JP6735587B2 - External composition - Google Patents

Description

The present invention relates to a composition for external use which contains a carboxyvinyl polymer, a heparin-like substance and glycyrrhizinic acid and can suppress phase separation while having a pH of 4.8 to 6.0 and is excellent in stability.

BACKGROUND ART Conventionally, a carboxyvinyl polymer has been blended in a composition for external use for the purpose of imparting viscosity and improving a film feeling (coating feeling). On the other hand, a formulation containing a carboxyvinyl polymer has a drawback that the components are likely to be separated into two phases (phase separated state) over time, and it is difficult to stably maintain the appearance properties. Heretofore, various studies have been conducted on techniques for overcoming the drawbacks of phase separation of the preparation containing such carboxyvinyl polymer. For example, Patent Document 1 contains (A) water in an amount of 20 to 50% by mass, and (B) a carboxyvinyl polymer and (C) one or two selected from xanthan gum, carrageenan, alginic acid and salts thereof, and carboxymethylcellulose salt. (C)/(B) mass ratio is 1.0 to 5 and (D) an oil absorption amount of 150 to 300 g/100 g of silicic anhydride is 1 to 10% by mass; It has been reported that the separation stability is improved by adding (F) propylene glycol alginate and setting the pH at 25°C to 6-9.

On the other hand, heparin-like substances are polysulfated mucopolysaccharides such as chondroitin polysulfate, moisturizing action, anti-inflammatory action, blood circulation promoting action, etc. are known, and since there are few side effects, the active ingredient of the external composition It is used as (for example, refer to Patent Document 2). Glycyrrhizic acid, glycyrrhetinic acid, and salts thereof such as glycyrrhizinic acid are known to have antiallergic action and antiinflammatory action, and are used as an active ingredient of an external composition. Therefore, if carboxyvinyl polymer can be provided with an external composition containing a heparin-like substance and glycyrrhizic acid, it is expected that the use of the carboxyvinyl polymer will improve the feeling of use, and that the heparin-like substance and the glycyrrhizic acid will exert a medicinal effect. It is expected to meet the ever-increasing consumer needs in recent years, with further improvements in functionality.

However, conventionally, a formulation technique in which a heparin-like substance and glycyrrhizic acid are mixed with an external composition containing a carboxyvinyl polymer has not been studied.

JP 2012-116772 A Japanese Patent Publication No. 62-4362

The present inventor conducted a study to put into practical use a composition for external use containing a heparin-like substance and glycyrrhizic acid together with a carboxyvinyl polymer. As a result, a composition for external use containing a carboxyvinyl polymer, a heparin-like substance and glycyrrhizic acid had a pH of 6. When the pH was 5 or more, phase separation did not occur, but in the range of pH 6.0 or less, phase separation occurred and the stability was inferior.

Therefore, an object of the present invention is to solve the above-mentioned new problems, that is, it contains a carboxyvinyl polymer, a heparin-like substance and glycyrrhizinates, and suppresses phase separation while maintaining pH 6.0 or less, thereby improving stability. It is to provide an excellent composition for external use.

The present inventor has conducted diligent studies to solve the above-mentioned problems. As a result, in a composition for external use containing carboxyvinyl polymer, a heparin-like substance and glycyrrhizinic acid, and having a pH of 4.8 to 6.0, hydroxypropyl was used. It has been found that by incorporating methyl cellulose, phase separation can be suppressed and the appearance properties can be stably maintained. The present invention has been completed by further studies based on these findings.

That is, the present invention provides the inventions of the following modes.
Item 1. (A) Carboxyvinyl polymer, (B) Heparin analog, (C) Glycyrrhizic acid, Glycyrrhetinic acid, derivatives thereof, and at least one selected from the group consisting of salts thereof, and (D) Hydroxypropyl methylcellulose Then
A composition for external use, which has a pH of 4.8 to 6.0.
Item 2. Item 2. The external composition according to Item 1, wherein the content of the component (D) is 0.1% by weight or more.
Item 3. Furthermore, the external composition according to Item 1 or 2, further comprising (E) a polyhydric alcohol.
Item 4. Furthermore, the external composition according to any one of Items 1 to 3, further comprising at least one selected from the group consisting of (F) allantoin and its derivatives.
Item 5. Item 5. The external composition according to any one of Items 1 to 4, which is in the form of a gel.
Item 6. (A) a carboxyvinyl polymer, (B) a heparin-like substance, and (C) glycyrrhizic acid, glycyrrhetinic acid, a derivative thereof, and a composition for external use containing at least one selected from the group consisting of these salts, A method of suppressing the separation,
A method for suppressing phase separation, which comprises blending (D) hydroxypropylmethylcellulose into the external composition and setting the pH of the external composition to 4.8 to 6.0.

The composition for external use of the present invention contains a carboxyvinyl polymer, a heparin-like substance and glycyrrhizic acid, and can suppress phase separation while maintaining a good appearance property even at a pH of 4.8 to 6.0. Stability can be provided. Furthermore, the external use composition of the present invention can suppress phase separation and have excellent stability even when further mixed with a medicinal component such as allantoin, and can be applied to various pharmaceutical formulations.

1. External composition The external composition of the present invention may be described as a carboxyvinyl polymer (hereinafter, also referred to as “(A) component”) and a heparin-like substance (hereinafter, referred to as “(B) component”). ), glycyrrhizinic acid, glycyrrhetinic acid, derivatives thereof, and at least one selected from the group consisting of salts thereof (hereinafter, also referred to as “(C) component”) and hydroxypropylmethylcellulose (hereinafter , "(D) component" may be written), and the pH is 4.8 to 6.0. Hereinafter, the composition for external use of the present invention will be described in detail.

(A) Carboxyvinyl Polymer The external composition of the present invention contains a carboxyvinyl polymer. Carboxyvinyl polymer is a water-soluble vinyl polymer having a carboxyl group, specifically, a polymer having a cross-linking structure such as allyl sucrose or allyl ether of pentaerythritol with acrylic acid and/or methacrylic acid as a main chain. is there.

The viscosity of the carboxyvinyl polymer used in the present invention is not particularly limited, but for example, in a 0.5 wt% aqueous solution (20° C.) adjusted to pH 6.5, the viscosity is 2000 mPa·s or more, preferably 2000 to 200,000 mPas. -The thing which is s is mentioned. Here, the said viscosity uses the rotor: M3 (rotation speed: 20 rpm, time: 1 min, unit: mPa*s) in the B-type viscometer "TOKI SANGYO VISCOMETER TVB-10" (made by Toki Sangyo Co., Ltd.). The value measured by

In the composition for external use of the present invention, a commercially available product can be used as the carboxyvinyl polymer. As commercially available products of carboxyvinyl polymer, specifically, "Carbopol 940", "Carbopol 941", "Carbopol 980", "Carbopol 981" manufactured by Lubrizol Advanced Materials Co., Ltd.; Wako Pure Chemical Industries, Ltd. "Hibiswako 103", "Hibiswako 104", "Hibiswako 105" manufactured by Toagosei Co., Ltd. "Junron PW-120", "Junron PW-121", "Junron PW-312S"; Sumitomo Seika Examples include "AQPEC HV-501E" and "AQPEC HV-505E" manufactured by Co., Ltd.; "Syntalen K" and "Syntalen L" manufactured by 3V Sigma.

In the composition for external use of the present invention, one kind of carboxyvinyl polymer may be used alone, or two or more kinds thereof may be used in combination.

In the external use composition of the present invention, the content of the component (A) is not particularly limited, and may be appropriately set according to the viscosity to be imparted to the external use composition, the feeling of use, and the like. -5 wt%, preferably 0.1-3 wt%, more preferably 0.3-2 wt%. The component (A) causes phase separation when the component (B) and the component (C) coexist in the absence of the component (D), which will be described later, within a pH range of 6.0 or less. According to this, even when the component (A) is contained in the above-mentioned content, phase separation can be suppressed and excellent stability can be provided.

(B) Heparin-like substance The external composition of the present invention contains a heparin-like substance. The heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, which is a known drug known to have moisturizing action, anti-inflammatory action, blood circulation promoting action and the like.

The origin of the heparin-like substance used in the present invention is not particularly limited, but for example, those obtained by polysulfating mucopolysaccharides, tissues of edible animals (for example, tracheal cartilage of cattle, pigs, etc.) And the like extracted from the lung). In the emulsified composition of the present invention, as the heparin-like substance, a heparin-like substance included in the Japanese Pharmacopoeia Standards is preferably used.

The content of the component (B) in the composition for external use of the present invention may be appropriately set in consideration of the degree of moisturizing action to be imparted, and for example, 0.01 to 5% by weight, preferably 0. 05 to 3% by weight, more preferably 0.1 to 1.0% by weight, particularly preferably 0.1 to 0.5% by weight, and most preferably 0.1 to 0.3% by weight. When the component (B) coexists with the component (A) and the component (C) in the absence of the component (D) in the range of pH 6.0 or less, it induces phase separation by the component (A). According to the composition for external use, phase separation can be suppressed and excellent stability can be provided even if the component (B) is contained in the above-mentioned content.

In the composition for external use of the present invention, the ratio of the component (B) to the component (A) is determined according to the respective contents of the component (A) and the component (B), for example, 1 part by weight of the component (A). The component (B) is used in an amount of 0.05 to 10 parts by weight, preferably 0.05 to 5 parts by weight, and more preferably 0.05 to 3 parts by weight.

(C) Glycyrrhizic acid, glycyrrhetinic acid, their derivatives, and/or their salts The emulsion composition of the present invention comprises (C) component glycyrrhizinic acid, glycyrrhetinic acid, their derivatives, and/or their salts. contains.

Glycyrrhizic acid is a known drug known to have an anti-inflammatory effect, an anti-allergic effect, and the like.

The glycyrrhizic acid derivative is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and specific examples thereof include methyl glycyrrhizinate and stearyl glycyrrhizinate. These glycyrrhizic acid derivatives may be used alone or in combination of two or more.

Glycyrrhetinic acid is a known drug known to have an anti-inflammatory effect, an anti-allergic effect, and the like.

The derivative of glycyrrhetinic acid is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, but specifically, pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, monoglucuronide glycyrrhetinate, etc. Can be mentioned. These glycyrrhetinic acid derivatives may be used alone or in combination of two or more.

The salts of glycyrrhizinic acid, glycyrrhetinic acid and/or its derivatives are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, but specifically, alkali metal salts such as sodium salt and potassium salt. An ammonium salt and the like can be mentioned. These salts may be used alone or in combination of two or more.

In the emulsion composition of the present invention, as the component (C), glycyrrhizic acid, a salt of glycyrrhizic acid, a derivative of glycyrrhizic acid, a salt of a derivative of glycyrrhizic acid, glycyrrhetinic acid, a salt of glycyrrhetinic acid, a derivative of glycyrrhetinic acid, and glycyrrhetinic acid. From the salts of the derivatives of, one kind may be selected and used, or two or more kinds may be used in combination.

Among these (C) components, preferably glycyrrhizic acid, a salt of glycyrrhizic acid, a derivative of glycyrrhizic acid, a salt of a derivative of glycyrrhizic acid; more preferably glycyrrhizic acid, a salt of glycyrrhizic acid; particularly preferably a salt of glycyrrhizic acid; Even more preferably, dipotassium glycyrrhizinate is used.

In the external composition of the present invention, the content of the component (C) is not particularly limited and may be appropriately set according to the drug effect to be imparted, for example, 0.01 to 15% by weight, preferably 0.05 to 8% by weight, and more preferably 0.1 to 5% by weight. When the component (C) coexists with the component (A) and the component (B) in the absence of the component (D) described below in the range of pH 6.0 or less, phase separation by the component (A) is induced. According to the topical composition for external use, even if the component (C) is contained in the above-described content, phase separation can be suppressed and excellent stability can be provided.

In the composition for external use of the present invention, the ratio of the component (C) to the component (A) is determined according to the respective contents of the component (A) and the component (C), for example, 1 part by weight of the component (A). The component (C) is used in an amount of 0.05 to 15 parts by weight, preferably 0.05 to 10 parts by weight, and more preferably 0.05 to 5 parts by weight.

(D) Hydroxypropyl methylcellulose The external composition of the present invention contains hydroxypropylmethyl cellulose. By thus setting the pH to 4.8 to 6.0 while containing hydroxypropylmethylcellulose, phase separation is suppressed even when components (A) to (C) coexist, and excellent stability is obtained. Can be provided.

Hydroxypropyl methylcellulose is a cellulose derivative and is a compound also called hypromellose.

The substitution degree type of hydroxypropylmethyl cellulose used in the present invention is not particularly limited and may be any of 1828, 2208, 2906 and 2910, but from the viewpoint of more effectively suppressing phase separation. , Preferably 2906 and 2910 substitution degree types.

The viscosity of the hydroxypropylmethyl cellulose used in the present invention is not particularly limited, but for example, a viscosity of 1000 mPa·s or more, preferably 1000 to 200,000 mPa·s in a 2 wt% aqueous solution (20° C.). Can be mentioned. Here, the said viscosity uses the rotor: M3 (rotation speed: 20 rpm, time: 1 min, unit: mPa*s) in the B-type viscometer "TOKI SANGYO VISCOMETER TVB-10" (made by Toki Sangyo Co., Ltd.). The value measured by

In the composition for external use of the present invention, hydroxypropyl methylcellulose may be a commercially available product. As commercially available products of hydroxypropylmethyl cellulose, specifically, "Metroses 90SH-100SR", "Metroses 90SH-4000SR", "Metroses 90SH-15000SR", "Metroses 90SH-100000SR", manufactured by Shin-Etsu Chemical Co., Ltd. "Metroses 65SH-50", "Metroses 65SH-400", "Metroses 65SH-1500", "Metroses 65SH-4000", "Metroses 60SH-50", "Metroses 60SH-4000", "Metroses 60SH-10000", "Metroses". "TC-5E", "Metroses TC-5M", "Metroses TC-5R", "Metroses TC-5S", "Metroses SB-4"; "Methocel E4M" and "Methocel E4M" manufactured by Dow Chemical Japan Co., Ltd. , "Methocel 40-100", "Methocel 40-101", "Methocel 40-202"; and "Marporose 60MP-4000" manufactured by Matsumoto Yushi-Seiyaku Co., Ltd. and the like.

In the composition for external use of the present invention, one kind of hydroxypropylmethyl cellulose may be used alone, or two or more kinds thereof may be used in combination.

In the composition for external use of the present invention, the content of the component (D) may be appropriately set according to the content of the components (A) to (C) described above, for example, 0.1% by weight or more. , Preferably 0.1 to 3% by weight, more preferably 0.1 to 2.5% by weight, particularly preferably 0.1 to 2% by weight. By satisfying such a content of the component (D), the phase separation induced by the coexistence of the components (A) to (C) described below in the pH range of 4.8 to 6.0 is effectively suppressed. be able to.

In the composition for external use of the present invention, the ratio of the component (D) to the component (A) is determined according to the respective contents of the component (A) and the component (D), for example, 1 part by weight of the component (A). The component (D) is used in an amount of 0.02 to 30 parts by weight, preferably 0.05 to 10 parts by weight, and more preferably 0.1 to 10 parts by weight.

(E) Polyhydric alcohol In addition to the components (A) to (D), the external composition of the present invention may, if necessary, be a polyhydric alcohol (hereinafter, also referred to as (E). Yes) may be included. By containing a polyhydric alcohol, phase separation can be suppressed more effectively, and the moisturizing action of the component (B) can be enhanced.

The polyhydric alcohol is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, for example, 1,3-butylene glycol, ethylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, Examples thereof include polyethylene glycol and glycerin. Of these polyhydric alcohols, propylene glycol is preferable.

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

When the component (E) is contained in the composition for external use of the present invention, the content thereof may be appropriately set according to the kind of the polyhydric alcohol used and the like, but is, for example, 1% by weight or more, preferably 3%. -20% by weight, and more preferably 5-20% by weight.

(F) Allantoin and/or its derivative The external composition of this invention WHEREIN: In addition to the said (A)-(D) component, as needed, allantoin and/or its derivative (henceforth, it describes with a (F) component. May be included). Even if the composition for external use of the present invention contains allantoin and/or its derivative, the allantoin and/or its derivative can be stably retained while suppressing phase separation.

Allantoin is a compound also called 5-ureidohydantoin, which is a known drug known to have anti-inflammatory action, antipruritic action, and the like.

The allantoin derivative is not particularly limited as long as it is pharmaceutically acceptable, and specific examples thereof include allantoin chlorhydroxyaluminum and allantoin hydroxyaluminum. These allantoin derivatives may be used alone or in combination of two or more.

In the composition for external use of the present invention, one kind may be used alone from allantoin and its derivative, or two or more kinds may be used in combination.

When the component (F) is contained in the composition for external use of the present invention, its content is not particularly limited, but is, for example, 0.01 to 15% by weight, preferably 0.05 to 8% by weight, and more preferably Is 0.1 to 5% by weight.

(G) Monohydric Lower Alcohol The composition for external use of the present invention may contain a monohydric lower alcohol (hereinafter sometimes referred to as the component (G)), if necessary.

The monohydric lower alcohol is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and examples thereof include ethanol, propanol, isopropanol, butanol and isobutanol. Among these monohydric lower alcohols, isopropanol is preferable.

In the composition for external use of the present invention, when the component (G) is contained, its content may be appropriately set according to the type of polyhydric alcohol used, for example, 1 to 70% by weight, preferably 1 to 50% by weight, and more preferably 5 to 50% by weight.

Composition for external use of the water present invention are prepared in an aqueous composition containing water. In the external composition of the present invention, the content of water may be appropriately set according to the formulation form, for example, 5 to 95% by weight, preferably 5 to 90% by weight, more preferably 10 to 90% by weight. Are listed.

Other Components In addition to the components described above, the external composition of the present invention may contain other pharmacological components, if necessary. Such pharmacological components include, for example, antihistamines (diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilukaine or salts thereof, orthocaine, oxesazein, oxypolyentoxy. Decane, roto extract, percamine pase, tesit decitin, etc.), anti-inflammatory agent (indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectant (colodion, castor oil, etc.), blood circulation promoting component (nonyl acid vanillyl amide, nicotinic acid benzyl ester) , Capsaicin, capsicum extract, etc., cooling agents (menthol, camphor, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.) and the like.

In addition, the external composition of the present invention may contain a base material and an additive other than the above-mentioned components, if necessary, in order to obtain a desired formulation form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable, but examples thereof 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 oil (liquid paraffin, paraffin, gelled hydrocarbon, vaseline, etc.), waxes and waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, Microcrystalline wax, etc.), ester oil (isopropyl myristate, isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc.), fatty acid alkyl ester, fatty acid (stearic acid, oleic acid) , Palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol) , Lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, an oily base such as silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); POE (10 to 50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyl tetradecyl ether, POE (10-50 mol) oleyl ether, POE (2- 50 mol) cetyl ether, POE (5 to 50 mol) behenyl ether, POE (5 to 30 mol) polyoxypropylene (5 to 30 mol) 2-decyltetradecyl ether, POE (10 to 50 mol) polyoxypropylene ( 2 to 30 mol) polyoxyethylene alkyl ether such as cetyl ether, phosphoric acid/phosphoric acid salt thereof (POE cetyl ether sodium phosphate etc.), POE (20 to 60 mol) sorbitan monooleate, POE (10 to 60 mol) ) Sorbitan monoisostearate, POE (10 to 80 mol) glyceryl monoisostearate, POE (10 to 30 mol) glyceryl monostearate, POE (20 to 100 mol)/polyoxypropylene-modified silicone, POE/alky 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, polyoxy Surfactants such as ethylene hydrogenated castor oil (5 to 100), polysorbate (20 to 85), glycerin fatty acid ester (glyceryl monostearate, etc.), hydrogenated soybean phospholipid, hydrogenated lanolin alcohol, etc.; cooling agent (menthol, Camphor, borneol, peppermint water, peppermint oil, etc., preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-cionele, citronellal, farnesol, etc.), Coloring agents (tar dyes (brown 201, blue 201, yellow 4, yellow 403, etc.), cocoa dyes, chlorophyll, aluminum oxide, etc.), thickeners (polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethyl cellulose, Xanthan gum, carrageenan, etc.), pH adjusting agent (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agent (dl- Sodium pyrrolidonecarboxylate 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, solubilizing agents, solubilizing agents Examples include additives such as agents and preservatives.

pH
The pH of the composition for external use of the present invention is set to 4.8 to 6.0. When components (A) to (C) coexist within a pH range of 4.8 to 6.0, phase separation due to the component (A) is induced. However, in the present invention, by incorporating the component (D), Even in the pH range, it is possible to suppress the phase separation due to the component (A). Further, if the pH is lower than 4.8, phase separation cannot be suppressed even if the components (A) to (D) coexist.

Further, in the range of pH 5.0 to 6.0, particularly 5.2 to 6.0, and particularly 5.5 to 6.0, the components (A) to (C) are allowed to coexist in the absence of the component (D). Then, the phase separation due to the component (A) tends to be remarkable, but in the present invention, the phase separation due to the component (A) can be effectively suppressed even in such a pH range. In view of such effects of the present invention, the pH of the external composition of the present invention is preferably pH 5.0 to 6.0, more preferably pH 5.2 to 6.0, and particularly preferably 5.5 to 6.0. Are listed.

In addition, in this invention, pH is a value measured at 25 degreeC. The pH of the external composition of the present invention can be adjusted by using a pH adjusting agent.

Formulation Form The preventive or therapeutic agent of the present invention is not particularly limited in its formulation form as long as it has a dosage form that can be applied transdermally, and it may be liquid or semisolid (gel, paste) Good.

The component (A) can be formed into a gel when the composition for external use is blended in an amount of about 0.1% by weight or more, particularly 0.3% by weight or more, while the component (A) has such a high content. In this case, when the components (A) to (C) coexist in the absence of the component (D) within a pH range of 6.0 or less, the phase separation by the component (A) tends to be remarkable. On the other hand, the external composition of the present invention can effectively suppress the phase separation due to the component (A) even if the component (A) has a high content. In view of such effects of the present invention, a gel form may be mentioned as a preferable formulation form of the external composition of the present invention.

When the composition for external use of the present invention is made into a gel, its viscosity is not particularly limited, but the viscosity at 25° C. is about 500 to 2,000,000 mPa·s, preferably 1,000 to 1,000, It is about 000 mPa·s, and more preferably about 3,000 m to 800,000 mPa·s.

The viscosity is measured at 25° C. using a B type viscometer. Specifically, the RB-85L viscometer (single cylindrical rotary viscometer) manufactured by Toki Sangyo Co., Ltd. can be used to measure the rotor number M4. The number is adjusted between 0.3 rpm and 60 rpm depending on the sample viscosity. Specifically, when the viscosity of the composition for external use is in the range of 10,000 mPa·s or less, 60 rpm, and when it is in the range of 10,000 to 50,000 mPa·s, 12 rpm, 50,000 to 400,000 mPa. The measurement is performed at 1.5 rpm in the range of s, and 0.3 rpm in the range of 400,000 to 2,000,000 mPas. For the viscosity, a value 30 seconds after the start of measurement is adopted.

As long as it is applied to the skin, the external composition of the present invention may be in the form of any preparation such as a skin external drug (including quasi drugs), cosmetics, and skin cleanser. As a formulation form of the external composition of the present invention, specifically, external preparations for skin such as gel, cream, lotion, emulsion, liquid, patch, aerosol, ointment and pack; gel, cream Cosmetics such as milky lotion, lotion, lotion and pack; skin cleansing agents such as body shampoo, hair shampoo and conditioner. Among these dosage forms, the external medicine for skin is preferable, and the gel agent is more preferable.

The composition for external use of the present invention can exhibit a moisturizing action, an anti-inflammatory action, a blood circulation promoting action and the like based on the contained (B) component, and an anti-inflammatory action based on the contained (C) component, an anti-allergic action, etc. Therefore, it is suitably used for the purpose of moisturizing, prevention or treatment of dry skin disease, prevention or treatment of inflammatory skin disease, and the like.

2. Method for suppressing phase separation of composition for external use The present invention further comprises (A) carboxyvinyl polymer, (B) heparin analogue, and (C) glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. A method for suppressing phase separation in a composition for external use containing at least one selected from the group consisting of (D) hydroxypropylmethylcellulose and the pH of the composition for external use being 4.8. The present invention provides a method for suppressing phase separation of the external composition, which is characterized in that the composition is set to ˜6.0.

In the suppression method of the present invention, the types and contents of (A) to (D) used, the types and contents of other components to be blended, the preferred pH range, the formulation form of the external composition, etc. are described above. 1. The same as in the case of the "composition for external use".

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

Test Example 1. Preparation of Gel-Type External Composition The gel-type external composition having the composition shown in Tables 1 and 2 was prepared. Specifically, a predetermined amount of heparin-like substance, dipotassium glycyrrhizinate, allantoin, and propylene glycol are dissolved in purified water and heated to around 80° C., and then a predetermined amount of carboxyvinyl polymer and hydroxypropylmethylcellulose are added. In addition, the mixture was stirred and swollen. After cooling this to room temperature with stirring, a predetermined amount of isopropanol and a pH adjusting agent (isopropanolamine) so as to have a predetermined pH were added and mixed until uniform to obtain a gel external composition.

2. Stability evaluation method Each of the obtained gel external compositions was subjected to a cycle test using a constant temperature and humidity chamber "LH33-14P" (manufactured by Nagano Science Co., Ltd.). Specifically, the temperature is lowered from 40° C. to −20° C. without performing gradient control, and a constant value operation is performed for 12 hours from the time when it reaches −20° C., and then gradient control is performed from −20° C. to 40° C. Without raising the temperature, the temperature was raised to 40° C. and the constant value operation for 12 hours was performed as one cycle, for a total of 10 cycles. The degree of phase separation of each external composition after the cycle test was determined according to the following criteria, and stability was evaluated.
<Criteria for the degree of phase separation>
⊚: Phase separation is not observed at all, and it is uniform.
◯: Phase separation is slightly recognized, but becomes uniform when shaken.
X: Clear phase separation was observed, and even if shaken, it was not uniform.

3. Evaluation results The results obtained are shown in Tables 1 and 2. Even when the carboxyvinyl polymer and dipotassium glycyrrhizinate were used in combination, no phase separation was observed even at pH 5.5 when no heparin-like substance was contained (Reference Example 3). Even when the carboxyvinyl polymer and the heparin-like substance were used in combination, phase separation was not observed even at pH 5.5 when dipotassium glycyrrhizinate was not included (Reference Example 4). Furthermore, at pH 6.5 or 7.0, phase separation was not observed even if it contained a carboxyvinyl polymer, a heparin-like substance, and dipotassium glycyrrhizinate (Reference Examples 1 and 2). On the other hand, at pH 4.5 or 5.5, when the carboxyvinyl polymer, the heparin-like substance, and dipotassium glycyrrhizinate were contained, clear phase separation was observed (Comparative Examples 1 to 4). That is, from these results, it became clear that a peculiar problem of phase separation occurs in the case of containing a carboxyvinyl polymer, a heparin-like substance, and dipotassium glycyrrhizinate at a pH of 6.0 or less.

Further, when the pH was 4.5, phase separation was observed even when hydroxypropylmethyl cellulose was blended with the carboxyvinyl polymer, the heparin-like substance, and dipotassium glycyrrhizinate (Comparative Example 4). On the other hand, when the pH is 4.8 to 6.0 and hydroxypropylmethyl cellulose is blended with the carboxyvinyl polymer, the heparin-like substance, and dipotassium glycyrrhizinate, phase separation can be suppressed and a good appearance can be obtained. The properties could be maintained (Examples 1 to 9).

In the gel external compositions of Examples 1, 5, 6 and Comparative Examples 1 and 3, carboxyvinyl polymer was used as Carbopol 980 (manufactured by Lubrizol Advanced Materials) or Hibiswako 104 (manufactured by Wako Pure Chemical Industries, Ltd.). ), the same cycle test was conducted, and the same tendency was observed. Furthermore, in the gel external compositions of Examples 1, 5, 6 and Comparative Examples 1 and 3, hydroxypropylmethylcellulose was used as Metroses 90SH-15000SR (substitution degree type 2208), Metroses 65SH-4000 (substitution degree type 2906) ( The same tendency was observed even when a similar cycle test was performed in place of Methcel E4M (substitution degree type 2910, manufactured by Dow Chemical Japan Co., Ltd.) or Shin-Etsu Chemical Co., Ltd.).

The stability of allantoin was also good in the gel external compositions of Examples 1 to 3 containing allantoin.

Formulation Example The gel external composition having the composition shown in Tables 3 and 4 was prepared in the same manner as in the above-mentioned Test Example. When each of the obtained gel-like compositions was subjected to a cycle test under the same conditions as in the above-mentioned test example, phase separation was suppressed and excellent stability was obtained in each case.

Claims (6)

(A) Carboxyvinyl polymer, (B) Heparin analog, (C) Glycyrrhizic acid, Glycyrrhetinic acid, derivatives thereof, and at least one selected from the group consisting of salts thereof, and (D) Hydroxypropyl methylcellulose Then
A composition for external use, which has a pH of 5.5 to 6.0. The composition for external use according to claim 1, wherein the content of the component (D) is 0.1% by weight or more. The composition for external use according to claim 1 or 2, further comprising (E) a polyhydric alcohol. The composition for external use according to any one of claims 1 to 3, further comprising at least one selected from the group consisting of (F) allantoin and its derivatives. The composition for external use according to any one of claims 1 to 4, which is in a gel form. (A) a carboxyvinyl polymer, (B) a heparin-like substance, and (C) glycyrrhizic acid, glycyrrhetinic acid, a derivative thereof, and a composition for external use containing at least one selected from the group consisting of these salts, A method of suppressing the separation,
A method for suppressing phase separation, which comprises blending (D) hydroxypropylmethylcellulose in the external composition and setting the pH of the external composition to 5.5 to 6.0.