JP6666068B2 - External composition - Google Patents

Description

  The present invention relates to an external composition having improved stability of allantoin and / or a derivative thereof and excellent storage stability.

  Allantoin and its derivatives have an anti-inflammatory action, a cell activating action, an action of removing necrotic tissue, an action of promoting new normal skin tissue, and the like, and are used in external compositions. However, allantoin and its derivatives have the drawback that decomposition and precipitation are apt to occur in the composition for external use, resulting in poor stability (for example, see Non-Patent Document 1).

  Therefore, conventionally, various formulation techniques for improving the stability of allantoin and / or its derivative in an external composition have been studied. For example, U.S. Pat. No. 6,086,086 discloses a composition comprising an oil-in-water emulsion comprising (a) allantoin, and (b) at least one anionic or nonionic emulsifier that is substantially hydrophilic and water soluble. Discloses that the stability of allantoin can be improved by setting the pH to about 3.0 to about 6.0. Patent Document 2 discloses that a skin external preparation contains (i) allantoin and / or an analog thereof, (ii) panthenol and / or an analog of panthenol, and (iii) diphenhydramine or a salt thereof in combination. It is disclosed that the stability of allantoin and / or its related substances is thereby improved.

  However, the conventional formulation technique for stabilizing allantoin and / or its derivative has limitations on the formulation, and thus cannot cope with the recent diversification of formulations for external use. Therefore, development of a new formulation technique for stabilizing allantoin and / or its derivative is required.

  On the other hand, heparin-like substances are known to have a moisturizing action, a blood flow increasing action, and the like, and are used in external compositions. In addition, glycyrrhizic acid, glycyrrhetinic acid, their derivatives, and their salts also have an anti-inflammatory effect, an anti-allergic effect, and the like, and are used in external compositions. However, the effects of these drugs on the stability of allantoin and / or its derivatives have not been clarified.

Nobuya Yamamoto et al., Stability of allantoin and identification of its degradation products, Pharmaceutical Journal, 113 (7), 515-524, 1993

JP 2004-513068 A JP 2006-335676 A

  An object of the present invention is to provide an external use composition in which the stability of allantoin and / or its derivative is improved and the storage stability is excellent.

  The present inventors have conducted intensive studies to solve the above-mentioned problems, and found that by using (A) allantoin and / or a derivative thereof and (B) a heparin-like substance together, allantoin and / or a derivative thereof can be stabilized. Found that the properties are improved. Further, the present inventor, in addition to (A) allantoin and / or its derivative, and (B) heparin analog, (C) glycyrrhizic acid, glycyrrhetinic acid, a derivative thereof, and / or a salt thereof in combination It has been found that by blending, the stability of allantoin and / or its derivative can be further improved. The present invention has been completed through further studies based on these findings.

That is, the present invention provides the following aspects of the invention.
Item 1. An external composition comprising (A) at least one selected from the group consisting of allantoin and a derivative thereof, and (B) a heparin-like substance.
Item 2. Item 3. The external composition according to Item 1, further comprising (C) at least one selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof.
Item 3. Item 3. The external composition according to Item 1 or 2, wherein the content of the component (A) is 0.01 to 5% by weight.
Item 4. Item 4. The external composition according to any one of Items 1 to 3, wherein the content of the component (B) is 0.01 to 5% by weight.
Item 5. Item 4. The external composition according to any one of Items 2 to 4, wherein the content of the component (C) is 0.01 to 10% by weight.
Item 6. Item 6. The composition for external use according to any one of Items 1 to 5, which has a pH of 4 to 7.
Item 7. A method for stabilizing allantoin and / or a derivative thereof, comprising coexisting (B) a heparin-like substance with at least one selected from the group consisting of (A) allantoin and a derivative thereof in an external composition.
Item 8. Item 8. The stabilizing method according to Item 7, wherein the topical composition further comprises (C) at least one selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof.
Item 9. A stabilizer used for stabilizing an external composition containing at least one selected from the group consisting of allantoin and a derivative thereof,
A stabilizer comprising a heparin-like substance.
Item 10. A stabilizer used for stabilizing an external composition containing at least one selected from the group consisting of allantoin and a derivative thereof,
A stabilizer comprising (B) a heparin analogue, and (C) at least one selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof.

  According to the present invention, the combined use of (A) allantoin and / or a derivative thereof and (B) a heparin-like substance improves the stability of allantoin and / or a derivative thereof. Even after storage, the medicinal effects of allantoin and / or a derivative thereof can be effectively exerted. Furthermore, according to the present invention, in addition to (A) allantoin and / or a derivative thereof, and (B) a heparin analog, (C) glycyrrhizic acid, glycyrrhetinic acid, a derivative thereof, and / or a salt thereof are combined. By blending it, the stability of allantoin and / or a derivative thereof is remarkably improved, so that it is possible to provide an externally useful composition having extremely high practical utility.

1. External composition The external composition of the present invention comprises at least one selected from the group consisting of allantoin and derivatives thereof (hereinafter, sometimes referred to as component (A)), and a heparin-like substance (hereinafter, (B) (Sometimes referred to as a component). Hereinafter, the external composition of the present invention will be described in detail.

(A) Component The external composition of the present invention contains, as the (A) component, at least one selected from the group consisting of allantoin and its derivatives. Allantoin and / or a derivative thereof has a drawback of poor stability, but according to the present invention, the stability of allantoin and / or a derivative thereof is improved by blending the component (B) described below. be able to.

  Allantoin is a compound also known as 5-ureidohydantoin, and is a known drug known to have an anti-inflammatory effect, an antipruritic effect, and the like.

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

  In the composition for external use of the present invention, as the component (A), one may be selected from allantoin and its derivatives, or two or more may be used in combination. Among these components (A), preferably, allantoin is used from the viewpoint of more effectively improving the stability.

  In the composition for external use of the present invention, the content of the component (A) may be appropriately set according to the medicinal properties to be provided in the composition for external use, for example, 0.01 to 5% by weight, preferably 0.05 to 3% by weight, more preferably 0.05 to 2% by weight, even more preferably 0.1 to 2% by weight.

(B) Component The external composition of the present invention contains a heparin-like substance as the (B) component. As described above, by using allantoin and / or a derivative thereof in combination with a heparin-like substance, the stability of allantoin and / or a derivative thereof can be improved, and excellent storage stability can be provided.

  The heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known drug known to have a moisturizing action, a blood flow increasing action, and the like.

  The origin of the heparin-like substance used in the present invention is not particularly limited, and examples thereof include those obtained by polysulfating mucopolysaccharides and tissues of edible animals (for example, tracheal cartilage such as cows and pigs). Extracted from the lungs). In the composition for external use of the present invention, a heparin-like substance listed in the Japanese Pharmacopoeia Non-Pharmaceutical Standards is suitably used as the heparin-like substance.

  In the composition for external use of the present invention, the content of the component (B) may be appropriately set as long as the stability of allantoin and / or a derivative thereof can be improved, and specifically, 0.01 to 5 % By weight, preferably 0.05 to 3% by weight, more preferably 0.1 to 1% by weight.

  Further, in the external composition of the present invention, the ratio of the component (A) and the component (B) may be appropriately set within a range that satisfies the content described above. The component (B) is 0.3 to 10000 parts by weight, preferably 2.5 to 6000 parts by weight, and more preferably 5 to 1000 parts by weight.

(C) Component The external composition of the present invention further contains, as the component (C), glycyrrhizic acid, glycyrrhetinic acid, a derivative thereof, and / or a salt thereof, in addition to the components (A) and (B). May be. Thus, by further containing the component (C), the stability of allantoin and / or a derivative thereof can be further improved, and the storage stability thereof can be dramatically increased.

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

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

  The salt of glycyrrhizic acid and its derivative is not particularly limited as long as it is pharmacologically acceptable, and specific examples thereof include alkali metal salts such as sodium salt, potassium salt, dipotassium salt and the like; ammonium salts and the like. Can be These salts of glycyrrhizic acid and its derivatives may be used alone or in a combination of two or more.

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

  The derivative of glycyrrhetinic acid is not particularly limited as long as it is pharmaceutically acceptable. Specific examples thereof include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, and monoglucuronide glycyrrhetinate. These glycyrrhetinic acid derivatives may be used alone or in a combination of two or more.

  In the composition for external use of the present invention, as the component (C), glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof, one may be selected and used, or two or more may be used in combination. May be used. Among these components (C), from the viewpoint of improving the stability of allantoin and / or a derivative thereof more effectively, preferably glycyrrhizic acid and a salt thereof, more preferably a salt of glycyrrhizic acid, particularly preferably An alkali metal salt of glycyrrhizic acid may be mentioned.

  In the composition for external use of the present invention, the content of the component (C) is not particularly limited, but is, for example, 0.01 to 10% by weight, preferably 0.05 to 5% by weight, and more preferably 0.05 to 3% by weight. % By weight, particularly preferably 0.1 to 3% by weight.

  In the composition for external use of the present invention, the ratio between the component (A) and the component (C) may be appropriately set within a range that satisfies the content described above. Component (C) is 0.2 to 100,000 parts by weight, preferably 1.7 to 10000 parts by weight, more preferably 2.5 to 6000 parts by weight, and particularly preferably 5 to 3000 parts by weight.

Composition for external use of the water present invention, in order to prepare the desired formulation, may contain water. Allantoin and / or a derivative thereof show a tendency to decrease in stability in the presence of water, but according to the external composition of the present invention, stability of allantoin and / or a derivative thereof caused in the presence of water is high. Can be effectively suppressed.

  In the composition for external use of the present invention, the content of water is appropriately set according to the preparation form and the like, but is, for example, 0.5 to 99% by weight, preferably 10 to 90% by weight, and more preferably 30% by weight. To 90% by weight, particularly preferably 50 to 85% by weight.

Other Components The external composition of the present invention may contain other pharmacological components, if necessary, in addition to the components described above. Such a pharmacological component is not particularly limited as long as it can be used in a composition for external use, but examples thereof include an antihistamine (such as chlorpheniramine maleate) and a local anesthetic (lidocaine, procaine, tetracaine, bupipacaine). , Mepipacaine, chloroprocaine, proparacaine, meprilcaine or salts thereof, orthocaine, oxesazein, oxypolyentoxydecane, funnel extract, percaminpase, tesit decithin, etc., anti-inflammatory agents (indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protection Agents (collodion, castor oil, etc.), blood circulation promoting components (nonylate wanilylamide, nicotinic acid benzyl ester, capsaicin, capsicum extract, etc.), freshener (menthol) Camphor), vitamins (vitamin A, vitamin E, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.) and the like.

  In addition, the composition for external use of the present invention may contain a base material and additives in addition to the above-described components, if necessary, to obtain a desired formulation. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. For example, lower alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propylene glycol, dipropylene glycol, Aqueous bases such as 1,3-butylene glycol and the like; animal and vegetable 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, gelled hydrocarbons, petrolatum, etc.), waxes and waxes (bee wax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), fatty acid alkyl esters, fatty acids (stearic acid) , Oleic acid, palmitic acid, Fatty acids (isopropyl myristate, isopropyl adipate, diethyl sebacate, isopropyl sebacate, cetyl palmitate, isopropyl palmitate, ethyl linoleate, ethyl oleate, etc.), higher alcohols (such as helic acid, linoleic acid, and lanolin) Stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.) Oily bases such as: POE (10 to 50 mol) phytosterol ether, POE (10 to 50 mol) dihydrocholesterol ether, POE (10 to 50 mol) 0 mol) 2-octyldodecyl ether, POE (10 to 50 mol) decyltetradecyl ether, POE (10 to 50 mol) oleyl ether, POE (2 to 50 mol) cetyl ether, POE (5 to 50 mol) behenyl ether Polyoxyethylene alkyl ethers such as POE (5 to 30 mol) polyoxypropylene (5 to 30 mol) 2-decyltetradecyl ether, POE (10 to 50 mol) polyoxypropylene (2 to 30 mol) cetyl ether; These phosphoric acid / phosphate (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 (10-30 G) glyceryl monostearate, POE (20 to 100 mol) / polyoxypropylene-modified silicone, POE / alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate, Polyethylene glycol palmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20-85), glycerin fatty acid ester (glyceryl monostearate, etc.) Surfactants such as hydrogenated soybean phospholipids and hydrogenated lanolin alcohol; refreshing agents (menthol, camphor, Neol, peppermint water, peppermint oil, etc.), preservatives (paraoxybenzoic acid ester such as methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-ionell, citronellal, Farnesol, etc.), coloring agents (tar dyes (brown 201, blue 201, yellow 4, yellow 403, etc.), cocoa dyes, chlorophyll, aluminum oxide, etc.), and thickeners (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone) , Sodium alginate, ethylcellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, etc.), pH adjusters (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine) Triisopropanolamine, etc.), wetting agents (sodium dl-pyrrolidonecarboxylate solution, D-sorbitol solution, macrogol, glycerin, 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, solubilizers, solubilizers, preservatives and other additives.

pH
The pH of the composition for external use of the present invention may be any range as long as it can be applied transdermally. However, from the viewpoint of more effectively improving the stability of allantoin and / or a derivative thereof, it is usually 3 to 9, and preferably 3 to 9. Is 4 to 8, more preferably 4 to 7, particularly preferably 4 to 6.

Formulation The dosage form of the composition for external use of the present invention is not particularly limited as long as it can be applied transdermally, and may be any of liquid, solid, semi-solid (gel, ointment, paste) and the like. Is also good.

  The formulation of the composition for external use of the present invention may be any formulation such as a drug for external use on the skin, a cosmetic, and a skin cleanser. Specific examples of the preparation form of the composition for external use of the present invention include external preparations for skin such as creams, lotions, gels, emulsions, solutions, patches, aerosols, ointments and packs; ointments and creams , Emulsions, lotions, lotions, packs, gels and the like; skin shampoos such as body shampoos, hair shampoos and rinses. Among these formulation forms, preferably, external preparations for skin, more preferably creams, lotions, gels, emulsions and packs, particularly preferably creams and emulsions are used.

  In the prior art, in oil-in-water creams and oil-in-water emulsions, especially oil-in-water creams, the tendency of the stability of allantoin and / or its derivatives to decrease is remarkable. According to the composition, it is possible to stably maintain allantoin and / or a derivative thereof even in such a formulation form. In view of such effects of the present invention, oil-in-water creams and oil-in-water emulsions, particularly preferably oil-in-water creams, are preferred examples of the formulation of the external composition of the present invention. No. Oil-in-water creams and oil-in-water emulsions are prepared from the above-mentioned bases and additives, water and an aqueous phase containing other aqueous components, an oily base, and other oily components. It can be produced by mixing with an oil phase containing the same and performing a known emulsification treatment.

The composition for external use of the present invention can exert an anti-inflammatory action and antipruritic action based on the component (A), a moisturizing action and a blood flow increasing action based on the component (B), and the like. Increased blood flow, keratosis of elbows, knees, heels, ankles, rough hands, cracks and rips in limbs, xerosis, dry skin in children, dry stomach (excluding soreness), and after bruising / spraining It can be applied to the skin for dry skin with muscular pain, arthralgia, itching (xeroderma in the elderly and adults, dry skin in children), and blue bruises.

  When the composition for external use of the present invention contains the component (C), in addition to the anti-inflammatory and antiallergic effects based on the component (C), the components (A) to (C) Can also act as a preventive or therapeutic agent for hypertrophic scars and / or keloids, so that discoloration (redness, dullness), pulling (pulling), lumps, loss of elasticity, etc. of the skin after wounds and burns It can also be used for improvement purposes.

2. A method for stabilizing allantoin and / or a derivative thereof is a method for stabilizing allantoin and / or a derivative thereof, which is selected from the group consisting of (A) allantoin and a derivative thereof in a composition for external use. (B) co-existence of a heparin-like substance together with at least one kind of compound. Further, in the stabilizing method of the present invention, stabilization of allantoin and / or a derivative thereof can be achieved by further coexisting (C) glycyrrhizic acid, glycyrrhetinic acid, a derivative thereof, and / or a salt thereof in the external use composition. Performance can be further improved.

  The types and contents of the components (A) to (C) used in the stabilization method of the present invention, their ratios, and the like are as described in the above-mentioned “1. In the stabilization method of the present invention, other components to be added to the external composition, the formulation of the external composition, the use of the external composition, and the like are also described in the above-mentioned section “1. External composition”. It is as follows.

3. Stabilizer for Allantoin and / or Derivative Thereof The stabilizer of the present invention is a stabilizer used for stabilizing an external composition containing at least one selected from the group consisting of allantoin and its derivative. , Characterized by containing a heparin-like substance. Further, the stabilizer of the present invention is a stabilizer used for stabilizing an external composition containing at least one selected from the group consisting of allantoin and derivatives thereof, and (B) heparin It is characterized by containing an analogous substance and (C) at least one selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. These stabilizers are used as additives for improving the stability of allantoin and / or a derivative thereof in an external composition containing allantoin and / or a derivative thereof and increasing the storage stability of the external composition. You.

  With respect to the type of allantoin and / or its derivative, the type of the component (B), the type of the component (C), the content thereof, the ratio thereof, and the like used in the stabilizer of the present invention, see “1. Externally applied composition ". Further, in the stabilizer of the present invention, other components to be added to the composition for external use, the formulation of the composition for external use, the use of the composition for external use, and the like are also described in the above-mentioned “1. Composition for external use”. It is.

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

Test Example 1 Evaluation of Allantoin Stability in Cream Preparations Creams (Examples 1 to 3 and Comparative Example 1) having the formulations shown in Table 1 were prepared. Specifically, an aqueous phase in which a predetermined amount of an aqueous phase component shown in Table 1 was mixed and an oil phase in which a predetermined amount of an oil phase component shown in Table 1 were mixed were prepared, and the aqueous phase and the oil phase were heated. After mixing and emulsification, the mixture was cooled to prepare an oil-in-water cream.

  The obtained cream was stored in a container (made of glass) and stored in a light-shielded environment at a temperature of 50 ° C. for 7 days. The amount of allantoin contained in each cream before and after storage was quantified by HPLC, and the reduction ratio of allantoin after storage was calculated according to the following formula.

  Table 1 shows the obtained results. From these results, when heparin analog was not contained (Comparative Example), the allantoin had a weight loss ratio of 7.2% after storage at 50 ° C. for 7 days, but allantoin and heparin analog were used in combination. As a result (Examples 1 to 3), the weight loss ratio of allantoin could be effectively reduced, and the stability of allantoin was improved. In particular, when a heparin-like substance and dipotassium glycyrrhizinate were combined and combined with allantoin (Example 2), the stability of allantoin was dramatically improved.

Test Example 2 Evaluation of Allantoin Stability in Emulsion An emulsion having the formulation shown in Table 2 (Example 4) was prepared. Specifically, an aqueous phase in which a predetermined amount of an aqueous phase component shown in Table 2 was mixed, and an oil phase in which a predetermined amount of an oil phase component shown in Table 2 were mixed were prepared, and the aqueous phase and the oil phase were heated. After mixing and emulsification, the mixture was cooled to prepare an oil-in-water emulsion.

  The obtained emulsion was stored in a container and stored for 11 days in a light-shielded environment at a temperature of 50 ° C. The amount of allantoin contained in each emulsion before and after storage was quantified by HPLC, and the reduction ratio of allantoin after storage was calculated according to the calculation formula shown in Test Example 1.

  Table 2 shows the obtained results. From these results, it was confirmed that the stability of allantoin can be remarkably improved by combining heparin-like substance and dipotassium glycyrrhizinate together with allantoin.

Formulation Examples Oil-in-water creams having the compositions shown in Table 3 (Formulation Examples 1 to 13), oil-in-water emulsions shown in Table 4 (Formulation Examples 14 to 23), and lotions shown in Table 5 (Formulation Example 24) ~ 32) were prepared. All of these preparations contain (B) a heparin analog, and (C) a preparation not containing at least one selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. In comparison, a stable effect of allantoin is exhibited.

Claims (2)

  A method for stabilizing allantoin and / or a derivative thereof, comprising coexisting (B) a heparin-like substance with at least one selected from the group consisting of (A) allantoin and a derivative thereof in an external composition.   The stabilizing method according to claim 1, wherein the topical composition further comprises (C) at least one selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof.