JPH07118145A - External preparation for treating skin lesion - Google Patents

Abstract

PURPOSE:To obtain an external preparation for treating skin lesion having excellent cutaneous absorption and improved promoting action on granulation hyperplasia and skin formation. CONSTITUTION:This external preparation for treating skin lesion comprises (i) 0.1-20wt.% of at least one pharmacodynamically effective substance selected from among plaunotol, teprenone and gefarnate, (ii) an oily substance, (iii) a bihydric alcohol selected from an alkylene glycol and a polyalkylene glycol, (iv) an alkanolamine or a 2-hydroxy-4-alkoxybenzophenone compound and (v) a surfactant and has 0.1-20wt.% content of the pharmacodynamically effective substance and 0.1-15wt.% content of the alkanolamine.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation for the treatment of skin damage, which is excellent in the treatment of skin damage such as skin ulcer, traumatic skin exfoliation wound, traumatic skin defect wound, leg ulcer, shingles and the like. It is a thing.

[0002]

2. Description of the Related Art In recent years, the number of bedridden elderly people has been increasing, and the number of bedsore patients due to bed sores has been increasing year by year. In addition, the number of traumatic skin wound patients due to traffic accidents is increasing year by year. As such a skin damage remedy, an external preparation containing antibiotics, isodine sugar, etc. is used, but its accelerating action on granulation and crust formation is unsatisfactory, and a sufficient therapeutic effect is obtained. The current situation is not. So far, some studies have been conducted on the development of a new external preparation for treating skin damage, and as its medicinal component,
Those containing teprenone (Japanese Patent Publication No. 64-10495) and those containing plaunotol (Japanese Patent Publication No. 2-330)
No. 08) has been reported, but these are only to the extent that the medicinal substance is dissolved in an oily substance such as olive oil, and their skin absorbability is still unsatisfactory.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide an external preparation for treating skin damage, which is excellent in skin absorbability and is excellent in promoting granulation and scab formation.

[0004]

The present inventor has completed the present invention as a result of intensive studies to solve the above-mentioned problems. That is, according to the present invention, (i) at least one medicinal substance selected from plaunotol, teprenone and gefarnate, (ii) an oily substance, and (iii)
A dihydric alcohol selected from alkylene glycols and polyalkylene glycols, (iv) an alkanolamine, and (v) a surfactant, and the content of the medicinal substance is 0.1 to 20% by weight, There is provided an external preparation for treating skin damage, wherein the alkanolamine content is 0.1 to 15% by weight. Further, according to the present invention,
(I) at least one medicinal substance selected from plaunotol, teprenone, and gefarnate; and (ii)
An oily substance, and (iii) a dihydric alcohol selected from alkylene glycols and polyalkylene glycols,
(Iv) a 2-hydroxy-4-alkoxybenzophenone compound and (v) a surfactant, the content of the medicinal substance is 0.1 to 20% by weight, and the 2-hydroxy-4-alkoxybenzophenone is There is provided an external preparation for treating skin damage, wherein the content of the compound is 0.1 to 15% by weight.

The external preparation for treating skin damage of the present invention (hereinafter, also simply referred to as external preparation) contains at least one selected from the following three kinds of compounds as its medicinal component. (1) Plaunotol (chemical name) (2E, 6Z, 10E) -7-hydroxymethyl-3,
11,15-Trimethyl-2,6,10,14-hexadecatetraen-1-ol (2) teprenone (chemical name) 6,10,14,18-tetramethyl-5,9,13,
17-Nonadecatetraen-2-one (3) Gefarnate trans-3,7-dimethyl-2,6-octadienyl-5,9,13-trimethyl-4,8,12-tetradecatrienoate

[0006] The plaunotol, teprenone and gefarnate used as the medicinal substance in the present invention (hereinafter, also simply referred to as medicinal substance) are liquids at room temperature, so it is not necessary to dissolve them in an organic liquid. If necessary, it can be used as a solution by dissolving it in an organic liquid having compatibility with it. In this case, as the organic liquid, aliphatic alcohol, terpene alcohol, fatty acid ester, N-alkylpyrrolidone, N, N
-Dialkylacetamide, partial ester of polyhydric alcohol, alkylene oxide adduct of partial ester of polyhydric alcohol, alkylene oxide adduct of monohydric or polyhydric alcohol, alkylene glycol monoalkyl ether, dialkyl imidazolidine, dialkyl sulfoxide and the like. To be Further, a nonionic surfactant having an HLB value of 1 to 12 can be used as the organic liquid.

The above-mentioned aliphatic alcohols include monohydric alcohols and polyhydric alcohols. Such alcohols include ethanol, propanol, isopropanol, octyl alcohol, decyl alcohol, 2-
Monohydric alcohols such as octyldodecanol, alkylene glycols such as ethylene glycol, propylene glycol, butylene glycol, isoprene glycol,
In addition to polyalkylene glycols such as polyethylene glycol and polypropylene glycol, glycerin, sorbit, sorbitan, mannite and the like can be mentioned. Examples of the terpene alcohol include farnesol, phytol, patchouli alcohol and the like.

Examples of the fatty acid ester include monovalent fatty acids such as ethyl myristate, isopropyl myristate, isotridecyl myristate, isopropyl laurate, isopropyl caprylate, isopropyl palmitate, isopropyl butyrate, amyl butyrate and octyl butyrate. In addition to esters, diethyl succinate, diisopropyl succinate, diethyl adipate, diisopropyl adipate, diisooctyl adipate, dioctyl adipate, didecyl adipate, decyl isooctyl adipate, diacetate azelate, diisopropyl azelate, diisooctyl azelate, Examples thereof include divalent fatty acid esters such as diethyl sebacate, diisopropyl sebacate, dibutyl sebacate, and dioctyl sebacate.

Examples of N-alkylpyrrolidone include N-methylpyrrolidone, N-octylpyrrolidone and N-dodecylpyrrolidone, and examples of N, N-dialkylacetamide include N, N-dimethylacetamide, N,
Examples thereof include N-dioctylacetamide, examples of the dialkyl sulfoxide include dimethyl sulfoxide, dioctyl sulfoxide, and the like, and examples of the alkylene carbonate include propylene carbonate, butylene carbonate, and the like. As the partial ester of polyhydric alcohol, a monoester of higher aliphatic carboxylic acid of polyhydric alcohol as described above, for example, monostearic acid ester of glycerin, monobehenic acid ester of glycerin, monostearic acid ester of polyethylene glycol, propylene glycol. Of monostearate of butylene glycol, monostearate of butylene glycol, monooleate of sorbitan, monolaurate of sorbitan, monopalmitate of sorbitan, monostearate of sorbitan, monoisostearate of sorbitan, etc. To be

As the alkylene oxide adduct of the partial ester of polyhydric alcohol, the ethylene oxide adduct or propylene oxide adduct of glycerin monostearate or the ethylene oxide adduct or propylene oxide of polyethylene glycol monostearate. Addition product, ethylene oxide addition product or propylene oxide addition product of propylene glycol monostearate ester, ethylene oxide addition product or propylene oxide addition product of polypropylene glycol monostearate ester, ethylene oxide addition product of propylene glycol monostearate ester or propylene Oxide adduct, sorbitan monofatty acid ester (lauric acid ester, palmitic acid ester, stearic acid ester Tel, oleic acid ester, etc.) ethylene oxide adduct or propylene oxide adduct, and batyl alcohol ethylene oxide adduct or propylene oxide adduct. Examples of the alkylene oxide adduct of monohydric or polyhydric alcohol include ethylene oxide adduct or propylene oxide adduct of dodecyl alcohol, ethylene oxide adduct or propylene oxide adduct of glycerin, ethylene oxide adduct or propylene oxide adduct of sorbitan, and the like. To be As the alkylene glycol monoalcohol ether, ethylene glycol monomethyl ether,
Examples thereof include ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monooctyl ether, isopropylene glycol monomethyl ether, isobutylene glycol monomethyl ether, and methylbutylene glycol monomethyl ether.

The external preparation of the present invention contains an oily substance, a dihydric alcohol, an alkanolamine and / or a 2-hydroxy-4-alkoxybenzophenone compound, and a surfactant together with the medicinal substance.

The 2-hydroxy-4-alkoxybenzophenone compound is represented by the following general formula.

[Chemical 1] In the above formula, R ¹ represents an alkyl group, R ² is hydrogen or —O.
R ⁴ represents an alkoxy group represented by (R ⁴ : alkyl group), and R ³ represents hydrogen or a hydroxyl group. The alkyl group R ¹ ,
R ⁴ can be an alkyl group having 1 to 22 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, butyl, octyl, dodecyl and the like. Further, specific examples of the 2-hydroxy-4-alkoxybenzophenone compound include, for example, 2-hydroxy-4-
Methoxybenzophenone, 2-hydroxy-4-octoxybenzophenone, 2-hydroxy-4-dodecyloxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,
4'-dimethoxy benzophenone etc. are mentioned.

The oily substance is a substance which is liquid or solid at room temperature, and includes fatty acid ester, aromatic carboxylic acid ester, aromatic alcohol, phosphoric acid ester, higher fatty acid triglyceride, higher aliphatic alcohol, higher fatty acid,
It includes terpenes, petrolatum, lanolin, liquid paraffin, squalane, beeswax and mixtures thereof.
As the fatty acid ester, a liquid or solid monovalent fatty acid ester or polyvalent fatty acid ester at room temperature is used. This fatty acid ester generally has 4 carbon atoms.
It may be a lower or higher alcohol ester of saturated or unsaturated linear or branched monovalent or polyvalent fatty acid having about 1 to 18 carbon atoms, preferably about 8 to 18 carbon atoms, or having about 1 to 18 carbon atoms. As the fatty acid component in this fatty acid ester, butyric acid, lactic acid, octanoic acid, isooctanoic acid, dimethyloctanoic acid, nonanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid,
Examples thereof include isostearic acid, oleic acid, behenic acid, adipic acid, azelaic acid and sebacic acid. On the other hand, examples of the alcohol component include ethanol, propanol, isopropanol, butanol, hexanol, decanol, myristyl alcohol, dodecanol, cetyl alcohol, hexadecyl alcohol, behenyl alcohol and the like. Suitable fatty acid esters include, for example, isopropyl myristate, isododecyl myristate, octyldodecyl myristate, myristyl myristate, decyl oleate, oleyl oleate, hexyldecyl isostearate, butyl stearate, cetyl isooctanoate, dimethyl octanoate. Hexyldecyl, isopropyl palmitate, hexyl laurate, isopropyl caprate, myristyl lactate, oleyl adipate, diethyl adipate, diisobutyl adipate, diisodecyl adipate, dioctyl adipate, dibenzyl adipate, di (2-methoxyethyl adipate) ), Dityl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl azelate, diisooctyl azelate, etc. And the like. Examples of the aromatic carboxylic acid ester include diethyl phthalate, dibutyl phthalate, dioctyl phthalate and the like. Examples of the phosphoric acid ester include trioleyl phosphate, tridodecyl phosphate, trioctyl phosphate and the like. Further, in the present invention, the above-mentioned partial ester of polyhydric alcohol or its alkylene oxide adduct can also be used as an oily substance.

As the higher fatty acid triglyceride, various types of liquid or semi-solid ones at room temperature, including naturally-occurring animal substances and vegetable substances can be used. These are generally called fats and oils and are widely available industrially. There are many kinds of vegetable oils, beef tallow, liver oil, lanolin, lard and the like, but preferably vegetable oils, especially olives,
Camellia oil, soybean oil, rapeseed oil, corn oil, castor oil, safflower oil and the like can be used. Examples of higher aliphatic alcohols include cetanol, stearyl alcohol, behenyl alcohol, lanolin alcohol, farnesol and the like. Examples of higher fatty acids include octanoic acid, nonanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, behenic acid, montanic acid, and elaidic acid.

As the dihydric alcohol, alkylene glycols such as ethylene glycol, propylene glycol, butylene glycol and isoprene glycol, and polyalkylene glycols such as polyethylene glycol and polypropylene glycol are used.

In the present invention, as a stabilizer for the medicinal substance, an alkanolamine and / or 2-hydroxy-
A 4-alkoxybenzophenone compound is used. The present inventor has conducted various studies on the development of stabilizers for medicinal substances, and has found that alkanolamines or 2-hydroxy-4-alkoxybenzophenone compounds, or a combination of both, shows excellent stabilizing effects. . As alkanolamine, diethanolamine, triethanolamine, isopropanolamine,
Examples thereof include diisopropanolamine, triisopropanolamine, dibutanolamine and tributanolamine. The external preparation of the present invention preferably further contains terpene alcohol. Examples of the terpene alcohol include farnesol, phytol, hinokiol, patchouli alcohol, oidesmol, menthol, geraniol, borneol, citronellol and the like. These terpene alcohols significantly enhance the skin absorbability of medicinal substances.

As the surfactant, various anionic, cationic, nonionic and amphoteric surfactants can be used, but from the viewpoint of low irritation to the skin, the nonionic surfactant is It is used to advantage. Examples of the nonionic surfactant include ethylene oxide-based surfactants, polyhydroxy-based surfactants, polymer-based surfactants and the like. Examples of the ethylene oxide surfactant include, for example,
Higher alcohol ethylene oxide adduct, higher fatty acid ethylene oxide adduct, alkylphenol ethylene oxide adduct, aliphatic amine ethylene oxide adduct, aliphatic amide ethylene oxide adduct, polyhydric alcohol ethylene oxide adduct, ethylene oxide / propylene oxide block copolymer Examples thereof include polymers. Examples of the polyhydroxy surfactant include glycerin monofatty acid ester, pentaerythritol fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, fatty acid amide of ethanolamine, and alkylene oxide adducts thereof. In the present invention, in particular, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glyceryl monofatty acid ester, polyoxypropylene monofatty acid ester,
Sorbitan fatty acid ester, polyoxyethylene alkyl ether and the like are advantageously used. These surfactants are used alone or in the form of a mixture.

In the external preparation of the present invention, the content of the medicinal compound is 0.1 to 20% by weight, preferably 1 to 10% by weight. The content of the oily substance is not particularly limited, and an appropriate amount is blended depending on the desired properties of the external preparation. When the surfactant is blended, the blending amount is not particularly limited, and an appropriate amount is blended depending on the desired properties of the external preparation. The surfactant is generally 5 to 50% by weight, preferably 20% by weight of the total external preparation when the external preparation is a non-emulsion type.
~ 45% by weight, in the case of emulsion type,
It is 1 to 20% by weight, preferably 5 to 15% by weight. The content of the dihydric alcohol is 1 to 20% by weight, preferably 3 to 15% by weight. This dihydric alcohol promotes the dispersion of the medicinal substance dissolved in the oily substance in water.

The content of alkanolamine is 0.1-0.1%.
It is 15% by weight, preferably 0.5 to 10% by weight. This alkanolamine acts as a stabilizer of the medicinal substance and promotes the skin absorbability of the medicinal substance.
The content of the 2-hydroxy-4-alkoxybenzophenone compound is 0.1 to 15% by weight, preferably 0.5 to
It is 10% by weight. The 2-hydroxy-4-alkoxybenzophenone compound prevents and stabilizes the oxidation of the medicinal substance. The content of the terpene alcohol preferably used in the present invention is 0.1 to 20% by weight, preferably 1 to 10%.
% By weight.

The external preparation of the present invention may contain water, a filler, a thickener (polymer compound), a colorant, an aromatic agent, an emulsion stabilizer, a bactericide, a fungicide, etc., if necessary. it can. As the filler, organic and inorganic fine powders are used. The particle size of this filler is usually 0.1 to 20 μm, preferably 0.5 to 10 μm. Preferable examples of the filler include silica, alumina, titania, resin powder, silicate powder, clay powder, sepiolite powder, montmorillonite powder, fluorine-containing mica powder, hydroxypropylcellulose powder and the like.

The external preparation of the present invention is applied in various forms such as an ointment, a cream and a lotion, and its composition is adjusted appropriately according to the form of the product. When the external preparation of the present invention is applied in the form of a non-emulsion type ointment-like mixture, the following component composition is preferable. (1) Medicinal substance 0.1 to 20% by weight, preferably 1 to 10% by weight (2) Organic liquid 0 to 40% by weight, preferably 2 to 20% by weight (3) Oily substance 20 to 80% by weight, preferably 20 to 60% by weight (4) Alkanolamine and / or 2-hydroxy-
4-alkoxybenzophenone compound (stabilizer) 0.1 to 15% by weight, preferably 0.5 to 10% by weight (5) Surfactant 20 to 80% by weight, preferably 40 to 70% by weight (6) Polyhydric alcohol 1 to 20% by weight, preferably 3 to 15% by weight (7) Filler 0 to 15% by weight, preferably 5 to 10% by weight (8) Purified water 0 to 10% by weight, preferably 1 to 5% by weight %

In the external preparation consisting of the non-emulsion type ointment mixture, a solid oily substance or a mixture of a solid oily substance and a liquid oily substance is used as the oily substance. In the case of this external preparation, it is necessary to contain a surfactant and / or an oily substance in a solid state at room temperature in an amount of 20 to 80% by weight, preferably 30 to 70% by weight.
Examples of the solid oily substance in this case include the various oily substances described above. Examples of solid surfactants include polyoxyethylene glycerin fatty acid esters such as POE (5) glyceryl monostearate, POE (15) glyceryl monostearate and POE (40) glyceryl monostearate, and tetraglyceryl monostearate. Polyglycerin fatty acid ester such as triglyceryl tristearate and decaglyceryl trioleate, glyceryl monomyristate, glyceryl monostearate, glyceryl fatty acid ester such as diglyceryl distearate, sorbitan monopalmitate, sorbitan monostearate, sesquistearin Acid sorbitan, sorbitan fatty acid esters such as sorbitan trisstearate, polyoxyethylene sorbitan such as POE (20) sorbitan trisstearate, Kisasutearin acid POE (6) polyoxyethylene sorbit fatty acid esters such as sorbitol monostearate PEG
(4EO), polyethylene glycol fatty acid ester such as polyethylene glycol distearate, POE (8
0) Polyethylene hydrogenated castor oil such as hydrogenated castor oil, POE (100) hydrogenated castor oil, polyoxyethylene alkyl ether such as POE (2) cetyl ether, POE (5) behenyl ether, and polyoxy such as POE (30) phytosterol Ethylene phytosterol, POE
(20) POP (8) cetyl ether, POE (20)
POP (6) polyoxyethylene polyoxypropylene alkyl ether such as decyl tetradecyl ether, P
OE (30) octyl phenyl ether and other polyoxyethylene alkyl phenyl ethers, POE (40) lanolin alcohol, POE (10) lanolin alcohol and other polyoxyethylene lanolin alcohols, POE
(6) Polyoxyethylene beeswax derivatives such as sorbit beeswax and POE (20) sorbit beeswax, diP
Examples include polyoxyethylene alkyl ether phosphoric acid such as OE (8) alkyl ether phosphoric acid. Any of these solid surfactants can also be used as an oily substance. The external preparation mixes a medicinal substance or an organic liquid solution thereof, an oily substance, a surfactant, a stabilizer, and a dihydric alcohol under heating, and then, if necessary, water and a filler. It can be prepared by adding, uniformly mixing and allowing to cool.

When the external preparation of the present invention is applied in the form of an emulsion type ointment-like mixture, the following component composition is preferable. (1) Medicinal substance 0.1 to 20% by weight, preferably 1 to 10% by weight (2) Organic liquid 0 to 40% by weight, preferably 2 to 20% by weight (3) Oily substance 60 to 90% by weight, preferably 70-85% by weight (4) Alkanolamine and / or 2-hydroxy-
4-alkoxybenzophenone compound (stabilizer) 0.1 to 15% by weight, preferably 0.5 to 10% by weight (5) Surfactant 1 to 20% by weight, preferably 2 to 10% by weight (6) Polyhydric alcohol 1 to 20% by weight, preferably 3 to 15% by weight (7) Filler 0 to 15% by weight, preferably 5 to 10% by weight (8) Purified water 0 to 10% by weight, preferably 0 to 5% by weight %

In the above external preparation, the oily substance is
A solid at room temperature or a mixture of a solid at room temperature and a liquid at room temperature is used. As the surfactant, one having an HLB of 8 to 15, preferably 9 to 12 is used. The external preparation is a mixture of a medicinal substance or an organic liquid solution thereof, an oily substance, and a surfactant under heating, and this mixture is gradually stirred into a mixture consisting of a stabilizer, a dihydric alcohol and water. It can be prepared by adding, mixing with a filler if necessary, and allowing the resulting mixture to cool.

When the external preparation of the present invention is applied in the form of an emulsion-type creamy mixture, the following component composition is preferable. (1) Medicinal substance 0.1 to 20% by weight, preferably 1 to 10% by weight (2) Organic liquid 0 to 40% by weight, preferably 2 to 20% by weight (3) Oily substance 2 to 50% by weight, preferably Is 10 to 40% by weight (4) alkanolamine and / or 2-hydroxy-
4-alkoxybenzophenone compound (stabilizer) 0.1 to 15% by weight, preferably 0.5 to 10% by weight (5) Surfactant 10 to 35% by weight, preferably 15 to 30% by weight (6) Polyhydric alcohol 1 to 20% by weight, preferably 3 to 15% by weight (7) Thickener (water-soluble polymer) 0.1 to 5% by weight, preferably 0.2 to 2% by weight (8) Purified water 30 -75 wt%, preferably 40-60 wt% (9) Filler 0-10 wt%, preferably 1-5 wt%

In order to produce the above-mentioned external preparation, the components (1), (2), (3), (4) and (5) are mixed under heating to prepare a mixture A. Next, this mixture A is gradually added to the mixture B of the components (4), (6), (7) and (8) with stirring, and then the component (9) is added and mixed and cooled.
In this case, the external preparation can be an oil / water type emulsion and a water / oil type emulsion. In the case of the oil / water type, a surfactant having HLB 9 to 18 is preferably used as the surfactant, and in the case of the water / oil type, the surfactant having HLB 2 to 8 is preferably used. As the oily substance, a solid substance at normal temperature or a mixture of a solid substance at normal temperature and a liquid substance at normal temperature is used. Examples of the thickener include water-soluble polymers such as carboxyvinyl polymer, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate, propylene glycol alginate propylene glycol ester, chitosan, polyvinyl alcohol, and sodium tempunglycolate.

In order to preferably produce the above-mentioned external preparation comprising a creamy mixture, the medicinal substance of component (1) or a solution prepared by dissolving it in an organic liquid solution of component (2) is added to the solid of component (3). To the mixture obtained by mixing the oily substance, the stabilizer of component (4) and the solid surfactant of component (5), the medicinal substance of component (1) or an organic liquid solution thereof, and component (6). And mix. In this mixing step, the temperature of the solid oily substance at room temperature and the temperature of the solid surfactant at room temperature are kept above the melting points of these substances, and care should be taken not to deposit these substances as solids. Next, the stabilizer of the component (4), the water of the component (8), and the thickener of the component (7), if necessary, are added to and mixed with the mixed solution obtained as described above, and if necessary. After adding and mixing the filler of the component (9), it is cooled. In this case, the thickener of component (7), which is optionally used, is preferably added after the addition of water of component (8), but it is dissolved in water of component (8) in advance and added at the same time as water. be able to. Also,
Other water-soluble substances such as urea and polyhydric alcohol may be dissolved in the component (8) water in advance. The amount of urea added is in the range of 5 to 20% by weight, preferably 5 to 10% by weight, based on the total external preparation.

In administration of the external preparation of the present invention, the external preparation is directly applied to the affected area several times a day, for example, 1 to 3 times, or
Alternatively, it can be processed into a form of a patch, plaster, pap, etc., and this can be similarly applied to the affected area several times a day. The number of times of application can be appropriately increased or decreased depending on the severity of the disease.

[0029]

INDUSTRIAL APPLICABILITY The external preparation of the present invention does not show a flammability because the medicinal compound contained therein is highly safe and exists in an organic liquid or an organic solid in a dissolved state.
It has excellent cutaneous or mucosal absorbability and shows a high therapeutic effect. Moreover, since the external preparation of the present invention is not administered systemically but to a diseased site, it can be safely administered without causing side effects such as skin irritation, redness, and itch. The external preparation of the present invention exhibits an excellent therapeutic effect on skin damage due to the action of its medicinal compound. The skin damage in this case includes, for example, skin ulcers such as pressure ulcers and burns; traumatic skin exfoliation wounds and skin defect wounds; and leg ulcers due to diabetes, Purger's disease and the like. When the pressure ulcer is treated using the external preparation of the present invention, the ulcer surface is replaced by the edematous, bleeding-prone whitened granulation tissue before the treatment, and after a few days, the reddish soft granulation tissue begins to rise. It was After 2 to 4 weeks of treatment, the ulcer surface was covered with fresh reddish granulation tissue as a whole, and as a result of the scabbing progressing from the peripheral part of the ulcer to the central part, the pressure ulcer surface decreased and the healing process. It became clear to enter. Further, using the external preparation of the present invention, when treating low-temperature burns, skin ulcers due to leg ulcers and shingles and skin traumas,
Similar effect is observed. The external preparation of the present invention exhibits a far superior therapeutic effect on intractable skin diseases as compared with conventional drugs.

[0030]

EXAMPLES Next, the present invention will be described in more detail by way of examples.

Example 1 (Preparation of plaunotol cream A) Plaunotol (trade name "Kernak") 80 g, 2-
Hydroxy-4-methoxybenzophenone (oxybenzone) 5 g, olive oil 100 g, isopropyl myristate 30 g, isotridecyl myristate 30 g, behenyl alcohol 30 g, stearic acid 30 g, spermaceti 50 g, polyoxyethylene (5) glyceryl stearate 30 g, polyethylene monostearate polyethylene Glycol 30 g, polyoxyethylene (2) cetyl ether 10
The mixture consisting of g is dissolved by heating at 82 ° C. or higher to form a uniform solution (solution A). Separately, 15 g of diisopropanolamine, 30 g of isoprene glycol,
40 g of propylene glycol, 1 g of propyl ester of paraaminobenzoic acid and 1 g of methyl ester of paraaminobenzoic acid are added to about 488 ml of purified water, and the mixture is heated to 80 ° C. and uniformly dispersed (solution B). Liquid B is maintained at 80 ° C., and liquid A is added little by little with stirring to emulsify. After the addition is completed, the heating is stopped, the whole is left to stand, and after defoaming, the cream container is filled.

Example 2 (Preparation of plaunotol cream B) Plaunotol 80 g, oxybenzone 10 g, olive oil 80 g, isopropyl myristate 30 g, farnesol 20 g, stearic acid 40 g, isotridecyl myristate 30 g, cetanol 30 g, polyethylene glycol (molecular weight 400). A mixture consisting of 10 g, cetyl palmitate 70 g, polyoxyethylene (5) glyceryl stearate 30 g, polyethylene glycol monostearate 20 g, and sorbitan monostearate 20 g was dissolved by heating at 82 ° C. or higher to form a uniform solution. Do (solution A). Separately, 10 g of diisopropanolamine, 5 g of carboxyvinyl polymer, 30 g of isoprene glycol, 20 g of butylene glycol, 1 g of propyl paraaminobenzoate and 1 g of methyl paraaminobenzoate were added to about 463 ml of purified water and heated to 80 ° C. Disperse evenly (liquid B). Keep solution B at 80 ° C,
The liquid A is added little by little with stirring to emulsify. After the addition is completed, the heating is stopped, the whole is allowed to cool, and after defoaming, the cream container is filled.

Example 3 (Preparation of teprenone cream A) 100 g of teprenone (product name "Cervex"), 5 g of oxybenzone, 100 g of olive oil, 30 g of isopropyl myristate, 30 g of isotridecyl myristate.
g, behenyl alcohol 30 g, stearic acid 30 g,
50 g of whale wax, polyoxyethylene stearate (5)
A mixture of 30 g of glyceryl, 30 g of polyethylene glycol monostearate and 10 g of polyoxyethylene (2) cetyl ether is dissolved by heating at 82 ° C. or higher to form a uniform solution (solution A). Separately from this, 15 g of diisopropanolamine and 5 of isoprene glycol
0 g, 1 g of para-aminobenzoic acid propyl ester and 1 g of para-aminobenzoic acid methyl ester were added to about 488 ml of purified water and heated to 80 ° C. to uniformly disperse (B
liquid). The liquid B is maintained at 80 ° C., and the liquid A is gradually added to this liquid B with stirring to emulsify the liquid. After the addition is completed, the heating is stopped, the whole is allowed to cool, and after defoaming, the cream container is filled.

Example 4 (Preparation of teprenone cream B) Teprenone 100 g, olive oil 80 g, oxybenzone 10 g, isopropyl myristate 30 g, farnesol 20 g, isotridecyl myristate 30 g, cetanol 30 g, polyethylene glycol (molecular weight 40
0) A mixture of 10 g, cetyl palmitate 70 g, polyoxyethylene (5) glyceryl stearate 30 g, polyethylene glycol monostearate 20 g, and sorbitan monostearate 20 g was dissolved by heating at 82 ° C. or higher to obtain a uniform solution. (Solution A). Separately, 10 g of diisopropanolamine, 5 g of carboxyvinyl polymer, 30 g of isoprene glycol, 20 g of butylene glycol, 1 g of propyl paraaminobenzoate and 1 g of methyl paraaminobenzoate were added to about 483 ml of purified water and heated to 80 ° C. Disperse evenly (B
liquid). Liquid B is maintained at 80 ° C., and liquid A is added little by little with stirring to emulsify. After the addition is completed, the heating is stopped, the whole is allowed to cool, and after defoaming, the cream container is filled.

Example 5 (Plaunotol Ointment) A solution A consisting of 80 g of pronotol, 20 g of propylene glycol, 10 g of isoprene glycol, 5 g of diisopropanolamine and 5 g of oxybenzone is prepared. Separately, 2 g of POE (60) hydrogenated castor oil, 10 g of isostearic acid, 20 g of sorbitan monostearate and 848 g of vaseline are heated and melted to prepare a melt B. Next, the solution A is mixed with the melt B heated to 60 ° C. under stirring, and then gradually cooled to room temperature.

Example 6 (Preparation of gefarnate cream A) 80 g of gefarnate, 5 g of oxybenzone, 100 g of olive oil, 30 g of isopropyl myristate, 30 g of isotridecyl myristate, 30 behenyl alcohol.
g, 30 g of stearic acid, 50 g of whale wax, 30 g of polyoxyethylene (5) glyceryl stearate, 30 g of polyethylene glycol monostearate, and 10 g of polyoxyethylene (2) cetyl ether 8 g.
Dissolve by heating above 2 ° C to make a uniform solution (A
liquid). Separately from this, diisopropanolamine 15
g, isoprene glycol 30 g, propylene glycol 40 g, paraaminobenzoic acid propyl ester 1 g,
About 488 ml of para-aminobenzoic acid methyl ester 1 g
To purified water and heated to 80 ° C. to uniformly disperse (liquid B). Liquid B is maintained at 80 ° C., and liquid A is added little by little with stirring to emulsify. After the addition is completed, the heating is stopped, the whole is left to stand, and after defoaming, the cream container is filled.

Example 7 (Preparation of Gefarnate Cream B) Gefarnate 80 g, oxybenzone 10 g, olive oil 80 g, isopropyl myristate 30 g, farnesol 20 g, stearic acid 40 g, isotridecyl myristate 30 g, cetanol 30 g, polyethylene glycol (molecular weight 400) 10 g, A mixture of 70 g of cetyl palmitate, 30 g of polyoxyethylene (5) glyceryl stearate, 20 g of polyethylene glycol monostearate and 20 g of sorbitan monostearate was dissolved by heating at 82 ° C. or higher to form a uniform solution ( Liquid A). Separately, 10 g of diisopropanolamine, 5 g of carboxyvinyl polymer, 30 g of isoprene glycol, 20 g of butylene glycol, 1 g of propyl paraaminobenzoate and 1 g of methyl paraaminobenzoate were added to about 463 ml of purified water and heated to 80 ° C. Disperse evenly (liquid B). Keep solution B at 80 ° C,
The liquid A is added little by little with stirring to emulsify. After the addition is completed, the heating is stopped, the whole is allowed to cool, and after defoaming, the cream container is filled.

In order to investigate the storage stability of the external preparation of the present invention, the following storage stability test was conducted. (Storage stability test) 20 g of an external preparation for a sample is put in a tube for an ointment and sealed, and the temperature is 40 ° C. and the humidity is 75% R.
After being left for 6 months under the condition of H, the residual rate (%) of the medicinal substance contained in the sample was measured. The residual rate of the medicinal substance was measured as follows. (Measurement of residual rate of medicinal substance) The sample after the test was dissolved in ethanol, and this was analyzed by high performance liquid chromatography to measure the amount of medicinal substance remaining in the sample, and the residual rate of medicinal substance in the sample was calculated. The results of the above storage stability test are shown in Table 1. The contents of the samples shown in Table 1 are as follows. (1) Sample A (I) Plaunotol Cream B shown in Example 2 (2) Sample A (II) From Plaunotol Cream B shown in Example 2, 2-
Removing hydroxy-4-methoxybenzophenone (OBZ) (3) Sample A (III) Removing plunotol cream B shown in Example 2 from diisopropanolamine (DIP) (4) Sample A ( IV) Plaunotol Cream B from Example 2 to OBZ and DI
(5) Sample B (I) Teprenone cream A shown in Example 4 (6) Sample B (II) Teprenone cream A shown in Example 4 with OBZ removed (7) ) Sample B (III) Teprenone cream A shown in Example 4 without DIP (8) Sample B (IV) Teprenone cream A shown in Example 4 with both OBZ and DZP removed (9) Sample C (I) Gefarnate cream B shown in Example 6 (10) Sample C (II) Gefarnate cream B to OBZ shown in Example 6
(11) Sample C (III) DIP from gefarnate cream B shown in Example 6
(12) Sample C (IV) Gefarnate cream B to OBZ shown in Example 6
Without both DIP and DIP

[0039]

[Table 1]

Example 8 Next, the clinical effects of the external preparation of the present invention will be shown. (Case 1) A male patient (72 years old) having a large decubitus wound having a major axis of about 7 cm, a minor axis of about 5 cm and a depth of 1 cm in the sacral region was started treatment with plaunotol cream (A). It should be noted that this patient is 6 months after the onset of pressure ulcer, and even if conventional therapeutic agents such as solcoceryl ointment and pohidon sugar are applied to the treatment, the patient shows resistance and a remarkable improvement effect is seen. It was not there. This patient was continuously applied with plaunotol cream (A) at a rate of 1 g once a day, and after 7 days, granulation tissue appeared in a band form from the margin of the pressure sore and the pressure sore. A thin granulation also appeared on the wound bottom, and it began to cover the sacrum. In the second week, granulations grew throughout the pressure sore, and the way of the growth became a tuft of grapes. At the third week, the swelling of the granulation became similar to that of the surrounding skin, and the surrounding skin began to lean toward the center, and the size of the pressure sore was reduced by about 2 cm in diameter.

(Case 2) A pressure ulcer (3 × 3c) on the right iliac dorsal region
m, depth 1.5 cm) for a male patient (76 years old) having 1 g of plaunotol cream (A) once,
The topical application was continued twice a day. One week after application, the pressure ulcer was raised to almost the same level as the surrounding skin, and the pressure ulcer size was reduced to about 1.7 × 2 cm.

(Case 3) A 68-year-old man. 8.5 on the sacrum
cm × 7.5 cm large decubitus appeared and the center was 1.5 ~
A sacral periosteum is exposed with a 2 cm depression. On the other hand, 1 to 5 g of teprenone cream A
When applied twice a day, one week later, vortex-like granulation formation was observed from the periphery toward the center, and the swelling of granulation tissue improved to a higher level than the surrounding skin. . Two weeks later, the exposed part of the sacral periosteum was covered with new granulation tissue, showing a marked improvement.

(Case 4) A 74-year-old man. 3.5 on the sacrum
cm × 4.5 cm large decubitus appeared and the center was 1.5 ~
A sacral periosteum is exposed with a 2 cm depression. On the other hand, gefarnate cream B3-5g
When applied twice a day, a spiral-shaped granulation formation was observed in the entire circumference from the periphery to the center one week later, and the swelling of the granulation tissue improved to a higher level than the surrounding skin. I've been Two weeks later, the exposed part of the sacral periosteum was covered with new granulation tissue, showing a marked improvement.

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Claims (3)

[Claims] 1. An (i) at least one medicinal substance selected from plaunotol, teprenone, and gefarnate, (ii) an oily substance, and (iii) a dihydric alcohol selected from alkylene glycols and polyalkylene glycols. And (iv) alkanolamine and (v) a surfactant, and the content of the medicinal substance is 0.1 to 2
An external preparation for treating skin damage, which is 0% by weight and the alkanolamine content is 0.1 to 15% by weight. 2. (i) At least one medicinal substance selected from prounol, teprenone and gefarnate, (ii) an oily substance, and (iii) a dihydric alcohol selected from alkylene glycols and polyalkylene glycols. And (iv) a 2-hydroxy-4-alkoxybenzophenone compound, and (v) a surfactant,
The external preparation for treating skin damage, wherein the content of the medicinal substance is 0.1 to 20% by weight and the content of the 2-hydroxy-4-alkoxybenzophenone compound is 0.1 to 15% by weight. 3. 0.1 to 15% by weight of alkanolamine
The external preparation according to claim 2, which comprises: