Pharmaceutical composition

Abstract

To provide a pharmaceutical preparation technique which suppresses yellowing due to light exposure and achieves excellent pharmaceutical preparation stability in a pharmaceutical composition containing ethyl aminobenzoate and quaternary ammonium salt.SOLUTION: A pharmaceutical composition, which is produced by blending one or more selected from polyhydric alcohol, monoterpene, polyvinyl pyrrolidone, and hydroxyethyl cellulose together with ethyl aminobenzoate and quaternary ammonium salt, suppresses yellowing due to light exposure and achieves excellent pharmaceutical preparation stability.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition which contains ethyl aminobenzoate and a quaternary ammonium salt, yet is inhibited from yellowing due to exposure to light and has excellent formulation stability. [Background technology]

[0002] Ethyl aminobenzoate is known as a local anesthetic and is widely used to relieve local itching and pain in mucous membranes and skin, and various formulations of pharmaceutical compositions containing ethyl aminobenzoate have been investigated. For example, Patent Document 1 reports that a local anesthetic composition containing a basic local anesthetic such as ethyl aminobenzoate and its hydrochloride can provide both rapid and sustained local anesthetic action.

[0003] In addition, quaternary ammonium salts such as cetylpyridinium chloride and benzalkonium chloride are known as disinfectants and are widely used in various pharmaceuticals, and various formulations of pharmaceutical compositions containing quaternary ammonium salts have been investigated. For example, Patent Document 2 reports that an external pharmaceutical composition containing 0.05-2% by weight of a quaternary ammonium salt, 0.1-4% by weight of chlorpheniramine maleate, and 0.01-10% by weight of a chloride ion source can realize a stable preparation in which crystal formation is suppressed.

[0004] In recent years, pharmaceutical compositions are required to be multifunctional, and formulations using local anesthetics and bactericides in combination have been developed. However, in order to put pharmaceutical compositions into practical use, it is necessary to take into consideration not only functionality but also formulation stability. However, in the prior art, the formulation stability of pharmaceutical compositions containing ethyl aminobenzoate and quaternary ammonium salts has not been fully examined. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 8-259464 [Patent Document 2] JP 2010-159251 A Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have conducted research aimed at commercializing a pharmaceutical composition containing ethyl aminobenzoate and a quaternary ammonium salt, and have encountered new problems with the topical composition, such as discoloration (yellowing) to yellow upon exposure to light, failure to maintain good appearance properties, and poor formulation stability.

[0007] Therefore, an object of the present invention is to provide a formulation technology that can suppress yellowing caused by exposure to light in a pharmaceutical composition containing ethyl aminobenzoate and a quaternary ammonium salt, and provide excellent formulation stability. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems and have found that a pharmaceutical composition containing ethyl aminobenzoate and a quaternary ammonium salt in combination with one or more of polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethylcellulose is inhibited from yellowing due to exposure to light and has excellent formulation stability. The present invention was completed based on this finding and through further research.

[0009] That is, the present invention provides the following aspects. Item 1. A pharmaceutical composition comprising (A) ethyl aminobenzoate, (B) a quaternary ammonium salt, and (C) at least one member selected from the group consisting of a polyhydric alcohol, a monoterpene, polyvinylpyrrolidone, and hydroxyethylcellulose. Item 2. The pharmaceutical composition according to Item 1, wherein the component (B) is cetylpyridinium chloride. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the polyhydric alcohol is propylene glycol and / or glycerin. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, wherein the monoterpene is menthol. Item 5. The pharmaceutical composition according to any one of Items 1 to 4, comprising a polyhydric alcohol and polyvinylpyrrolidone as the component (C). Item 6. The pharmaceutical composition according to any one of Items 1 to 5, which is an external medicine or a medicine for mucosal application. Item 7. A method for inhibiting yellowing caused by exposure to light of a pharmaceutical composition containing ethyl aminobenzoate and a quaternary ammonium salt, comprising: The pharmaceutical composition is formulated with (A) ethyl aminobenzoate and (B) a quaternary ammonium salt, and (C) at least one selected from the group consisting of polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethylcellulose. A method for inhibiting yellowing caused by exposure of the pharmaceutical composition to light. Effect of the Invention

[0010] According to the pharmaceutical composition of the present invention, even in the presence of ethyl aminobenzoate and a quaternary ammonium salt, yellowing caused by exposure to light can be suppressed, and excellent formulation stability can be achieved. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] 1. Pharmaceutical Compositions The pharmaceutical composition of the present invention is characterized by containing ethyl aminobenzoate (sometimes referred to as component (A)), a quaternary ammonium salt (sometimes referred to as component (B)), and at least one member selected from the group consisting of polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethyl cellulose (sometimes referred to as component (C)). The pharmaceutical composition of the present invention will be described in detail below.

[0012] (A) Ethyl aminobenzoate Ethyl aminobenzoate, also known as ethyl 4-aminobenzoate, benzocaine, etc., is a known local anesthetic.

[0013] In the pharmaceutical composition of the present invention, the content of component (A) is not particularly limited and may be appropriately set depending on the level of local anesthetic effect to be imparted to the pharmaceutical composition, the formulation form and application of the pharmaceutical composition, etc., and may be, for example, 0.1 to 5% by weight, preferably 0.3 to 2% by weight, and more preferably 0.3 to 1% by weight.

[0014] (B) Quaternary ammonium salts The quaternary ammonium salt used in the present invention may be any salt that has a bactericidal effect and is pharma- ceutically acceptable, and the type is not particularly limited. Examples of the salt include cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, dequalinium chloride, alkyldimethylammonium chloride, alkyltrimethylammonium chloride, methylbenzethonium chloride, lauroylcholaminoformylmethylpyridinium chloride, and the like.

[0015] These quaternary ammonium salts may be used alone or in combination of two or more.

[0016] Among these quaternary ammonium salts, from the viewpoint of more effectively suppressing yellowing due to exposure to light, preferred are cetylpyridinium chloride, benzalkonium chloride, and benzethonium chloride, and more preferred are cetylpyridinium chloride.

[0017] In the pharmaceutical composition of the present invention, the content of component (B) is not particularly limited and may be appropriately set depending on the degree of bactericidal action to be imparted to the pharmaceutical composition, the formulation form and use of the pharmaceutical composition, etc., and may be, for example, 0.05 to 1 wt %, preferably 0.1 to 0.5 wt %, and more preferably 0.3 to 0.5 wt %.

[0018] In the pharmaceutical composition of the present invention, the ratio of component (B) to component (A) is determined depending on the respective contents of component (A) and component (B). For example, the ratio of component (B) per 100 parts by weight of component (A) is 10 to 300 parts by weight, preferably 50 to 200 parts by weight, and more preferably 50 to 150 parts by weight.

[0019] (C) polyhydric alcohol, monoterpene, polyvinylpyrrolidone, and / or hydroxyethyl cellulose The pharmaceutical composition of the present invention contains a polyhydric alcohol, a monoterpene, a polyvinylpyrrolidone, and / or a hydroxyethyl cellulose as component (C). By including the component (C), it is possible to suppress yellowing that occurs when ethyl aminobenzoate and a quaternary ammonium salt coexist and are exposed to light.

[0020] The type of polyhydric alcohol used as component (C) is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include dihydric alcohols such as 1,3-butylene glycol, ethylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, polyethylene glycol, etc.; trihydric alcohols such as glycerin, etc. These polyhydric alcohols may be used alone or in combination of two or more.

[0021] Among these polyhydric alcohols, from the viewpoint of more effectively suppressing yellowing due to exposure to light, propylene glycol and glycerin are preferred.

[0022] The monoterpene used as component (C) is a known component having a structure containing two isoprene units in the molecule and having a cooling effect. The type of monoterpene used as component (C) is not particularly limited as long as it is pharmacologic acceptable, and examples thereof include alcohol monoterpenes such as menthol, thymol, geraniol, linalool, borneol, cineole, and terpineol; aldehyde monoterpenes such as citral, citronellal, perillaldehyde, and safranal; and ketone monoterpenes such as camphor, menthone, carbomenthone, and ionone. When optical isomers exist, these monoterpenes may be d-, l-, or dl-isomers. These monoterpenes may be used alone or in combination of two or more.

[0023] In addition, in the present invention, the monoterpene may be used in the form of an essential oil containing monoterpene. The essential oil containing monoterpene can be appropriately selected from known ones and used, and for example, essential oil containing menthol includes peppermint oil, peppermint oil, spearmint oil, etc. In addition, the description of the content and ratio of monoterpene in this specification is the value converted into the amount of monoterpene contained in the essential oil when an essential oil containing monoterpene is used.

[0024] Among these monoterpenes, from the viewpoint of more effectively suppressing yellowing due to exposure to light, preferred are alcohol-based monoterpenes, more preferred are menthol, and particularly preferred is 1-menthol.

[0025] The polyvinylpyrrolidone used as component (C) is a water-soluble polymeric compound obtained by polymerization of N-vinyl-2-pyrrolidone. The weight-average molecular weight of the polyvinylpyrrolidone used as component (C) is not particularly limited, but may be, for example, about 5,000 to 3,000,000, more preferably about 40,000 to 3,000,000. Here, the weight-average molecular weight of the polyvinylpyrrolidone refers to a value measured by gel filtration chromatography / multi-angle light scattering photometer (GPC / MALLS). The K value (viscosity characteristic value) of the polyvinylpyrrolidone is not particularly limited, but one having a K value of about 10 to 120 can be preferably used. In the present invention, a commercially available product can be used as the polyvinylpyrrolidone. Specific examples of commercially available polyvinylpyrrolidone products include "Eiftact K-30PH" manufactured by Daiichi Kogyo Seiyaku Co., Ltd., "Polyvinylpyrrolidone K-30," "Polyvinylpyrrolidone K-85," and "Polyvinylpyrrolidone K-90" manufactured by Nippon Shokubai Co., Ltd., and "PVP K-90" manufactured by ISP Japan.

[0026] The hydroxyethyl cellulose used as component (C) is a cellulose derivative in which ethylene oxide has been added to cellulose to improve its water solubility. There are no particular limitations on the average number of moles of ethylene oxide added, the average molecular weight, etc. of the hydroxyethyl cellulose used as component (C), and any of those commonly used in the medical field may be used. For example, the viscosity of a 2.0% by weight aqueous solution (20°C) is 500 mPa·s or more, preferably 500 to 50,000 mPa·s. The viscosity is measured using a B-type viscometer "TOKI SANGYO VISCOMETER TVB-10" (Toki Sangyo Co., Ltd.). The viscosity is measured by using a rotor M3 or M4 (rotation speed: 12 to 30 rpm, time: 1 min, unit: mPa·s) in a viscometer manufactured by Sumitomo Seika Chemicals Co., Ltd., depending on the viscosity to be measured. In the present invention, commercially available hydroxyethyl cellulose can be used. Specific examples of commercially available hydroxyethyl cellulose include "HEC CF-V", "HEC CF-W", "HEC CF-X", "HEC CF-Y", "HEC AH-15F", "HEC AV-15F", "HEC AW-15F", and "HEC SW-25F" manufactured by Sumitomo Seika Chemicals Co., Ltd., "HEC Daicel SP500", "HEC Daicel SP600", "HEC Daicel SP850", and "HEC Daicel SP900" manufactured by Daicel FineChem Co., Ltd., and "NATROSOL 250HX" manufactured by Ashland Corporation.

[0027] In the pharmaceutical composition of the present invention, the component (C) may be one selected from polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethyl cellulose, or two or more may be used in combination.

[0028] From the viewpoint of more effectively suppressing yellowing due to exposure to light, the component (C) is preferably a combination of a polyhydric alcohol and polyvinylpyrrolidone, and more preferably a combination of propylene glycol and polyvinylpyrrolidone.

[0029] When a polyhydric alcohol and polyvinylpyrrolidone are used in combination as component (C), there are no particular limitations on the ratio between them. From the viewpoint of more effectively suppressing yellowing due to exposure to light, the ratio of polyvinylpyrrolidone is usually 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight, and more preferably 0.5 to 5 parts by weight per 100 parts by weight of polyhydric alcohol.

[0030] In the pharmaceutical composition of the present invention, the content of the component (C) may be appropriately set depending on the type of the component (C) used, the formulation form or application of the pharmaceutical composition, and the like, and may be, for example, 0.01 to 80% by weight, preferably 0.05 to 70% by weight, and more preferably 0.1 to 65% by weight, of the total amount of the component (C).

[0031] More specifically, the content of each type of component (C) may be in the following range: When using polyhydric alcohol : 1 to 80% by weight, preferably 5 to 60% by weight. When a dihydric alcohol is used as the polyhydric alcohol: more preferably 1 to 60% by weight, particularly preferably 1 to 50% by weight, most preferably 5 to 40% by weight. When a trihydric alcohol is used as the polyhydric alcohol: more preferably 10 to 60% by weight, particularly preferably 30 to 60% by weight, most preferably 30 to 50% by weight. When to use monoterpenes : 0.01 to 3% by weight, preferably 0.05 to 1% by weight, and more preferably 0.1 to 1% by weight. When to use polyvinylpyrrolidone : 0.05 to 3% by weight, preferably 0.1 to 1% by weight, and more preferably 0.5 to 1% by weight. When to Use Hydroxyethyl Cellulose : 0.05 to 3% by weight, preferably 0.1 to 1% by weight, and more preferably 0.5 to 1% by weight.

[0032] In the pharmaceutical composition of the present invention, the ratio of component (C) to component (A) is determined depending on the respective contents of component (A) and component (C), and may be, for example, 10 to 20,000 parts by weight, and preferably 15 to 18,000 parts by weight, of component (C) per 100 parts by weight of component (A).

[0033] More specifically, the ratio of each type of component (C) to 100 parts by weight of component (A) may be in the following ranges: When using polyhydric alcohol : A total amount of 1,500 to 20,000 parts by weight, preferably 3,000 to 18,000 parts by weight. When a dihydric alcohol is used as the polyhydric alcohol: the total amount is more preferably 1,500 to 18,000 parts by weight, particularly preferably 3,000 to 18,000 parts by weight, and most preferably 5,000 to 18,000 parts by weight. When a trihydric alcohol is used as the polyhydric alcohol: the total amount is more preferably 2000 to 18000 parts by weight, particularly preferably 5000 to 18000 parts by weight, and most preferably 8000 to 18000 parts by weight. When to use monoterpenes A total amount of 15 to 500 parts by weight, preferably 15 to 400 parts by weight, and more preferably 15 to 350 parts by weight. When to use polyvinylpyrrolidone A total amount of 10 to 500 parts by weight, preferably 20 to 400 parts by weight, and more preferably 50 to 350 parts by weight. When to Use Hydroxyethyl Cellulose The total amount is 30 to 500 parts by weight, preferably 50 to 500 parts by weight, and more preferably 50 to 400 parts by weight.

[0034] Lower alcohol The pharmaceutical composition of the present invention may contain a lower alcohol, if necessary, for stably dissolving ethyl aminobenzoate.

[0035] The type of lower alcohol used in the present invention is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include lower alcohols having 2 to 6 carbon atoms, such as ethanol, propanol, butanol, pentanol, hexanol, isopropanol, etc. Among these lower alcohols, ethanol is preferable.

[0036] These lower alcohols may be used alone or in combination of two or more.

[0037] When the pharmaceutical composition of the present invention contains a lower alcohol, the content thereof is not particularly limited, and may be, for example, 0.5 to 20% by weight, preferably 1 to 10% by weight, and more preferably 5 to 10% by weight.

[0038] water A preferred embodiment of the pharmaceutical composition of the present invention is that it contains water (i.e., it is an aqueous preparation). In the prior art, when ethyl aminobenzoate and a quaternary ammonium salt are present together in the presence of water, yellowing due to exposure to light tends to occur significantly, but in the present invention, even when water is present, the yellowing can be effectively suppressed.

[0039] When the pharmaceutical composition of the present invention is prepared as an aqueous preparation, the water content is not particularly limited and may be appropriately set depending on the formulation form and application of the pharmaceutical composition, and may be, for example, 1 to 80% by weight, preferably 5 to 60% by weight, and more preferably 10 to 50% by weight.

[0040] Other Ingredients The pharmaceutical composition of the present invention may contain other pharmacological ingredients, if necessary, in addition to the above-mentioned ingredients. Examples of such pharmacological ingredients include antihistamines (diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics other than ethyl aminobenzoate (procaine, tetracaine, bupivacaine, mepipacaine, chloroprocaine, proparacaine, meprylcaine or salts thereof, orthocaine, oxethazaine, oxypolyethyleneoxydecane, Scopolia extract, percaminepase, tesitdesitin, lidocaine, etc.), disinfectants other than quaternary ammonium salts (iodine, povidone-iodine, , potassium iodide, chlorhexidine gluconate, acrinol, etc.), anti-inflammatory agents (dipotassium glycyrrhizinate, glycyrrhetinic acid, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (vanillylamide nonylate, benzyl nicotinate, capsaicin, chili pepper extract, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.). ) etc.

[0041] In addition, the pharmaceutical composition of the present invention may contain base materials and additives other than the above-mentioned components as necessary to obtain a desired formulation. Such base materials and additives are not particularly limited as long as they are pharma- ceutically acceptable, and examples of such base materials and additives include oils (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, cetyl palmitate, ethyl oleate, etc.), oily bases such as 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.), lower alcohols (ethanol, propanol, isopropanol, butanol, isobutanol, 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.);Polyoxyethylene alkyl ethers such as POE (10-50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether, and phosphoric acid salts thereof (e.g., sodium POE cetyl ether phosphate), POE (20-60 mol) sorbitan monooleate, and POE (10-60 mol) sorbitan monoisostearate , POE (10-80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100 mol)·polyoxypropylene modified silicone, POE·alkyl 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), glycerin fatty acid ester (glycerin monostearate, etc.), hydrogenated soybean phospholipid, hydrogenated lanolin alcohol, and other surfactants;Cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-thioneol, citronellal, farnesol, etc.), coloring agents (tar dyes (brown No. 201, blue No. 201, yellow No. 4, yellow No. 403, etc.), cacao dyes, chlorophyll, aluminum oxide, etc.), thickeners (sodium alginate, ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, carboxyvinyl polymer, sodium polyacrylate, etc.), pH adjusters (phosphoric acid, hydrochloric acid, citric acid, kue Examples of additives include sodium phosphate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (sodium dl-pyrrolidone carboxylate solution, D-sorbitol solution, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, ultraviolet absorbers, chelating agents, adhesives, buffers, dissolution aids, solubilizers, preservatives, etc.;

[0042] Formulation The dosage form of the pharmaceutical composition of the present invention is not particularly limited and may be any of liquid, semi-solid (gel, ointment, paste, etc.), solid, etc., but is preferably a liquid or semi-solid aqueous preparation.

[0043] The pharmaceutical composition of the present invention may be any of external medicines, mucosal medicines, and internal medicines. Specific examples of external medicines include gels, creams, lotions, emulsions, liquids, patches, aerosols, ointments, and packs. Specific examples of mucosal medicines include gels, creams, lotions, emulsions, liquids, ointments, and internal medicines. Specific examples of internal medicines include liquids and jellies. Preparation into these formulations can be carried out by formulating the formulations using additives according to the formulations according to the known methods described in the General Provisions for Preparations of the 17th Revised Japanese Pharmacopoeia, etc.

[0044] Among these formulations, preferred are pharmaceuticals for external application to the skin and pharmaceuticals for application to mucosa, such as gels, creams, lotions, emulsions, and liquids.

[0045] 2. Methods for preventing yellowing Furthermore, the present invention relates to a method for suppressing yellowing caused by exposure to light of a pharmaceutical composition containing (A) ethyl aminobenzoate and (B) a quaternary ammonium salt, characterized in that the pharmaceutical composition is blended with (C) at least one member selected from the group consisting of polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethylcellulose.

[0046] In the method for inhibiting yellowing, the types and contents of (A) to (C) used, the types and contents of other ingredients to be blended, the formulation form of the pharmaceutical composition, etc. are the same as those in "1. Pharmaceutical composition" above. EXAMPLES

[0047] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these.

[0048] Test Example 1. Preparation of Pharmaceutical Compositions The pharmaceutical compositions (external skin medicines, liquid preparations) shown in Tables 1 and 2 were prepared. Specifically, a predetermined amount of ethyl aminobenzoate and 1-menthol were each dissolved in ethanol, and then added to water together with other ingredients and mixed to obtain the pharmaceutical compositions (external skin medicines, liquid preparations).

[0049] 2.Evaluation of formulation stability by light exposure Each pharmaceutical composition was placed in a screw tube (a transparent glass container with a diameter of 24 mm and a height of 50 mm) and left to stand for 96 hours in a growth chamber set at 25°C and 12,000 lx·hr under fluorescent light irradiation. The screw tube was then inverted 2-3 times to mix, and the appearance of the pharmaceutical composition was visually observed to evaluate the formulation stability due to exposure to light according to the following criteria. <Evaluation criteria for formulation stability upon exposure to light> ⊚: No yellowing was observed, and there was no problem in practical use. ○: A slight yellowing was observed, but this did not pose a problem for practical use. △: Obvious yellowing was observed, and the product was not suitable for practical use. ×: Significant yellowing was observed, and the sample was not suitable for practical use.

[0050] 3.Results The results are shown in Tables 1 and 2. The pharmaceutical composition in which only ethyl aminobenzoate was dissolved did not show any yellowing even when exposed to light (Reference Example 1). However, when ethyl aminobenzoate was coexisted with cetylpyridinium chloride, significant yellowing was observed due to exposure to light (Comparative Example 1). In contrast, when ethyl aminobenzoate and cetylpyridinium chloride were coexisted with one or more of glycerin, propylene glycol, menthol, polyvinylpyrrolidone, and hydroxyethylcellulose, yellowing due to exposure to light was significantly improved (Examples 1 to 22). In particular, among the pharmaceutical compositions in which the formulation stability due to exposure to light was evaluated as ⊚, when ethyl aminobenzoate, cetylpyridinium chloride, polyhydric alcohol (particularly propylene glycol), and polyvinylpyrrolidone were contained in combination, a significantly more remarkable formulation stability was observed.

[0051] [Table 1]

[0052] [Table 2]

[0053] Prescription Examples The pharmaceutical compositions (medicines for application to the oral mucosa) shown in Table 3 were prepared. The pharmaceutical compositions obtained were evaluated for formulation stability by exposure to light in the same manner as in the above-mentioned Test Example, and no yellowing was observed in any of them.

[0054] [Table 3]

Claims

1. A pharmaceutical composition comprising (A) ethyl aminobenzoate, (B) a quaternary ammonium salt, and (C) hydroxyethyl cellulose.

2. The pharmaceutical composition according to claim 1, wherein the component (B) is cetylpyridinium chloride.

3. The pharmaceutical composition according to claim 1 or 2, which is an external medicine or a mucosally applied medicine.

4. A method for inhibiting yellowing caused by light exposure of a pharmaceutical composition comprising ethyl aminobenzoate and a quaternary ammonium salt, comprising: The pharmaceutical composition contains (A) ethyl aminobenzoate and (B) a quaternary ammonium salt together with (C) hydroxyethyl cellulose. A method for inhibiting yellowing caused by exposure of the pharmaceutical composition to light.

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