Oil-based emulsions in water

Abstract

To provide an oil-in-water emulsion composition that shows stable dispersion.SOLUTION: An oil-in-water emulsion composition contains (A) ufenamate, (B) polyoxyethylene hardened 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 Art

[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 various pharmaceutical formulations. Further, the oil-in-water emulsion composition also has an excellent feeling of use on the skin and is widely used in the fields of external pharmaceuticals and cosmetics.

[0003] Ufenamate is used as a non-steroidal anti-inflammatory agent in combination with a skin external preparation of a pharmaceutical or quasi-drug. 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 skin external composition having a high antipruritic effect (see, for example, Patent Documents 1 and 2).

[0004] Further, as a skin external composition for improving skin darkening, an oil-in-water emulsion composition containing ufenamate, glycyrrhetinic acid, and diphenhydramine (see, for example, Patent Document 3), or a gel ointment excellent in the stability of a poorly water-soluble drug and safe without irritation, containing ufenamate, a nonionic surfactant, and an auxiliary agent such as glycyrrhetinic acid has been disclosed (see, for example, Patent Document 4).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

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

[0007] Patent Document 3 discloses a formulation of an oil-in-water emulsion topical composition 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 because the diameter of the oil droplet particles dispersed in the aqueous phase is large.

[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 of poorly water-soluble drugs.

[0009] The present invention aims to provide an oil-in-water emulsion composition with excellent dispersion stability. [Means for solving the problem]

[0010] As a result of diligent research into the above-mentioned problems, the present inventors have discovered that by incorporating ufenamate, which is commonly used as an active ingredient, into a formulation that uses polyoxyethylene hydrogenated castor oil, which has excellent solubilizing power and low skin irritation, and polyoxyethylene alkyl ether acid or a salt thereof, which has high emulsifying power due to electrostatic repulsion, the average particle size of oil droplets can be reduced and dispersion stability can be dramatically improved, thus completing the present invention.

[0011] In other words, 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. Furthermore, the oil-in-water emulsion composition of the present invention contains (D) a poorly water-soluble agent. Furthermore, in the oil-in-water emulsion composition of the present invention, (D) the poorly water-soluble agent is diphenhydramine. Furthermore, 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 and (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) a poorly water-soluble agent is 1:1 to 5:1. Furthermore, in the oil-in-water emulsion composition of the present invention, (B) polyoxyethylene hydrogenated castor oil has an average number of added moles of polyoxyethylene of 10 to 40. Furthermore, in the oil-in-water emulsion composition of the present invention, (C) polyoxyethylene alkyl ether acid or a salt thereof is selected from polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl ether acetic acid, and polyoxyethylene alkyl ether sulfuric acid, or salts thereof. Furthermore, the oil-in-water emulsion composition of the present invention is an emulsion in which the average particle size of the oil droplets 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 droplets, 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. [Modes for carrying out 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 composition 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 modified as appropriate without departing from the spirit of the present invention.

[0014] (A) Ufenamat 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 is also known as butyl flufenamate and is a well-known component as a poorly water-soluble nonsteroidal anti-inflammatory agent. 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 two surfactant components described later.

[0015] In the oil-in-water emulsion composition of the present invention, the content of ufenamate is appropriately set according to the amount of (B) polyoxyethylene hydrogenated castor oil and (C) polyoxyethylene alkyl ether acid or a salt thereof used, as 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 availability in the market and solubilizing power of the dispersion component, polyoxyethylene hydrogenated castor oil having an average added mole number of polyoxyethylene of 5 to 60 is preferred, and polyoxyethylene hydrogenated castor oil having an average added mole number 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 kinds.

[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% by mass, more preferably 1.0 to 3.0% by mass, and particularly preferably 1.5 to 2.5% by mass from the viewpoint of the dispersion stability of the oil droplet particles.

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

[0019] The oil-in-water emulsion composition of the present invention is not particularly limited as the polyoxyethylene alkyl ether inorganic acid or a salt thereof, and examples thereof include polyoxyethylene alkyl ether phosphoric acid, polyoxyethylene alkyl ether sulfuric acid, polyoxyethylene alkyl ether nitric acid, polyoxyethylene alkyl ether hydrochloric acid, and the like. From the viewpoint of the dispersion stability of the oil droplet particles, polyoxyethylene alkyl ether phosphoric acid, polyoxyethylene alkyl ether sulfuric acid, and polyoxyethylene alkyl ether nitric acid are preferred, polyoxyethylene alkyl ether phosphoric acid and polyoxyethylene alkyl ether sulfuric acid are more preferred, and polyoxyethylene alkyl ether phosphoric acid is still more preferred.

[0020] The oil-in-water emulsion composition of the present invention is not particularly limited as a polyoxyethylene alkyl ether organic acid or a salt thereof, but examples include polyoxyethylene alkyl ether acetic acid and polyoxyethylene alkyl ether formic acid. 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 polyoxyethylene alkyl ether acids to be used include esters of polyoxyethylene alkyl ethers, which are ethers of polyoxyethylene with an average number of added moles of 1 to 30 and an alcohol having 12 to 24 carbon atoms, and an acid. Specifically, polyoxyethylene lauryl ether (average number of added moles of EO: 2 to 25) acid, polyoxyethylene pareth (C12 to C15) 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, polyoxyethylene behenyl ether (average number of added moles of EO: 2 to 20) acid, etc. are preferred. Examples of polyoxyethylene alkyl ether salts include the sodium and potassium salts of the polyoxyethylene alkyl ether acids mentioned above. Preferred polyoxyethylene alkyl ether salts include, for example, sodium polyoxyethylene lauryl ether (average number of moles of EO added: 10), polyoxyethylene pareth (C12-15) ether (average number of moles of EO added: 2-8), sodium polyoxyethylene cetyl ether (average number of moles of EO added: 5), and sodium polyoxyethylene oleyl ether (average number of moles of EO added: 8).

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

[0023] Surfactants (other than polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether acid, or their salts) The oil-in-water emulsion composition of the present invention may contain surfactants other than polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether acid or its salts in order to stably form an emulsion state. The surfactant (other than polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether acid or its salts) is not particularly limited to the extent that 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 salts), cationic surfactants, or amphoteric surfactants may be used.

[0024] Nonionic surfactants (polyoxyethylene hydrogenated castor oil) include, specifically, polyoxyethylene (10-50 mol) phytosterol ether, polyoxyethylene (10-50 mol) dihydrocholesterol ether, polyoxyethylene (10-50 mol) 2-octyldodecyl ether, polyoxyethylene (10-50 mol) decyltetradecyl ether, polyoxyethylene (10-50 mol) oleyl ether, polyoxyethylene (2-50 mol) cetyl ether, polyoxyethylene (5-50 mol) behenyl ether, polyoxyethylene (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, polyoxyethylene (20-60 mol) sorbitan monooleate, and polyoxyethylene (10-60 mol) sorbitan monooleate. Examples include rubitan 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 (such as glyceryl monostearate). These nonionic surfactants (other than polyoxyethylene hydrogenated castor oil) may be used individually or in combination of two or more.

[0025] Examples of anionic surfactants include sodium polyoxyethylene lauryl ether sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium N-lauroyl sarcosinate, sodium N-myristoyl sarcosinate, sodium dodecylbenzenesulfonate, hydrogenated coconut fatty acid monoglyceride monosulfate, sodium lauryl sulfoacetate, sodium α-olefin sulfonate, sodium N-palmitoyl glutarmate, and sodium N-methyl-N-acyl taurate. These anionic surfactants may be used individually or in combination of two or more.

[0026] Examples of cationic surfactants include lauryltrimethylammonium chloride, stearyltrimethylammonium chloride, benzethonium chloride, benzalkonium chloride, and stearyldimethylbenzylammonium chloride. These cationic surfactants may be used individually or in combination of two or more.

[0027] Examples of amphoteric surfactants include coconut oil fatty acid amidopropyl betaine, lauryldimethylaminoacetic acid betaine, lauryldimethylamine oxide, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolium betaine, N-lauryldiaminoethylglycine, N-myristyldiaminoethylglycine, and sodium N-alkyl-1-hydroxyethylimidazoline betaine. These amphoteric surfactants may be used individually or in combination of two or more.

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

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

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

[0031] (D) Water-soluble drugs The oil-in-water emulsion composition of the present invention preferably contains a poorly water-soluble agent as an active ingredient. Whether or not an agent is poorly water-soluble can be determined, for example, by its partition coefficient (n-octanol / water). The partition coefficient is expressed as the ratio of the concentration of the drug that dissolves in n-octanol to the concentration of the drug that dissolves in water. In this specification, agents with a partition coefficient greater than 1 are defined as poorly water-soluble agents.

[0032] The water-insoluble agents used in the oil-in-water emulsion composition of the present invention are not limited to those that can be used as topical compositions, and examples include diphenhydramine, prednisolone acetate valerate, dexamethasone, prednisone acetate valerate, 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, it is preferable to include diphenhydramine as the water-insoluble agent. Diphenhydramine may also be an acid addition salt such as hydrochloride, citrate, succinate, or tartrate. These water-insoluble agents may be used individually or in combination of two or more. Furthermore, the oil-in-water emulsion composition of the present invention may contain a water-soluble agent in addition to a water-poorly soluble agent.

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

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

[0035] Examples of higher alcohols used in the oil-in-water emulsion composition of the present invention include alcohols with 6 or more carbon atoms. Higher alcohols with 6 to 34 carbon atoms are preferred, and higher alcohols with 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 polyoxyethylene arachidyl ether / stearyl alcohol mixtures, can also be suitably used.

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

[0037] The ester oils used in the oil-in-water emulsion composition of the present invention include isopropyl myristate, octyldodecyl myristate, octyldodecyl oleate, dipentaerythritol fatty acid ester, 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, and stearic acid. Butyl butyl, ethyl laurate, hexyl laurate, cetyl oleate, decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, lanolin lactate, 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 monohydric or higher alcohols and monohydric carboxylic acids such as 2-hexyldecyl palmitate, propylene glycol dicaprylate, dioctanoic acid Neopentyl glycol, neopentyl glycol dicaprate, glycerin dipeptyl undecanoate, diester oil of dihydric or higher alcohols such as di(caprylic / capric acid)butylene glycol and two molecules of monohydric carboxylic acid, triethylhexanoin (glyceryl triethylhexanoate), diglyceryl triisostearate, tri(caprylic / capric acid)glyceryl, glyceryl triisopalmitate, glyceryl triisooctanoate, glyceryl trimiristicate, glyceryl triisooctanoate, trimethylol triethylhexanoate Tryesters of trivalent or higher alcohols such as propane, glyceryl triisostearate, glyceryl trimyristate, and glyceride tri-2-heptylundecanoate with three molecules of monovalent carboxylic acid; tetraesters of tetravalent or higher alcohols such as pentaerythrityl tetraethylhexanoate and pentaerythrityl tetraoctanoate with four molecules of monovalent carboxylic acid; diethyl sebacate, diisopropyl sebacate, di-2-ethylhexyl sebacate, diisostearyl malate, diethylhexyl naphthalene dicarboxylate, di-2-hexyldecyl adipate,Examples include diesters of two monohydric alcohols (such as di-2-heptyl undecyl adipic acid and di-2-ethylhexyl succinate) with a dihydric carboxylic acid, fatty acid cholesteryls (such as aliphatic cholesteryl lanolinate, cholesteryl hydroxystearate, and macadamia nut fatty acid cholesteryl) and others.

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

[0039] Examples of animal oils 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 with 6 or more carbon atoms. Fatty acids with 6 to 34 carbon atoms are preferred, and fatty acids with 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 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 fatty acid triglycerides used in the oil-in-water emulsion composition of the present invention are generally called MCTs (Medium Chain Triglycerides) and are triglycerides mainly composed 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 the base component of the aqueous phase. The water content is preferably 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% by mass, more preferably 0.5 to 3.0% by mass, and particularly preferably 1.0 to 2.0% by mass.

[0045] In addition to the oily base material described above, the oil-in-water emulsion composition of the present invention may optionally contain other commonly used additives. Examples of additives include polyhydric alcohols, thickeners, pH adjusters, buffers, solubilizers, chelating agents, preservatives, antioxidants, stabilizers, light enhancers, and colorants.

[0046] (Oil-in-water emulsion composition) The oil-in-water emulsion composition of the present invention exhibits excellent inhibitory effects on the separation of the oil phase and the aqueous phase, thereby effectively demonstrating superior dispersion stability of oil droplet particles and preventing phase separation and the formation of 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 includes an oily base material, (A) ufenamate, and (D) a poorly water-soluble agent. 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 droplets can be reduced, and the 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 droplets can be reduced and the dispersion stability can be improved.

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

[0050] Furthermore, the oil-in-water emulsion composition of the present invention is not particularly limited, but examples include emulsions (other than microemulsions and nanoemulsions), microemulsions, nanoemulsions, etc. From the viewpoint of more effectively achieving the effects of the present invention, it is preferably an emulsion or a microemulsion, and more preferably an emulsion.

[0051] Furthermore, the oil-in-water emulsion composition of the present invention is not particularly limited, but the average particle size of the oil droplets is 120 nm or less. This improves the dispersion stability of the oil droplets, thus improving storage stability. In addition, because the average particle size of the oil droplets in the oil-in-water emulsion composition of the present invention is small, the transfer rate of (D) poorly water-soluble drugs from the oil droplets to the aqueous phase is greater than that of compositions with larger oil droplets, and the permeability of (D) poorly water-soluble drugs to the skin can be improved. From the viewpoint of more effectively improving the transfer rate of drugs, 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 is not particularly limited, but the average particle size of the oil droplets is 1 to 120 nm. From the viewpoint of more effectively improving the transfer rate of the drug, the average particle size of the oil droplets 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 is not particularly limited, but has a turbidity of 0.5 or less. 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 compositions) The oil-in-water emulsion composition of the present invention can be used as a topical preparation applied transdermally. The oil-in-water emulsion composition of the present invention can be used as a topical preparation such as a quasi-drug, a topical drug, or a cosmetic. Since the oil-in-water emulsion composition of the present invention contains ufenamate, it can be used for antipruritic purposes, and if it contains diphenhydramine as a poorly water-soluble agent, its use for antipruritic purposes is even more preferable.

[0055] (Method for producing oil-in-water emulsion composition) The oil-in-water emulsion composition of the present invention can be produced by known methods for producing emulsifying formulations. For example, to produce the oil-in-water emulsion composition of the present invention, an oil phase composition is prepared by 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 agent, and an oily base material. Separately, an aqueous phase composition is prepared by appropriately heating and mixing purified water and other water-soluble components as needed. The obtained aqueous phase composition and the oil phase composition are then mixed and emulsified using an emulsification method such as a homogenizer to produce 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, but examples include creams, ointments, emulsions, gels, oils, lotions, liniments, aerosols, etc. Among these, creams, ointments, emulsions, and lotions are preferred, more preferably creams, emulsions, and lotions, even more preferably creams and emulsions, and particularly preferably creams. [Examples]

[0057] The present invention will be described in detail below with reference to examples. However, 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(registered trademark) WAX-230", Nikko Chemicals Co., Ltd. Squalane: "Squalane", Nikko Chemicals Co., Ltd. Medium-chain triglyceride: "NIKKOL® Triester F-810", Nikko Chemicals Co., Ltd. Polyoxyethylene hydrogenated castor oil: "NIKKOL(registered trademark) HCO-20", Nikko Chemicals Co., Ltd. Sodium polyoxyethylene cetyl ether phosphate: "NIKKOL(registered trademark) 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 measured in predetermined amounts, heated to 80°C, and mixed to prepare the oil phase composition. Separately, the aqueous phase components from Table 1 were measured in predetermined amounts and mixed to prepare the aqueous phase composition. After heating the prepared aqueous phase composition to 80°C, the oil phase composition at 80°C was added little by little while mixing to perform emulsification. After that, it was cooled to 30°C to obtain the oil-in-water emulsion compositions of Examples 1 and 2 and Comparative Examples 1 to 6. The units of the numerical values ​​showing the content of each component in the table are in mass percent.

[0060] (Test method) <Turbidity> The prepared oil-in-water emulsion composition was diluted 10 times (by mass) with purified water, and the resulting sample was packed into a quartz glass container (optical path length: 1 mm). The absorbance at 660 nm was measured using a visible-ultraviolet spectrophotometer (Ubest-3.5, manufactured by JASCO Corporation). Turbidity was determined according to the following criteria. Judgment criteria 0.5 or less ○ 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, and the resulting sample was packed into quartz glass (optical path length: 1 mm). The average cumulant particle size was measured using a particle size analyzer based on dynamic light scattering (ELSZ-1000, manufactured by Otsuka Electronics Co., Ltd.). The average 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 composition was filled into glass bottles and left to stand at room temperature for one week, after which its appearance was observed. Dispersion stability was determined according to the following criteria. Judgment criteria No change ○ Two-phase separation, aggregate formation ×

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

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

[0065] Furthermore, as shown in Tables 2 and 3, 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. The formulations described in Formulation Examples 1 to 11 had a small average particle size of 100 nm or less for the oil droplets and exhibited excellent dispersion stability.

[0066] [Table 2]

[0067] [Table 3]

Claims

1. (A) Ufenamat and, (B) Polyoxyethylene hydrogenated castor oil and (C) Polyoxyethylene alkyl ether acid or a salt thereof, Includes, An oil-in-water emulsion composition in which the average particle size of oil droplets is 120 nm or less.

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

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

4. The oil-in-water emulsion composition according to any one of claims 1 to 3, 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. The oil-in-water emulsion composition according to any one of claims 1 to 4, wherein the mass ratio of (B) polyoxyethylene hydrogenated castor oil and (C) polyoxyethylene alkyl ether acid or a salt thereof is 1:1 to 10:

1.

6. An oil-in-water emulsion composition according to any one of claims 1 to 5, for use as an antipruritic.

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

1.

8. (B) The oil-in-water emulsion composition according to any one of claims 1 to 7, wherein the polyoxyethylene hydrogenated castor oil has an average number of added moles of polyoxyethylene of 10 to 40.

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

Images