which the average particle size of the oil droplet particles is 120 nm or less. [Effects of the Invention]

[0012] The oil-in-water emulsion composition of the present invention can reduce the diameter of oil droplet particles, thereby enabling efficient drug delivery. Furthermore, the oil-in-water emulsion composition of the present invention can be an emulsion composition with excellent dispersion stability. DETAILED DESCRIPTION OF THE INVENTION

[0013] The oil-in-water emulsion composition of the present invention is characterized by comprising (A) ufenamate, (B) polyoxyethylene hydrogenated castor oil, and (C) polyoxyethylene alkyl ether acid or a salt thereof. The configuration of the present invention will be described in detail below. The present invention is not limited by the following description, and each component can be appropriately modified within the scope of the present invention.

[0014] (A) Ufenamart The oil-in-water emulsion composition of the present invention contains ufenamate as a component that stably emulsifies oil droplet particles in the aqueous phase. Ufenamate, also known as butyl flufenamate, is a component known as a poorly water-soluble nonsteroidal anti-inflammatory drug. In the oil-in-water emulsion composition of the present invention, ufenamate functions as an auxiliary agent that contributes to the stabilization of the oil-in-water emulsion composition, together with the two surfactant components described below.

[0015] In the oil-in-water emulsion composition of the present invention, the content of ufenamate is appropriately set depending on the amounts of (B) polyoxyethylene hydrogenated castor oil and (C) polyoxyethylene alkyl ether acid or a salt thereof used, which will be described later. For example, a content of 1 to 20% by mass is preferred, and from the viewpoint of dispersion stability of oil droplet particles, a content of 2 to 15% by mass is more preferred, 3 to 10% by mass is even more preferred, and 3 to 7% by mass is particularly preferred.

[0016] (B) Polyoxyethylene hydrogenated castor oil The oil-in-water emulsion composition of the present invention contains polyoxyethylene hydrogenated castor oil. From the viewpoints of commercial availability and solubilizing power of dispersible components, polyoxyethylene hydrogenated castor oil having an average number of added moles of polyoxyethylene of 5 to 60 is preferred, and polyoxyethylene hydrogenated castor oil having an average number of added moles of polyoxyethylene of 10 to 40 is more preferred. The polyoxyethylene hydrogenated castor oil may be used alone or in combination of two or more types.

[0017] In the oil-in-water emulsion composition of the present invention, the content of polyoxyethylene hydrogenated castor oil is preferably 0.5 to 5.0 mass %, and from the viewpoint of dispersion stability of oil droplet particles, the content is more preferably 1.0 to 3.0 mass %, and particularly preferably 1.5 to 2.5 mass %.

[0018] (C) Polyoxyethylene alkyl ether acid or its salt In the oil-in-water emulsion composition of the present invention, the polyoxyethylene alkyl ether acid or its salt is not particularly limited, but examples thereof include polyoxyethylene alkyl ether inorganic acids and polyoxyethylene alkyl ether organic acids. From the viewpoint of dispersion stability of oil droplet particles, polyoxyethylene alkyl ether inorganic acids are preferred.

[0019] In the oil-in-water emulsion composition of the present invention, the polyoxyethylene alkyl ether inorganic acid or its salt is not particularly limited, but examples thereof include polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl ether sulfate, polyoxyethylene alkyl ether nitric acid, polyoxyethylene alkyl ether hydrochloride, etc. From the viewpoint of dispersion stability of oil droplet particles, preferred are polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl ether sulfate, and polyoxyethylene alkyl ether nitric acid, more preferred are polyoxyethylene alkyl ether phosphate and polyoxyethylene alkyl ether sulfate, and even more preferred is polyoxyethylene alkyl ether phosphate.

[0020] In the oil-in-water emulsion composition of the present invention, the polyoxyethylene alkyl ether organic acid or its salt is not particularly limited, but examples thereof include polyoxyethylene alkyl ether acetic acid, polyoxyethylene alkyl ether formic acid, etc. From the viewpoint of dispersion stability of oil droplet particles, polyoxyethylene alkyl ether acetic acid is preferred.

[0021] The oil-in-water emulsion composition of the present invention contains a polyoxyethylene alkyl ether acid or a salt thereof. Examples of the polyoxyethylene alkyl ether acid to be used include esters of an acid and a polyoxyethylene alkyl ether, which is an ether of polyoxyethylene having an average number of added moles of 1 to 30 and an alcohol having 12 to 24 carbon atoms. Specific examples include polyoxyethylene lauryl ether (average number of added moles of EO: 2 to 25) acid, polyoxyethylene pareth (C12-15) ether (average number of added moles of EO: 5 to 12) acid, polyoxyethylene cetyl ether (average number of added moles of EO: 2 to 25) acid, polyoxyethylene oleyl ether (average number of added moles of EO: 2 to 20) acid, and polyoxyethylene behenyl ether (average number of added moles of EO: 2 to 20) acid. Examples of polyoxyethylene alkyl ether acid salts include sodium salts and potassium salts of the above-mentioned polyoxyethylene alkyl ether acids. Preferred examples of polyoxyethylene alkyl ether acid salts include sodium polyoxyethylene lauryl ether (average number of EO added moles: 10) acid, sodium polyoxyethylene pareth (C12-15) ether (average number of EO added moles: 2-8) acid, sodium polyoxyethylene cetyl ether (average number of EO added moles: 5) acid, and sodium polyoxyethylene oleyl ether (average number of EO added moles: 8) acid.

[0022] In the oil-in-water emulsion composition of the present invention, the content of the polyoxyethylene alkyl ether acid or its salt is preferably 0.5 to 3.0 mass %, and from the viewpoint of dispersion stability of the oil droplet particles, the content is more preferably 0.5 to 2.5 mass %, and particularly preferably 1.0 to 2.0 mass %.

[0023] Surfactants (other than polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether acid or its salts) The oil-in-water emulsion composition of the present invention may contain a surfactant other than the polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether acid or its salt in order to form a stable emulsion. The surfactant (other than polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether acid or its salt) is not particularly limited as long as it is pharmaceutically acceptable, and any of nonionic surfactants (other than polyoxyethylene hydrogenated castor oil), anionic surfactants (other than polyoxyethylene alkyl ether acid or its salt), cationic surfactants, and amphoteric surfactants may be used.

[0024] Specific examples of the nonionic surfactant (polyoxyethylene hydrogenated castor oil) include polyoxyethylene (10 to 50 mol) phytosterol ether, polyoxyethylene (10 to 50 mol) dihydrocholesterol ether, polyoxyethylene (10 to 50 mol) 2-octyldodecyl ether, polyoxyethylene (10 to 50 mol) decyltetradecyl ether, polyoxyethylene (10 to 50 mol) oleyl ether, polyoxyethylene (2 to 50 mol) cetyl ether, polyoxyethylene (5 to 50 mol) behenyl ether, polyoxyethylene (5 to 30 mol) polyoxypropylene (5 to 30 mol) 2-decyltetradecyl ether, polyoxyethylene (20 to 60 mol) sorbitan monooleate, and polyoxyethylene (10 to 60 mol) soybean oil. Examples of suitable nonionic surfactants include glycerin monoisostearate, polyoxyethylene (10-80 mol) glyceryl monoisostearate, polyoxyethylene (10-30 mol) glyceryl monostearate, polyoxyethylene (20-100 mol) polyoxypropylene-modified silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20-85), and glycerin fatty acid esters (glycerin monostearate, etc.). These nonionic surfactants (other than polyoxyethylene hydrogenated castor oil) may be used alone or in combination of two or more.

[0025] Specific examples of anionic surfactants include sodium polyoxyethylene lauryl ether sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium N-lauroyl sarcosinate, sodium N-myristyl sarcosinate, sodium dodecylbenzenesulfonate, hydrogenated coconut fatty acid monoglyceride sodium monosulfate, sodium lauryl sulfoacetate, sodium α-olefin sulfonate, sodium N-palmitoyl glutamate, sodium N-methyl-N-acyltaurate, etc. These anionic surfactants may be used alone or in combination of two or more.

[0026] Specific examples of the cationic surfactant include lauryltrimethylammonium chloride, stearyltrimethylammonium chloride, benzethonium chloride, benzalkonium chloride, stearyldimethylbenzylammonium chloride, etc. These cationic surfactants may be used alone or in combination of two or more.

[0027] Specific examples of amphoteric surfactants include coconut oil fatty acid amidopropyl betaine, lauryl dimethylaminoacetic acid betaine, lauryl dimethylamine oxide, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolium betaine, N-lauryl diaminoethyl glycine, N-myristyl diaminoethyl glycine, N-alkyl-1-hydroxyethyl imidazoline betaine sodium, etc. These amphoteric surfactants may be used alone or in combination of two or more.

[0028] Among these surfactants, nonionic surfactants (polyoxyethylene hydrogenated castor oil) are preferred from the viewpoint of maintaining a stable emulsified state.

[0029] These surfactants may be used alone or in combination of two or more.

[0030] In the oil-in-water emulsion composition of the present invention, the content of the surfactant (other than polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether acid or a salt thereof) may be appropriately set depending on the type of surfactant, the form of emulsification, etc., and may be, for example, 0.5 to 10 mass %, preferably 1 to 9 mass %, and more preferably 2 to 8 mass %.

[0031] (D) Poorly water-soluble drugs The oil-in-water emulsion composition of the present invention preferably contains a poorly water-soluble drug as an active ingredient. Whether a drug is poorly water-soluble can be determined, for example, by the partition coefficient (n-octanol / water). The partition coefficient is expressed as the ratio of the drug concentration soluble in n-octanol to the drug concentration soluble in water. In this specification, a drug with a partition coefficient greater than 1 is considered to be poorly water-soluble.

[0032] The poorly water-soluble drug used in the oil-in-water emulsion composition of the present invention is not limited as long as it can be used as a topical composition. Examples include diphenhydramine, prednisolone valerate acetate, dexamethasone, prednisone valerate acetate, hydrocortisone butyrate, prednisolone butyrate, prednisolone, hydrocortisone acetate, hydrocortisone, cortisone acetate, ibuprofen piconol, salicylic acid, methyl salicylate, bufexamac, crotamiton, ethyl aminobenzoate, lidocaine, dibucaine, undecylenic acid, homosulfamine, isopropylmethylphenol, methylparaben, and butylparaben. Among these, diphenhydramine is preferably included as a poorly water-soluble drug. Diphenhydramine may be an acid addition salt such as hydrochloride, citrate, succinate, or tartrate. These poorly water-soluble drugs may be used alone or in combination of two or more. The oil-in-water emulsion composition of the present invention may contain a water-soluble drug in addition to a poorly water-soluble drug.

[0033] In the oil-in-water emulsion composition of the present invention, the content of the poorly water-soluble drug is preferably 0.1 to 3.0 mass %, more preferably 0.2 to 2.0 mass %, and particularly preferably 0.5 to 1.5 mass %.

[0034] (E) Other materials The oil-in-water emulsion composition of the present invention contains an oily base that constitutes an oil phase. The oily base is not limited as long as it is pharmaceutically acceptable, and examples thereof include higher alcohols, mineral oils, ester oils, vegetable oils, animal oils, cholesterol, fatty acids, silicone oils, and medium-chain fatty acid triglycerides.

[0035] Examples of higher alcohols used in the oil-in-water emulsion composition of the present invention include alcohols having 6 or more carbon atoms. Higher alcohols having 6 to 34 carbon atoms are preferred, and higher alcohols having 14 to 22 carbon atoms are more preferred. Specific examples of higher alcohols include lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, cetostearyl alcohol, oleyl alcohol, and batyl alcohol. Mixtures of polyoxyethylene arachidyl ether and higher alcohols, such as a polyoxyethylene arachidyl ether-stearyl alcohol mixture, can also be suitably used.

[0036] Examples of mineral oils that can be used in the oil-in-water emulsion composition of the present invention include paraffin, hydrogenated polyisobutene, liquid paraffin, gelled hydrocarbons (such as Plastibase), ceresin, microcrystalline wax, and petrolatum.

[0037] Examples of the ester oils that can be used in the oil-in-water emulsion composition of the present invention include isopropyl myristate, octyldodecyl myristate, octyldodecyl oleate, dipentaerythritol fatty acid esters, isopropyl adipate, isobutyl adipate, isopropyl sebacate, cetyl ethylhexanoate, palmityl ethylhexanoate, myristyl myristate, isopropyl palmitate, cetyl palmitate, ethyl oleate, batyl stearate, hexyldecyl isostearate, isopropyl linoleate, cetyl octanoate, stearic acid Butyl, ethyl laurate, hexyl laurate, cetyl oleate, decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, lactated lanolin, isocetyl stearate, isocetyl isostearate, dipentaerythritol fatty acid ester, N-alkyl glycol monostearate, alkyl benzoate, castor oil fatty acid methyl ester, oleyl oleate, monoester oil of monovalent or higher alcohol and monovalent carboxylic acid such as 2-hexyldecyl palmitate, propylene glycol dicaprylate, dioctanoic acid Neopentyl glycol, neopentyl glycol dicaprate, dipeptylundecanoate glycerin, di(caprylic / capric) butylene glycol and other diester oils of two molecules of monovalent carboxylic acids with dihydric or higher alcohols, triethylhexanoin (glyceryl triethylhexanoate), diglyceryl triisostearate, caprylic / capric triglyceride, glyceryl triisopalmitate, glyceryl triisooctanoate, glyceryl trimyristate, glyceryl triisooctanoate, trimethylol triethylhexanoate propane, triesters of trivalent or higher alcohols such as glyceryl triisostearate, glyceryl trimyristate, and tri-2-heptylundecanoic acid glyceride with three molecules of monocarboxylic acid, tetraesters of tetravalent or higher alcohols such as pentaerythrityl tetraethylhexanoate and pentaerythrityl tetraoctanoate with four molecules of monocarboxylic acid, diethyl sebacate, diisopropyl sebacate, di-2-ethylhexyl sebacate, diisostearyl malate, diethylhexyl naphthalene dicarboxylate, and di-2-hexyldecyl adipate,Examples include diesters of two molecules of a monohydric alcohol with a dicarboxylic acid, such as di-2-heptylundecyl adipate and di-2-ethylhexyl succinate, and fatty acid cholesteryls, such as aliphatic cholesteryl lanolate, cholesteryl hydroxystearate, and cholesteryl macadamiate.

[0038] Examples of vegetable oils that can be used in the oil-in-water emulsion composition of the present invention include olive oil, wheat germ oil, rice bran oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sesame oil, castor oil, sunflower oil, cottonseed oil, peanut oil, jojoba oil, hardened oil, avocado oil, fennel oil, clove oil, peppermint oil, eucalyptus oil, lemon oil, orange oil, carnauba wax, candelilla wax, rice bran wax, Japan wax, and rice wax.

[0039] Examples of animal oils that can be used in the oil-in-water emulsion composition of the present invention include lard, fish oil, squalane, and beeswax.

[0040] Examples of fatty acids used in the oil-in-water emulsion composition of the present invention include fatty acids having 6 or more carbon atoms. Fatty acids having 6 to 34 carbon atoms are preferred, and fatty acids having 14 to 22 carbon atoms are more preferred. Examples of fatty acids include capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, and arachidonic acid.

[0041] Examples of silicone oils that can be used in the oil-in-water emulsion composition of the present invention include methylpolysiloxane, dimethylpolysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, acrylic silicone, and phenyl-modified silicone.

[0042] The medium-chain triglyceride used in the oil-in-water emulsion composition of the present invention is generally called MCT (Medium Chain Triglyceride), and is a triglyceride composed mainly of saturated fatty acids having 8 to 12 carbon atoms. Examples of saturated fatty acids having 8 to 12 carbon atoms include n-octanoic acid, n-nonanoic acid, n-decanoic acid, and dodecanoic acid.

[0043] The oil-in-water emulsion composition of the present invention contains water as a base component of the aqueous phase, preferably in an amount of 50 to 95% by mass, more preferably 60 to 90% by mass, and particularly preferably 70 to 90% by mass.

[0044] In the oil-in-water emulsion composition of the present invention, the total content of the oily base material is preferably 0.1 to 5.0 mass %, more preferably 0.5 to 3.0 mass %, and particularly preferably 1.0 to 2.0 mass %.

[0045] In addition to the oily base material, the oil-in-water emulsion composition of the present invention may contain, if necessary, other commonly used additives, such as polyhydric alcohols, thickeners, pH adjusters, buffers, solubilizers, chelating agents, preservatives, antioxidants, stabilizers, light intensity, and colorants.

[0046] (Oil-in-water emulsion composition) The oil-in-water emulsion composition of the present invention has an excellent effect of inhibiting separation of the oil phase and the aqueous phase, and therefore can effectively exhibit excellent dispersion stability of oil droplet particles and can prevent the occurrence of phase separation and aggregates.

[0047] In the oil-in-water emulsion composition of the present invention, the mass ratio of the oil phase component to the surfactant component containing (B) polyoxyethylene hydrogenated castor oil and (C) polyoxyethylene alkyl ether acid or a salt thereof is preferably 1:1 to 2.5:1. Here, the oil phase component contains an oily base, (A) ufenamate, and (D) a poorly water-soluble drug. By setting the mass ratio of the oil phase component to the surfactant component within the above range, the average particle size of the oil droplet particles can be reduced and dispersion stability can be improved.

[0048] In the oil-in-water emulsion composition of the present invention, the mass ratio of (B) polyoxyethylene hydrogenated castor oil to (C) polyoxyethylene alkyl ether acid or a salt thereof is preferably 1: 1 to 10: 1. By setting the mass ratio of (B) polyoxyethylene hydrogenated castor oil to (C) polyoxyethylene alkyl ether acid or a salt thereof within the above range, the diameter of the oil droplet particles can be reduced and dispersion stability can be improved.

[0049] Furthermore, in the oil-in-water emulsion composition of the present invention, the mass ratio of (A) ufenamate to (D) the poorly water-soluble drug is 1: 1 to 5: 1. By setting the mass ratio of (A) ufenamate to (D) the poorly water-soluble drug within this range, the average particle size of the oil droplet particles can be reduced, and dispersion stability can be improved.

[0050] Furthermore, the oil-in-water emulsion composition of the present invention is not particularly limited, and examples thereof include emulsions (other than microemulsions and nanoemulsions), microemulsions, nanoemulsions, etc. From the viewpoint of more effectively exhibiting the effects of the present invention, emulsions or microemulsions are preferred, and emulsions are more preferred.

[0051] Furthermore, the oil-in-water emulsion composition of the present invention is not particularly limited, but has an average particle size of 120 nm or less. The improved dispersion stability of the oil droplets results in improved storage stability. Furthermore, since the oil-in-water emulsion composition of the present invention has a small average particle size of the oil droplets, the migration rate of the poorly water-soluble drug (D) from the oil droplets to the aqueous phase is higher than in compositions with larger oil droplets, thereby improving the permeation of the poorly water-soluble drug (D) into the skin. From the perspective of more effectively improving the migration rate of the drug, the average particle size of the oil droplets is preferably 100 nm or less, more preferably 95 nm or less, even more preferably 92 nm or less, and particularly preferably 90 nm or less.

[0052] Furthermore, the oil-in-water emulsion composition of the present invention has an average particle size of 1 to 120 nm, although this is not particularly limited. From the viewpoint of more effectively improving the migration rate of the drug, the average particle size of the oil droplet particles is preferably 1 to 100 nm, more preferably 5 to 95 nm or less, even more preferably 10 to 92 nm, and particularly preferably 10 to 90 nm.

[0053] Furthermore, the oil-in-water emulsion composition of the present invention has a turbidity of 0.5 or less, although this is not particularly limited. From the viewpoint of making the appearance of the product clear, the turbidity is preferably 0.45 or less, more preferably 0.4 or less, even more preferably 0.35 or less, and particularly preferably 0.3 or less.

[0054] (Uses of oil-in-water emulsion composition) The oil-in-water emulsion composition of the present invention can be used as an external preparation for transdermal application. The oil-in-water emulsion composition of the present invention can be used as an external preparation such as an external quasi-drug, an external medicine, or a cosmetic. Since the oil-in-water emulsion composition of the present invention contains ufenamate, it can be used for antipruritic purposes, and when it contains diphenhydramine as a poorly water-soluble drug, it is more preferably used for antipruritic purposes.

[0055] (Method of producing oil-in-water emulsion composition) The oil-in-water emulsion composition of the present invention can be produced by a known method for producing an emulsion formulation. For example, the method for producing the oil-in-water emulsion composition of the present invention involves appropriately heating and mixing oil phase components such as (A) ufenamate, (B) polyoxyethylene hydrogenated castor oil, (C) polyoxyethylene alkyl ether acid or its salt, (D) a poorly water-soluble drug, and an oily base to prepare an oil phase composition. Separately, purified water and other water-soluble components added as needed are appropriately heated and mixed to prepare an aqueous phase composition. The obtained aqueous phase composition and oil phase composition are then mixed and emulsified using an emulsification method such as a homogenizer, thereby producing the oil-in-water emulsion composition of the present invention.

[0056] (Product form of oil-in-water emulsion composition) The product form of the oil-in-water emulsion composition of the present invention is not particularly limited, and examples thereof include creams, ointments, emulsions, gels, oils, lotions, liniments, aerosols, etc. Among these, creams, ointments, emulsions, and lotions are preferred, creams, emulsions, and lotions are more preferred, creams and emulsions are even more preferred, and creams are particularly preferred. [Example]

[0057] The present invention will be specifically described below with reference to examples, although the present invention is not limited to the examples shown below.

[0058] (Materials used) Ufenamart: "Ufenamart", Okami Chemical Industry Co., Ltd. Diphenhydramine: "Diphenhydramine," Kongo Chemical Co., Ltd. Polyoxyethylene arachidyl ether / stearyl alcohol mixture: "NIKKOL® WAX-230", Nikko Chemicals Co., Ltd. Squalane: "Squalane", Nikko Chemicals Co., Ltd. Medium-chain fatty acid triglyceride: "NIKKOL (registered trademark) Triester F-810", Nikko Chemicals Co., Ltd. Polyoxyethylene hydrogenated castor oil: "NIKKOL(R) HCO-20", Nikko Chemicals Co., Ltd. Polyoxyethylene cetyl ether sodium phosphate: "NIKKOL(R) TCP-5", Nikko Chemicals Co., Ltd. 1,3-Butylene Glycol: "1,3-Butylene Glycol", Daicel Corporation

[0059] (Preparation of oil-in-water emulsion composition) The oil phase components and surfactants shown in Table 1 were weighed out in predetermined amounts, heated to 80°C, and mixed to prepare an oil phase composition. Separately, the water phase components in Table 1 were weighed out in predetermined amounts and mixed to prepare an aqueous phase composition. The prepared aqueous phase composition was heated to 80°C, and then the oil phase composition at 80°C was added in small amounts while mixing to carry out emulsification. The mixture was then cooled to 30°C to obtain the oil-in-water emulsion compositions of Examples 1 and 2 and Comparative Examples 1 to 6. The numerical values ​​indicating the content of each component in the table are in mass%.

[0060] (Test Method) <Turbidity> The prepared oil-in-water emulsion composition was diluted 10 times (by mass) with purified water to prepare a sample, which was then filled into a quartz glass tube (optical path length: 1 mm) and the absorbance at 660 nm was measured using a visible-ultraviolet spectrophotometer (Ubest-3.5, manufactured by JASCO Corporation). The turbidity was determined according to the following criteria. Judgment criteria 0.5 or less 〇 0.5~1.0 △ 1.0 or higher ×

[0061] <Average particle size of oil droplets> The prepared oil-in-water emulsion composition was diluted 10 times (by mass) with purified water to prepare a sample, which was then packed into a quartz glass tube (optical path length: 1 mm), and the cumulant mean particle size was measured using a particle size measuring device based on dynamic light scattering (ELSZ-1000, manufactured by Otsuka Electronics Co., Ltd.). The mean particle size of the oil droplets was determined according to the following criteria. Judgment criteria 100nm or less 〇 100~200nm △ 200~500nm × 500nm or more ××

[0062] <Dispersion stability> The prepared oil-in-water emulsion compositions were filled into glass bottles and left to stand at room temperature for one week, after which the appearance was observed. Dispersion stability was evaluated according to the following criteria. Judgment criteria No change 〇 Two-phase separation and coagulation generation ×

[0063] Table 1 shows the components and evaluation results of the examples and comparative examples. [Table 1]

[0064] The results in Table 1 confirm that the oil-in-water emulsion composition containing (A) ufenamate, (B) polyoxyethylene hydrogenated castor oil, and (C) polyoxyethylene alkyl ether acid or its salt has a small average particle size of oil droplets of 100 nm or less and excellent dispersion stability.

[0065] Furthermore, oil-in-water emulsion compositions containing (A) ufenamate, (B) polyoxyethylene hydrogenated castor oil, and (C) polyoxyethylene alkyl ether acid or a salt thereof were prepared as shown in Tables 2 and 3. In the formulations described in Formulation Examples 1 to 11, the average particle size of the oil droplets was small, at 100 nm or less, and the dispersion stability was excellent.

[0066] [Table 2]

[0067] [Table 3]

Claims

1. (A) Ufenamat and (B) polyoxyethylene hydrogenated castor oil; (C) a polyoxyethylene alkyl ether acid or a salt thereof; An oil-in-water emulsion composition comprising:

2. The oil-in-water emulsion composition according to claim 1, further comprising (D) a poorly water-soluble drug.

3. 3. The oil-in-water emulsion composition according to claim 2, wherein the poorly water-soluble drug (D) is diphenhydramine.

4. 4. The oil-in-water emulsion composition according to claim 1, wherein the mass ratio of the oil phase component to the surfactant component containing (B) polyoxyethylene hydrogenated castor oil and (C) polyoxyethylene alkyl ether acid or a salt thereof is 1:1 to 2.5:

1.

5. 5. The oil-in-water emulsion composition according to claim 1, wherein the mass ratio of (B) polyoxyethylene hydrogenated castor oil to (C) polyoxyethylene alkyl ether acid or a salt thereof is 1:1 to 10:

1.

6. The oil-in-water emulsion composition according to any one of claims 1 to 5, which is used for antipruritic purposes.

7. 3. The oil-in-water emulsion composition according to claim 2, wherein the mass ratio of (A) ufenamate to (D) the poorly water-soluble drug is 1:1 to 5:

1.

8. 8. The oil-in-water emulsion composition according to claim 1, wherein the polyoxyethylene hydrogenated castor oil (B) has an average number of moles of polyoxyethylene added of 10 to 40.

9. 9. The oil-in-water emulsion composition according to any one of claims 1 to 8, wherein the (C) polyoxyethylene alkyl ether acid or a salt thereof is selected from polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl ether acetic acid, polyoxyethylene alkyl ether sulfate, or a salt thereof.

10. 10. The oil-in-water emulsion composition according to claim 1, wherein the oil droplets have an average particle size of 120 nm or less.

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