JP7586879B2 - Pharmaceutical Compositions - Google Patents

Description

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

Ethyl aminobenzoate is known as a local anesthetic and is widely used to relieve local itching and pain on mucous membranes and skin. 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 salt can provide both rapid and sustained local anesthetic action.

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 a topical pharmaceutical composition containing 0.05 to 2% by weight of a quaternary ammonium salt, 0.1 to 4% by weight of chlorpheniramine maleate, and 0.01 to 10% by weight of a chloride ion source can provide a stable formulation that suppresses the formation of crystals.

In recent years, pharmaceutical compositions are required to be multifunctional, and formulations that combine local anesthetics and bactericides have been developed. However, in order to put pharmaceutical compositions into practical use, it is necessary to give sufficient consideration not only to functionality but also to formulation stability. However, in the prior art, the formulation stability of pharmaceutical compositions containing ethyl aminobenzoate and a quaternary ammonium salt has not been fully examined.

Japanese Patent Application Publication No. 8-259464 JP 2010-159251 A

The present inventors have been investigating the practical application of a pharmaceutical composition containing ethyl aminobenzoate and a quaternary ammonium salt, but have encountered new problems with the topical composition, such as discoloration (yellowing) to yellow upon exposure to light, failure to maintain good appearance, and poor formulation stability.

The 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.

The present inventors conducted extensive research to solve the above problems and 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 can suppress yellowing caused by exposure to light and has excellent formulation stability. The present invention was completed based on this knowledge and through further research.

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 polyhydric alcohols, monoterpenes, 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 composition according to any one of Items 1 to 4, wherein the component (C) includes a polyhydric alcohol and polyvinylpyrrolidone.
5. The pharmaceutical composition according to any one of claims 4 to 4.
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:
(C) a pharmaceutical composition comprising (A) ethyl aminobenzoate and (B) a quaternary ammonium salt;
At least one selected from the group consisting of polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethyl cellulose is blended.
A method for inhibiting yellowing caused by exposure of the pharmaceutical composition to light.

The pharmaceutical composition of the present invention can suppress yellowing caused by exposure to light even in the presence of ethyl aminobenzoate and a quaternary ammonium salt, and can provide excellent formulation stability.

1. Pharmaceutical Composition 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 is described in detail below.

(A) Ethyl aminobenzoate Ethyl aminobenzoate, also known as ethyl 4-aminobenzoate or benzocaine, is a known local anesthetic.

In the pharmaceutical composition of the present invention, the content of component (A) is not particularly limited and may be appropriately determined depending on the degree 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.

(B) Quaternary ammonium salt The quaternary ammonium salt used in the present invention may be any salt that has a bactericidal effect and is pharma- ceutically acceptable, and there is no particular limitation on the type. Examples of the salt include cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, dequalinium chloride, alkyldimethylammonium chloride, alkyltrimethylammonium chloride, methylbenzethonium chloride, lauroylcholaminoformylmethylpyridinium chloride, and the like.

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

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.

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 %.

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.

(C) Polyhydric alcohol, monoterpene, polyvinylpyrrolidone, and/or hydroxyethyl cellulose The pharmaceutical composition of the present invention contains a polyhydric alcohol, monoterpene, polyvinylpyrrolidone, and/or 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.

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.

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

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.

In the present invention, the monoterpene may be used in the form of an essential oil containing a monoterpene. The essential oil containing a monoterpene may be appropriately selected from known essential oils, and examples of essential oils containing menthol include peppermint oil, peppermint oil, and spearmint oil. In this specification, the description of the content and ratio of monoterpene is the value converted into the amount of monoterpene contained in the essential oil when an essential oil containing a monoterpene is used.

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

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

The hydroxyethyl cellulose used as component (C) is a cellulose derivative in which ethylene oxide is added to cellulose to improve its water solubility. The average number of moles of ethylene oxide added, the average molecular weight, etc. of the hydroxyethyl cellulose used as component (C) are not particularly limited, and may be any that is commonly used in the medical field. For example, the viscosity in a 2.0% by weight aqueous solution (20°C) is 500 mPa·s or more, preferably 500 to 50,000 mPa·s. Here, the viscosity refers to a value appropriately measured using a B-type viscometer "TOKI SANGYO VISCOMETER TVB-10" (manufactured by Toki Sangyo Co., Ltd.) using rotors: M3 or M4 (rotation speed: 12 to 30 rpm, time: 1 min, unit: mPa·s) depending on the viscosity to be measured. In addition, in the present invention, commercially available hydroxyethyl cellulose can be used. Specific examples of commercially available hydroxyethyl cellulose products 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 Ltd.; and "NATROSOL 250HX" manufactured by Ashland.

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

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

When a polyhydric alcohol and polyvinylpyrrolidone are used in combination as component (C), there are no particular limitations on the ratio between them, but from the viewpoint of more effectively suppressing yellowing due to exposure to light, the ratio 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 of polyvinylpyrrolidone per 100 parts by weight of polyhydric alcohol.

In the pharmaceutical composition of the present invention, the content of component (C) may be appropriately set depending on the type of component (C) used, the formulation form or application of the pharmaceutical composition, and the like; for example, the content of component (C) may be 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 component (C).

More specifically, the content of each type of component (C) may be in the following range:
When a polyhydric alcohol is used : 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 a monoterpene is used , the amount is 0.01 to 3% by weight, preferably 0.05 to 1% by weight, and more preferably 0.1 to 1% by weight.
When polyvinylpyrrolidone is used : 0.05 to 3% by weight, preferably 0.1 to 1% by weight, and more preferably 0.5 to 1% by weight.
When hydroxyethyl cellulose is used : 0.05 to 3% by weight, preferably 0.1 to 1% by weight, and more preferably 0.5 to 1% by weight.

In the pharmaceutical composition of the present invention, the ratio of component (C) to component (A) is determined according to the respective contents of components (A) and (C), but for example, the ratio of component (C) is 10 to 20,000 parts by weight, preferably 15 to 18,000 parts by weight, per 100 parts by weight of component (A).

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 a polyhydric alcohol is used : 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: a 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: a total amount is more preferably 2,000 to 18,000 parts by weight, particularly preferably 5,000 to 18,000 parts by weight, and most preferably 8,000 to 18,000 parts by weight.
When monoterpenes are used : 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 polyvinylpyrrolidone is used : 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 hydroxyethyl cellulose is used : a total amount of 30 to 500 parts by weight, preferably 50 to 500 parts by weight, and more preferably 50 to 400 parts by weight.

Lower Alcohol The pharmaceutical composition of the present invention may contain a lower alcohol as necessary in order to stably dissolve ethyl aminobenzoate.

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

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

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

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.

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, but may be, for example, 1 to 80% by weight, preferably 5 to 60% by weight, and more preferably 10 to 50% by weight.

Other components The pharmaceutical composition of the present invention may contain other pharmacological components, if necessary, in addition to the components described above. Examples of such pharmacological components 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.), and disinfectants other than quaternary ammonium salts (iodine, povidone-iodine, iodine Examples of suitable active ingredients include potassium chloride, chlorhexidine gluconate, acrinol, etc.), anti-inflammatory agents (dipotassium glycyrrhizinate, glycyrrhetinic acid, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protective agents (collodion, castor oil, etc.), blood circulation promoting ingredients (vanillyl nonyl acid amide, nicotinic acid benzyl ester, capsaicin, chili pepper extract, etc.), vitamins (vitamin A, etc.), and mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.).

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. There are no particular limitations on such base materials and additives, provided that they are pharma- ceutical acceptable. 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 hydrocarbons, petrolatum, etc.), waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oils (isopropyl myristate, isopropyl adipate, etc.), and the like. Pyrus, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), lower alcohols (ethanol, propanol, isopropanol, butanol, isobutanol, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myrisol, oily bases 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 alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); polyoxyethylene alkyl ethers such as 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, phosphoric acids and phosphates thereof (e.g., sodium POE cetyl ether phosphate), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan monoisostearate, POE ( 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, diricinoleic acid Surfactants such as polyethylene glycol, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20-85), glycerin fatty acid esters (glycerin monostearate, etc.), hydrogenated soybean phospholipids, and hydrogenated lanolin alcohol; freshening 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.), colorants (tar dyes (brown Color No. 201, Blue No. 201, Yellow No. 4, Yellow No. 403, etc.), cocoa coloring, 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, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents Additives include (dl-sodium 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, UV absorbers, chelating agents, adhesives, buffers, dissolution aids, solubilizers, preservatives, etc.

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

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.

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

2. Method for inhibiting yellowing The present invention further relates to a method for inhibiting yellowing caused by exposure to light of a pharmaceutical composition containing (A) ethyl aminobenzoate and (B) a quaternary ammonium salt, which is characterized by comprising blending the pharmaceutical composition with (C) at least one member selected from the group consisting of polyhydric alcohols, monoterpenes, polyvinylpyrrolidone, and hydroxyethylcellulose.

In the yellowing inhibition method, the types and amounts of (A) to (C) used, the types and amounts of other ingredients mixed in, and the formulation form of the pharmaceutical composition are the same as those in "1. Pharmaceutical composition" above.

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

Test Example 1. Preparation of pharmaceutical compositions Pharmaceutical compositions (drugs for external use on the skin, 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 the solution was added to water together with other ingredients and mixed to obtain pharmaceutical compositions (drugs for external use on the skin, liquid preparations).

2. Evaluation of formulation stability due to 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 allowed to stand for 96 hours in a growth chamber set at 12,000 lx·hr and 25° C. 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 light exposure 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.
Δ: 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.

3. Results The results obtained 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.

The pharmaceutical compositions (medicines for oral mucosa application) shown in Formulation Example 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.

Claims (5)

A pharmaceutical composition comprising (A) ethyl aminobenzoate, (B) a quaternary ammonium salt, and (C) polyvinylpyrrolidone (excluding, however, (1) the case where dibucaine hydrochloride is contained , and (2) the case where an oral ointment containing 0.1 to 1.0% by mass of alginate and 2.0% by mass or more of carboxyvinyl polymer, in which the content mass ratio of alginate to carboxyvinyl polymer, expressed as carboxyvinyl polymer/alginate, is 5 or more, and the pH is 3.0 or more and less than 6.00 ). The pharmaceutical composition according to claim 1, wherein the component (B) is cetylpyridinium chloride. The pharmaceutical composition according to claim 1 or 2, further comprising a polyhydric alcohol. The pharmaceutical composition according to any one of claims 1 to 3, which is a pharmaceutical for external application or a pharmaceutical for mucosal application. A method for suppressing yellowing caused by exposure to light in a pharmaceutical composition containing ethyl aminobenzoate and a quaternary ammonium salt (excluding, however, (1 ) the case where dibucaine hydrochloride is contained, and (2) the case where an oral ointment containing 0.1 to 1.0 mass % of alginate and 2.0 mass % or more of carboxyvinyl polymer, in which the mass ratio of alginate to carboxyvinyl polymer, expressed as carboxyvinyl polymer/alginate, is 5 or more, and the pH is 3.0 or more and less than 6.00, comprising :
A pharmaceutical composition is formulated with (A) ethyl aminobenzoate and (B) a quaternary ammonium salt together with (C) polyvinylpyrrolidone.
A method for inhibiting yellowing caused by exposure of the pharmaceutical composition to light.