JP2005343890A - Skin care preparation for external use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a liquid or semi-solid skin care preparation for external use improved in the preparation stability of an esterified steroid. <P>SOLUTION: This liquid or semi-solid skin care preparation is obtained by containing one or more substances selected from the group consisting of lidocaine, dibucaine, benzocaine, procaine, meprylcaine and mepivacaine, one or more substances selected from the group consisting of starch, crystalline cellulose and polyvinylpyrrolidone, and the esterified steroid. Another version of this skin care preparation further improved in the preparation stability is obtained by incorporating the above skin care preparation with a chelating agent or oily base. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an external preparation comprising an esterified steroid and a basic organic compound, and relates to an external preparation capable of stably holding the esterified steroid.

Compounds with a steroid skeleton are known to show high physiological activity in trace amounts, and corticosteroids are eczema (eg, atopic dermatitis), rash (eg, rash, hives, insect bites), dermatitis, psoriasis, pustules It is used for the treatment. Steroid compounds have been enhanced by introducing double bonds on the skeleton or by changing substituents in various ways. For this reason, various derivatives of steroid compounds exist, and examples of ester derivatives include acetylated or valerylated steroids having a hydroxyl group at the 17- or 21-position. These esterified steroids are known to be easily decomposed in the preparation depending on the compound used in combination, and stabilization is a very important issue.
Compounds that are difficult to use in combination with esterified steroids include basic compounds such as imidazole antifungals, urea, glycerin, etc. For example, destabilization with imidazole antifungals includes polyhydric alcohols and HEC / HPC (Patent Document 1: Japanese Patent Laid-Open No. 4-124134) and destabilization with urea are stabilized by using neutral amino acids and inorganic salts (Patent Document 2: Japanese Patent Laid-Open No. 7-97326), respectively. It has been reported that It has also been reported that the destabilization by glycerin and the promotion of destabilization by glycerin and diphenhydramine are suppressed by polar oil (Patent Document 3: JP 2001-247463 A).
By the way, an external preparation for skin containing lidocaine, which is a basic local anesthetic, or a similar compound to esterified steroids, is widely marketed in order to suppress pain and itching in affected areas in skin diseases accompanied by inflammation. Yes. The suppression of the degradation of esterified steroids by the combined use of a basic local anesthetic is known due to organic acid or hydrochloric acid (Patent Document 4: Japanese Patent Laid-Open No. 2001-72603), but the effect is not sufficient. Also, the effects of starch, crystalline cellulose and polyvinylpyrrolidone on the stabilization of esterified steroids have not been studied.

  This invention makes it a subject to provide the skin external preparation by which decomposition | disassembly of the esterified steroid by combined use of a lidocaine or its analog compound was suppressed more.

  As a result of diligent research to solve the above problems, the present inventors have found that esterification steroid and a specific basic compound are mixed with starch, crystalline cellulose, or polyvinylpyrrolidone. It has been found that the steroid formulation stability is improved.

That is, this invention is a liquid or semi-solid skin external preparation shown to the following (1)-(7).
(1) (A) esterified steroid, (B) one or more selected from the group consisting of lidocaine, dibucaine, benzocaine, procaine, meprilucaine and mepivacaine, and (C) consisting of starch, crystalline cellulose and polyvinylpyrrolidone A liquid or semisolid external preparation for skin containing one or more selected from the group.
(2) The liquid or semisolid external preparation for skin according to (1), wherein the esterified steroid is hydrocortisone-21-acetate, prednisolone-21-acetate, prednisolone-17-valerate-21-acetate.
(3) The liquid or semisolid external preparation for skin according to (1) or (2), further containing a chelating agent.
(4) The liquid or semisolid external preparation for skin according to any one of (1) to (3), further containing an oily base.
(5) The liquid or semisolid external preparation for skin according to any one of (1) to (4), which is substantially anhydrous.
(6) The liquid or semisolid external preparation for skin according to any one of (1) to (5), which is for hemorrhoids.
(7) The liquid or semisolid external preparation for skin according to any one of (1) to (6), which is an ointment or liquid.
Moreover, this invention also includes the stabilization method of the esterified steroid shown to the following (8)-(10).
(8) A method for stabilizing an esterified steroid, comprising using at least one of starch, crystalline cellulose, and polyvinylpyrrolidone, a basic compound, and an esterified steroid.
(9) The method for stabilizing an esterified steroid according to (8), wherein either a chelating agent or an oily base is used in combination.
(10) The method for stabilizing an esterified steroid according to (8) or (9), which is substantially anhydrous.
In the present specification, “%” means “% by weight” unless otherwise specified.

  In the present invention, the liquid or semisolid external preparation for skin containing a basic compound and an esterified steroid contains at least one of starch, crystalline cellulose, and polyvinylpyrrolidone, thereby stabilizing the formulation of the esterified steroid. Will improve.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the esterified steroid is not particularly limited as long as the steroid having a hydroxyl group is esterified, but those having a hydroxyl group at the 17-position or the 21-position are preferably esterified.
Examples of steroids include physiologically active hormones such as corticosteroids and sex hormones, and specific examples include hydrocortisone, prednisolone, methylprednisolone, clobetasone, betamethasone, dexamethasone, flumethasone, beclomethasone, fluticasone, and flunisolide. Are hydrocortisone, prednisolone and clobetasone.
Examples of the carboxylic acid to be esterified include acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, pivalic acid, benzoic acid and the like, preferably acetic acid, butyric acid and valeric acid.
Specific examples of esterified steroids include, for example, hydrocortisone-21-acetate, hydrocortisone-17-acetate, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, hydrocortisone-17-butyrate-21-propionic acid Ester, hydrocortisone-17-butyric acid-21-propionic acid ester, prednisolone-21-acetic acid ester, prednisolone-17-valeric acid-21-acetic acid ester, methylprednisolone-21-acetic acid ester, clobetasone-17-butyric acid ester, betamethasone- 21-acetate, betamethasone-17-valerate, betamethasone-17-benzoate, betamethasone-17,21-dipropionate, betamethasone-17-butyrate-21-propionate, dexamethasone-21-valerate S Dexamethasone-21-acetate, dexamethasone-21-propionate, flumethasone-21-acetate, flumethazone-21-pivalate, beclomethasone propionate, and the like, especially hydrocortisone-21-acetate (hydrocortisone acetate) ), Prednisolone-17-valeric acid-21-acetate (prednisolone valerate acetate) and clobetasone-17-butyrate (clobetasone butyrate) are preferred.
These esterified steroids can be used alone or in combination of two or more.

  The compounding amount of the esterified steroid in the liquid or semisolid external preparation of the present invention is not particularly limited as long as it can avoid the development of side effects while fully exhibiting the original pharmacological effect, and exhibits the effects of the present invention. Not. Specifically, for example, hydrocortisone-21-acetate, prednisolone-17-valerate-21-acetate or clobetasone-17-butyrate is usually 0.001 to each of the total weight of the liquid or semisolid skin external preparation. 10%, preferably 0.005 to 5%, more preferably 0.01 to 1%.

Lidocaine, dibucaine, benzocaine, procaine, meprilucaine and mepivacaine used in the present invention are known basic organic compounds having a pharmacological action and can be obtained as commercial products. These compounds may be pharmaceutically, pharmacologically or physiologically acceptable salts. Examples of such salts include inorganic acid salts (for example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), preferably hydrochloride, sulfate, nitrate, Preferred are hydrochlorides, and specific examples include lidocaine hydrochloride and dibucaine hydrochloride. The basic organic compounds can be used alone or in combination of two or more, but it is preferable to combine two or more.
The blending amount of lidocaine, dibucaine, benzocaine, procaine, meprilucaine, mepivacaine in the liquid or semisolid skin external preparation of the present invention may be usually 0.01 to 15% as the total amount of the basic organic compound, 0.05 to 10 % Is more preferable, and 0.1 to 5% is particularly preferable.

Starch, crystalline cellulose, and polyvinylpyrrolidone used in the present invention are compounds described in the Pharmaceutical Additives Dictionary. Starch is a D-glucose polymer composed of two components, amylopectin and amylose, and is a tasteless and odorless white powder, specifically, for example, wheat starch, corn starch, potato starch, rice starch, oat starch, Examples include tapioca starch, barley starch, soluble starch, pregelatinized starch, and partially pregelatinized starch. Polyvinylpyrrolidone may be any of K25, K30, and K90.
The blending amounts of starch, crystalline cellulose and polyvinylpyrrolidone in the liquid or semi-solid skin external preparation of the present invention are not particularly limited as long as the effects of the present invention are exhibited, but with respect to the total weight of the liquid or semi-solid skin external preparation. Usually, it may be 0.001 to 20%, more preferably 0.005 to 18%, and still more preferably 0.01 to 15%.

  Further, in the liquid or semisolid skin external preparation of the present invention, when the total amount in the preparation of lidocaine, dibucaine, benzocaine, procaine, meprilucaine and mepivacaine is 1, the weight blending ratio of starch, crystalline cellulose and polyvinylpyrrolidone is: Each is preferably 0.001 to 50, more preferably 0.005 to 20, and particularly preferably 0.01 to 10.

When the liquid or semisolid external preparation for skin of the present invention further contains a chelating agent, the esterified steroid can be further stabilized.
The chelating agent that can be used in the present invention is not particularly limited as long as it is usually used in pharmaceuticals or quasi drugs. For example, carboxylic acids (citric acid, succinic acid, tartaric acid, ethylenediaminetetraacetic acid, etc.) ), Phosphoric acids (metaphosphoric acid, polyphosphoric acid, pyrophosphoric acid, hexametaphosphoric acid, phytic acid, etc.), phosphonic acids (1-hydroxyethane-1,1-diphosphonic acid, etc.), and pharmaceutically acceptable salts thereof (ethylenediamine) And disodium tetraacetate dihydrate (sodium edetate), sodium citrate, sodium phytate) and the like.
The compounding amount of the chelating agent in the liquid or semisolid skin external preparation of the present invention is not particularly limited as long as the effect of the present invention is achieved, but is usually 0.001 to 1 relative to the total weight of the liquid or semisolid skin external preparation. %, Preferably 0.005 to 0.5%, particularly preferably about 0.01 to 0.1%. If it is 0.001% or less, a sufficient stabilizing effect is not obtained, and if it is 1% or more, the stabilizing effect is not impaired, but the quality as a liquid or semi-solid skin external preparation can be maintained by precipitation of the chelating agent in crystals. It tends to disappear.

When an oily base is used as the base of the liquid or semisolid external preparation of the present invention, the esterified steroid can be further stabilized.
The oily base that can be used in the present invention is not particularly limited as long as it is usually used in pharmaceuticals or quasi drugs, but for example, white petrolatum, yellow petrolatum, liquid paraffin, paraffin, squalane, squalene. , Gelled hydrocarbon, hard fat, microcrystalline wax, ozokerite, ceresin, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid, isopropyl myristate, cetyl octanoate, octyldodecyl myristate, palmitic acid Isopropyl, butyl stearate, hexyl laurate, myristyl myristate, hexyl decyl dimethyloctanoate, cetyl lactate, myristyl lactate, isocetyl stearate, isononyl isononanoate, tridecone isononanoate , Isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene glycol di-2-ethylhexanoate, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, di- 2-Heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, triisostearic acid trimethylolpropane, tetra-2-ethylhexanoic acid pentaerythritol, tri-2-ethylhexanoic acid glycerin, trioctanoic acid glycerin, triiso Glycerol palmitate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, glyceryl trimyristate Serine, tri (caprylic / capric acid) glyceryl, tri-2-heptylundecanoic acid glyceride, 2-heptylundecyl palmitate, diisobutyl adipate, di-2-heptylundecyl adipate, di-2-ethylhexyl sebacate, Oils such as 2-hexyldecyl myristate, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, diisopropyl sebacate, highly polymerized methylpolysiloxane, diphenylpolysiloxane, methylpolysiloxane, dimethylpolysiloxane, alkyl-modified dimethylpoly Siloxane, methylphenyl polysiloxane, methyl hydrogen polysiloxane, trimethylsiloxysilicic acid, methylcyclopolysiloxane, dimethylsiloxane methyl (polyoxyethylene) siloxa・ Methyl (polyoxypropylene) siloxane copolymer, dimethylsiloxane ・ methyl (polyoxyethylene) siloxane copolymer, dimethylsiloxane ・ methyl (polyoxypropylene) siloxane copolymer, polyoxyethylene ・ methylpolysiloxane copolymer , Poly (oxyethylene / oxypropylene) / methylpolysiloxane copolymer, dimethylsiloxane / methylcetyloxysiloxane copolymer, dimethylsiloxane / methylstearoxysiloxane copolymer, stearoxymethylpolysiloxane, cetoxymethylpolysiloxane , Cetyl dimethicone, cetyl dimethicone copolyol, lauryl methicone copolyol, stearyl dimethicone copolyol, alkyl acrylate copolymer methylpolysiloxane ester, crosslinking Examples thereof include silicones such as methylpolysiloxane, crosslinked methylphenylpolysiloxane, crosslinked polyether-modified silicone, crosslinked alkylpolyether-modified silicone, and crosslinked alkyl-modified silicone, preferably white petrolatum, liquid paraffin, squalane, gel Hydrocarbons, hard fats and microcrystalline waxes.
These can be used alone or in combination of two or more.

  The blending amount of the oily base in the liquid or semisolid skin external preparation of the present invention is not particularly limited as long as the effect of the present invention is exerted, but usually 2 to the total weight of the liquid or semisolid skin external preparation. It can be appropriately selected and prepared depending on the purpose from the range of 95%, preferably 5 to 90%, particularly preferably 10 to 85%.

  Moreover, since the liquid or semi-solid external preparation for skin of this invention is substantially anhydrous, since esterified steroid can be stabilized more, it is preferable. However, water that is originally contained in blending components such as polyhydric alcohols such as macrogol and glycerin and plant extracts is judged to be anhydrous even if it is contained in the preparation. Specifically, “substantially anhydrous” means that the content of water in the external preparation for skin is usually 5% by weight or less, preferably 3% by weight or less, more preferably 1% by weight or less.

  The liquid or semisolid external preparation for skin of the present invention may be used as long as it belongs to the category of pharmaceuticals or quasi drugs having various uses, and can be used as an agent for treating or preventing various symptoms. Examples of the use of the liquid or semi-solid skin external preparation of the present invention include, for example, atopic dermatitis, allergic dermatitis, papules, erythema, eczema (childhood eczema, housewife eczema, seborrheic eczema, etc.), rash (diaper) Rashes, makeup rashes, razor mushrooms, uruma mushrooms, etc.), hives, insect bites, mosquitoes, dermatitis, dermatitis remedies for treating itching and inflammation, cuts, abrasions, crotch, shoe rubs, scratches, bruises , Bactericidal disinfectants and wound healing agents to prevent or exacerbate burns, purulent wounds, hemorrhoids, external hemorrhoids, fissures, perianal inflammation, hemorrhoids, cracks, scratches, etc., athlete's foot, acne, Infectious skin disease treatment or antibacterial agent for the treatment of sores, etc., cheilitis, keratitis, lip cracking, sore lip treatment, finger lip, elbow, knee, heel, ankle Etc. Pharmaceuticals such as keratin softener, dandruff, itching, hair loss treatment for hair loss and hair growth treatment, rough skin, lips, rash, cracks, redheads, acne, rash Quasi-drugs used for prevention, cosmetics used for moisturizing, etc. can be exemplified, and particularly suitable uses include atopic dermatitis, allergic dermatitis, papules, erythema, eczema (such as housewife eczema), rash, A dermatitis treatment agent for treating itching and inflammation, such as hives, insect bites, mosquitoes, and bruises; a bactericidal disinfectant and wound healing agent to prevent wrinkles and the like; and to treat athlete's foot, acne, etc. Infectious skin disease therapeutic agents or antibacterial agents are exemplified. Among them, it is preferably for hemorrhoids used for the treatment of epilepsy.

  The liquid or semisolid external preparation of the present invention can be applied to any skin such as the face, hands, feet, body, etc., even in delicate areas such as the genital area, the anal area, etc. Can be used without problems.

  The liquid or semi-solid skin external preparation of the present invention can be blended with one or more of various components (including pharmacologically active components and physiologically active components) as necessary. Such a component is not particularly limited as long as it is a component that is generally used for an external preparation in the pharmaceutical, quasi-drug or cosmetic field. For example, an antipruritic agent, an anti-inflammatory agent, a vasoconstrictor, a vitamin agent, Antibacterial agents (including anti-acne drugs, anti-odor agents), antiviral agents, antifungal agents, wound healing agents, keratin softeners, moisturizers, whitening agents, astringents, antioxidants, hair growth inhibitors, anti Examples include wrinkles. Examples of suitable components in the present invention include the following components.

Antipruritic: Nonylic acid vanillyl amide, salicylic acid, methyl salicylate, glycol salicylate, capsaicin, camphor, thymol, menthol, eugenol, hinokitiol, polyoxyethylene lauryl ether, comfrey extract, sage extract, sage extract, bodge extract, body stalk extract, etc.
Antihistamines: chlorpheniramine, chlorpheniramine maleate, diphenhydramine, diphenhydramine hydrochloride, diphenylpyraline, diphenylpyraline hydrochloride, iproheptin, isothipentyl, dipheterol, triprolidine, tripelenamine, tondiamine, promethazine, methodirazine, carbinoxamine or alimemazine

Anti-inflammatory agents: licorice extract, glycyrrhizic acid, dipotassium glycyrrhizinate, glycyrrhizic acid derivatives such as monoammonium glycyrrhizinate, glycyrrhetinic acid or its derivatives, allantoin or its derivatives, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl fenfenamic acid , Salicylic acid derivatives such as bendazac, piroxicam, ketoprofen, felbinac, methyl salicylate or glycol salicylate. Preferably, licorice extract, glycyrrhizic acid or a derivative thereof, glycyrrhetinic acid or a derivative thereof, allantoin or a derivative thereof, and the like.
Vasoconstrictor: tetrahydrozoline, naphazoline, oxymetazoline, phenylephrine, ephedrine, methylephedrine, epinephrine, methoxyphenamine or salts thereof.

  Vitamins: Retinol, retinol acetate, retinol palmitate, etc. (vitamin A), retinal, retinoic acid, retinoic acid methyl, retinoic acid ethyl, retinoic acid retinol, vitamin A oil, vitamin A fatty acid ester, etc. , Β-carotene, α-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, cryptoxanthine, echinone and other provitamins A, dl-α-tocopherol, dl-α-tocopherol acetate, dl-succinate Vitamin E such as α-tocopherol, dl-α-tocopherol calcium succinate, riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin Vitamin B2 such as sodium 5′-phosphate, riboflavin tetranicotinate, dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methyl nicotinate) Nicotinic acids such as phenyl) ethyl, vitamin C such as ascorbigen-A, ascorbic stearate, ascorbyl palmitate, L-ascorbyl dipalmitate, vitamin D such as methyl hesperidin, ergocalciferol, cholecalciferol , Vitamin K such as phylloquinone, farnoquinone, γ-oryzanol, dibenzoyl thiamine, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine laurie Hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, Vitamin B1 such as thiamine triphosphate monophosphate, vitamin B6 such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-phosphate pyridoxal hydrochloride, pyridoxamine hydrochloride, vitamin B12 such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin Folic acid such as folic acid, pteroylglutamic acid, nicotinic acid such as nicotinic acid and nicotinamide, pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenolic acid) ), D-pantetheine, D-panthetin, coenzyme A, pantothenic acids such as pantothenyl ethyl ether, biotins such as biotin and bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate Vitamin C, which is an ascorbic acid derivative such as magnesium ascorbate phosphate, and other vitamin-like agents such as carnitine, ferulic acid, α-lipoic acid and orotic acid.

Antibacterial agents: isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, benzalkonium chloride, cetylpyridinium chloride, polyhexamethylene biguanide, triclosan, trichlorocarbanilide, cresol and the like.
Antiviral agents: acyclovir, penciclovir, etc.
Antifungal agents: Itraconazole, amorolfine hydrochloride, croconazole hydrochloride, terbinafine hydrochloride, neticonazole hydrochloride, butenafine hydrochloride, clotrimazole, ketoconazole, ciclopirox olamine, isoconazole nitrate, econazole nitrate, oxyconazole nitrate, sulconazole nitrate, bifonazole, pmaricin , Fluconazole, flucytosine, miconazole, lanoconazole and so on.
Wound healing agent: aluminum chlorohydroxy allantoate, zinc oxide, etc.

  Keratin softener: ethyl alcohol, isopropyl alcohol, propanol, butanol, 1,3-butylene glycol, propylene glycol, polyethylene glycol (macrogol), glycerin, benzyl alcohol, phenylethyl alcohol, propylene carbonate, hexyldodecanol, allantoin, dimethyl Sulfoxide, dimethylacetamide, dimethylformamide, triethanolamine, diisopropyl adipate, ethyl laurylate, lanolin, fatty acid dialkyrolamide, salicylic acid, salicylic acid derivative, urea, sulfur, resorcin, glycolic acid, phytic acid, lactic acid, lactate, water Sodium oxide, potassium hydroxide, etc.

  Painkillers: mefenamic acid, flufenamic acid, indomethacin, methyl salicylate, glycol salicylate, diclofenac, diclofenac sodium, felbinac, alclofenac, bufexamac, aspirin, acetaminophen, ibuprofen, ketoprofen, pranoprofen, fenoprofen, fenglofen, Flurbiprofen, zaltoprofen, naproxen, flurbiprofen, flurbiprofen axetil, fenbufen, ricipfen, piroxicam, ampiroxicam, tenoxicam, oxyphenbutazone, phenylbutazone, clofesone, sulindac, clindac, benzaduck, L -Menthol, camphor, sulpyrine, thiaramide hydrochloride, orsenone, fenthiazac, benta Shin, such as Mepirizoru.

  Moisturizer: polyglycerin such as glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, diglycerin trehalose, hyaluronic acid, sodium hyaluronate, heparin analog, chondroitin sulfate sodium, collagen, elastin, Polymer compounds such as keratin, chitin and chitosan, amino acids such as glycine, aspartic acid and arginine, natural moisturizing factors such as sodium lactate, urea and sodium pyrrolidonecarboxylate, lipids such as ceramide, cholesterol and phospholipid, chamomile extract, aloe Extracts such as extracts, hamamelis extract, rosemary extract, thyme extract, tea extract and perilla extract.

  Whitening agents: vitamin A or derivatives thereof, vitamin C or derivatives thereof, vitamin E or derivatives thereof, vitamins such as pantothenic acid or derivatives thereof, placenta, arbutin, kojic acid, cysteine, phytic acid, iris (iris), almond, Aloe, Ginkgo, Oolong tea, Ages, Ogon, Ouren, Hypericum, Olysam, Seaweed, Cascon, Licorice, Gardenia, Kujin, Wheat, Rice, Rice haiga, Oryzanol, Rice bran, Perilla, Peonies, Senkyu, Sakuhachi, Saki, Tea, Soy Ingredients, extracts and essential oils derived from plants such as eucalyptus, hamamelis, safflower, button pi, yokuinin, touki, enoki, oyster (Diospyros kaki), clove.

Astringents: citric acid, tartaric acid, lactic acid, aluminum chloride, aluminum sulfate, allantoinchlorohydroxyaluminum, allantoindihydroxyaluminum, aluminum phenolsulfonic acid, aluminum chlorohydroxide, tannin, caffeine, tea extract, hamamelis extract, seaweed extract, etc.
Antioxidants: dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid, erythorbic acid, sodium edetate, sorbic acid, sodium sulfite, L-cysteine hydrochloride and the like.

Hair growth inhibitor: isoflavone, soybean extract, cypress extract, docami extract, iris root extract, papain enzyme and the like.
Anti-wrinkle agents: Vitamin A and its derivatives, glycolic acid, acylated glucosamine, kinetin, vitamin C, vitamin E, aloe, collagen, hyaluronic acid, tripeptide, seaweed extract, maroni extract, rosemary extract, cornflower extract and the like.

  The liquid or semi-solid skin external preparation of the present invention does not impair quality such as storage stability and viscosity, and does not impair the effects of the present invention. Various components commonly used in the external or cosmetic field, such as bases, surfactants, thickeners, preservatives, pH adjusters, stabilizers, irritation reducers, preservatives, colorants, dispersants Perfumes and the like can be blended.

  Base: lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, cetostearyl alcohol, hexyl decanol, octyl dodecanol, isostearyl alcohol, ethanol, macrogol, polyethylene powder, etc.

  Surfactants: Sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate Glyceryl fatty acids such as glyceryl monostearate and glyceryl monostearate malate, polyglyceryl fatty acids such as polyglyceryl monoisostearate and polyglyceryl diisostearate, propylene glycol fatty acid esters such as propylene glycol monostearate, polyoxyethylene cured Hardened castor oil derivatives such as castor oil 40, polyoxyethylene hardened castor oil 60, polyoxyethylene (20) sorbitan monolaurate Sorbate 20), monostearate polyoxyethylene (20) sorbitan (Polysorbate 60), polyoxyethylene sorbitan fatty acid esters such as monooleate polyoxyethylene (20) sorbitan (Polysorbate 80), and glycerin alkyl ether.

  Thickener: Guar gum, locust bean gum, carrageenan, xanthan gum, dextran, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol ester of alginate, polyvinyl alcohol, polyvinyl methyl ether, carboxy Vinyl polymer, sodium polyacrylate, polyethylene glycol, bentonite, dextrin fatty acid ester, etc.

  Preservatives: Benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, benzyl paraoxybenzoate, paraoxybenzoic acid Methyl, phenoxyethanol, etc.

  pH adjusters: inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propion) Acid, acetic acid, aspartic acid, epsilon-aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic base (sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, Magnesium hydroxide), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.).

  These components can be used alone or in combination of two or more. Moreover, those compounding amounts are not particularly limited as long as the effects of the present invention are obtained, but can be suitably selected and used as long as the upper limit compounding amount allowed by the Pharmaceutical Affairs Law is desirable.

  The liquid or semisolid external preparation for skin of the present invention can be prepared in various forms. For example, dosage forms such as ointments, liquids (including lotions, emulsions, aerosols), gels, creams, etc. are mentioned, and in particular, ointments and liquids (including lotions, emulsions, aerosols) It is useful to apply. In the case of a gel or ointment, the preparation may be substantially anhydrous.

  The method for preparing the liquid or semisolid skin external preparation of the present invention is not particularly limited, and various components necessary for preparing a normal liquid or semisolid skin external preparation are appropriately selected and blended. It can be prepared by the method. Moreover, the application amount and usage of the liquid or semisolid external preparation of the present invention to the outer skin are not particularly limited, and it can be used by applying an appropriate amount to the outer skin such as the skin several times a day.

The present invention also includes a method for stabilizing esterified steroids. In the method of the present invention, stabilization of an esterified steroid in a preparation in which a basic compound coexists can be achieved by using one or more of starch, crystalline cellulose, and polyvinylpyrrolidone in combination.
In the method of the present invention, the compounding ratio of starch, crystalline cellulose and polyvinylpyrrolidone to esterified steroid, starch, crystalline cellulose, polyvinylpyrrolidone and esterified steroid is the same as that used in the liquid or semisolid skin external preparation. .

In the method of the present invention, the basic compound may be an inorganic compound or an organic compound, but the known medicinal component is mostly an organic compound, and the basic organic compound is used in combination with the esterified steroid. The usefulness of inhibiting the degradation by is higher. Such basic organic compounds are not particularly limited, but are preferably organic amines or organic amides, and have structures such as toluidine derivatives, ethanolamine derivatives, allylpropylamine derivatives, ephedrine derivatives, ethylenediamine derivatives, imidazoline derivatives, procaine derivatives and the like. It is preferable to have, specifically, chlorpheniramine, chlorpheniramine maleate, diphenhydramine, diphenhydramine hydrochloride, diphenylpyraline, diphenylpyraline hydrochloride, iproheptin, isothipentyl, dipheterol, triprolysine, tripelenamine, tondilamine, promethazine, methodirazine, Antihistamines such as carbinoxamine and alimemazine, tetrahydrozoline, naphazoline, oxymetazoline, phenylephrine Vasoconstrictors such as ephedrine, methylephedrine, epinephrine, methoxyphenamine, itraconazole, amorolfine hydrochloride, croconazole hydrochloride, terbinafine hydrochloride, neticonazole hydrochloride, butenafine hydrochloride, clotrimazole, ketoconazole, ciclopirox olamine, isoconazole nitrate, econazole nitrate And antifungal agents such as oxyconazole nitrate, sulconazole nitrate, bifonazole, pimaricin, fluconazole, flucytosine, miconazole, and lanoconazole, crotamiton, urea, and the like.
Among them, in addition to lidocaine, dibucaine, procaine, meprilucaine, mepivacaine, procainamide, which have multiple nitrogen atoms in the molecule, imidazoline derivatives such as ethylenediamine derivatives, vasoconstrictors and antifungal agents, procaine derivatives, carbinoxamine, doxylamine , Chlorpheniramine and triprolidine are preferred, and lidocaine, dibucaine, procaine, meprilucaine, mepivacaine and procainamide are particularly preferred. The basic compound may be a salt.
These basic compounds can be used alone or in combination of two or more. The blending ratio of the basic compound in the method of the present invention is usually about 0.001 to 15%, preferably about 0.005 to 10%, particularly preferably about 0.01 to 5% with respect to the total weight of the liquid or semisolid external preparation for skin.

In the method of the present invention, the weight ratio of starch, crystalline cellulose, and polyvinylpyrrolidone to the basic compound is 0.001 to 50 when the total amount of the basic compound in the liquid or semi-solid skin external preparation is 1. Preferably, 0.005 to 20 is more preferable, and 0.01 to 10 is particularly preferable.
Moreover, about the method of using together one or more types of starch, crystalline cellulose, or polyvinylpyrrolidone, an esterified steroid, and a basic compound, you may make it contain in the same formulation, but it contains in another formulation Can also be achieved by mixing or using them immediately before and after use. Depending on the preparation form of the composition, it can be divided into 1 to several times per day, and can be used in dosages and dosages by known or commonly used methods.

  In the method of the present invention, either a chelating agent or an oily base can be used in combination. Further, in the method of the present invention, water can be used substantially in the absence of water. In the method of the present invention, the chelating agent, oily base and substantially anhydrous are the same as those used in the liquid or semisolid skin external preparation.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

Test Example 1 Stabilization evaluation of esterified steroid in methanol solution
According to the formulation described in Table 1, polyvinyl pyrrolidone, crystalline cellulose or corn starch was added to a solution prepared by mixing 0.07 ml of a 0.1 mol / l sodium carbonate aqueous solution and about 20 ml of methanol, and after sufficient stirring, hydrocortisone-21-acetate Was added and dissolved, and the formulation (solution) was prepared by making the total volume 100 ml with methanol. This was stored in a thermostatic bath at 50 degrees, and after 24 hours, the residual rate of hydrocortisone-21-acetate was quantified by HPLC.
The results are shown in Table 1.

  In Formulation 1, the residual rate is reduced to 17%, but in Formulations 2 to 4, all the residual rates are maintained at 47% or more, and in a solution system containing a basic compound that is easily decomposed by esterified steroids, It was shown to be significantly stabilized by polyvinylpyrrolidone, crystalline cellulose or corn starch.

Test Example 2 Stabilization evaluation of esterified steroids
In accordance with the formulations described in Tables 2 and 3, the components (excluding 1-menthol) dissolved in the base are heated and dissolved in the oily base and / or macrogol, and then the remaining components are added sequentially. Then, the mixture was stirred and dispersed with a homomixer and cooled to 30 ° C. while stirring to prepare a semisolid external preparation for skin (ointment).
This was stored in a constant temperature bath at 40 ° C. and 75% humidity, and after 6 months, the concentration of hydrocortisone acetate was quantified by HPLC, and the residual rate (%) was calculated. Moreover, it quantified also after 3 months as needed.
The results are shown in Tables 2 and 3.

From Table 2, the residual rate was about 94% even after 6 months in Example 1 containing corn starch, but about 84% after 6 months in Comparative Example 1, which was not practical.
Further, from Table 3, the residual rate of Example 2 is almost 100% even after 6 months, and the residual rate is about 90% in Examples 3 to 5, whereas it is added in Comparative Examples 2 to 4. Various studies have been made on products and bases, but it has been found that the effect of stabilizing steroid esters is insufficient.

  From the above results, it was found that the decomposition of the esterified steroid when a basic compound is contained can be solved by blending any one of starch, crystalline cellulose, and polyvinylpyrrolidone. Furthermore, the stabilization of the esterified steroid can be further improved by adding a chelating agent and using an oily base.

  Examples are given below. In addition, the compounding quantity in the following Examples represents weight% about all the things which have no description of a unit especially.

Example 6 (ointment)
Prednisolone valerate acetate 0.15
Lidocaine 1.0
Corn starch 5.0
Hydroxypropyl methylcellulose 0.2
Alcloxa 0.5
Isostearyl alcohol 3.0
Octyldodecanol 2.0
Cetanol 1.5
Macrogol 400 50
Macrogol 4000 remaining
Total 100%

Example 7 (ointment)
Prednisolone acetate 0.1
Lidocaine hydrochloride 1.0
Crystalline cellulose 5.0
Paraffin 8.0
Liquid paraffin 2.0
White petrolatum
Total 100%

Example 8 (ointment)
Hydrocortisone acetate 0.5
Dibucaine hydrochloride 0.5
Potato starch 3.0
Paraffin 8.0
Liquid paraffin 2.0
Gelled hydrocarbon remaining
Total 100%

Example 9 (Liquid)
Prednisolone valerate acetate 0.15
Lidocaine hydrochloride 1.0
Polyvinylpyrrolidone K-90 3.0
Crotamiton 5.0
Diphenhydramine 1.0
Allantoin 0.2
Absolute ethanol 35
Propylene glycol 15
Carboxyvinyl polymer 0.5
Hydroxyethyl cellulose 0.3
Purified water remaining
Total 100%

Example 10 (Gel)
Dexamethasone acetate 0.5
Zibcaine 1.0
Polyvinylpyrrolidone K-30 3.0
Glycerin 10
1,3-butylene glycol 5.0
Absolute ethanol 15
Carboxyvinyl polymer 1.0
Carrageenan 0.1
Triethanolamine 0.4
Polyoxyethylene hydrogenated castor oil 60 4.0
Purified water remaining
Total 100%

Claims (3)

(A) esterified steroid, (B) one or more selected from the group consisting of lidocaine, dibucaine, benzocaine, procaine, meprilucaine and mepivacaine, and (C) selected from the group consisting of starch, crystalline cellulose and polyvinylpyrrolidone A liquid or semi-solid skin external preparation containing one or more kinds. The liquid or semi-solid skin external preparation according to claim 1, wherein the esterified steroid is hydrocortisone-21-acetate, prednisolone-21-acetate, prednisolone-17-valerate-21-acetate. A method for stabilizing an esterified steroid, comprising using at least one of starch, crystalline cellulose and polyvinylpyrrolidone, a basic compound and an esterified steroid.