JPS61293930A - Skin agent for external use - Google Patents

Abstract

PURPOSE:To obtain a skin agent for external use having remarkably improved transcutaneous absorption of the drug component, by compounding a gas selected from CO2, hydrogen sulfide and radon or a component generating said gas with zeolite and a drug component. CONSTITUTION:A drug component is added to an absorbefacient composed of (A) a gas selected from CO2, hydrogen sulfide and radon or a component capable of generating the above gas and (B) a zeolite. The zeolite is preferably a synthetic zeolite of formula (M is metallic atom having a valence of n; x=0.7-1.5; y=0.8-10; z>=0). The gaseous component of CO2, hydrogen sulfide and radon is used preferably in the form adsorbed to zeolite. It is supposed that the gas exhibits the activity to promote the dermatic blood flow and the transcutaneous absorption of the drug component and the transcutaneous adsorptivity of the drug component is accelerated remarkably by the synergistic effect of the heat of adsorption of the zeolite.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel external skin preparation, and more particularly to a skin external preparation in which transdermal absorption of medicinal ingredients is promoted.

[Conventional technology]

Conventionally, various transdermal absorption enhancers have been developed in order to promote transdermal absorption of medicinal ingredients and fully exhibit the effects of the medicinal ingredients. Such absorption enhancers include dimethylsulfoxide, dimethylacetamide, dimethylformamide, N.

Amide compounds such as N-diethyl-m-toluamide; 1
- azacycloalkan-2-one derivatives such as dodecyl azacyclohebutan-2-one; or esters of alcohols and carboxylic acids such as inpropyl myristate, impropyl palmitate, diethyl sebacate, diimpropyl adipate; Crotonyl-N-ethyl-〇-toluidine and the like are known.

[Problem that the invention seeks to solve]

However, the absorption promoting effects of conventional absorption enhancers are still insufficient; (2) practical pharmacological effects are often not obtained; and (3) the absorption enhancers themselves are skin irritating. Its general indications and usage are limited because it corrodes synthetic resins due to its strong solvent properties and elutes irritating and sensitizing substances from drug containers, clothing, jewelry, etc. The reality is that there are still problems with practicality.

[Means for solving problems]

In order to solve this problem, the present inventors have repeatedly studied from various aspects, and as a result, the present inventors have formulated a mixture of one or more gases or gas generating substances selected from carbon dioxide, hydrogen sulfide, and radon, and zeolite. The inventors have discovered that transdermal absorption of medicinal ingredients can be promoted and the above-mentioned drawbacks can be overcome by doing so, and the present invention has been completed.

That is, the present invention provides an external skin preparation characterized by containing one or more gases or gas generating substances selected from carbon dioxide, hydrogen sulfide, and radon, zeolite, and medicinal ingredients. .

The zeolite used in the present invention may be either a natural zeolite or a synthetic zeolite, but a synthetic zeolite represented by the following general formula, which contains fewer impurities and other impurities, is preferred.

(My O)x* kLzOs・(Sing)y・(
H2O)z (where M is a metal atom with a valence of n, and X is 0
．． 7 to 1.5, y is 0.8 to 10.2, and y represents a number of 0 or more. ) Among the synthetic zeolites of the above general formula, metal atoms represented by M include sodium, potassium, calcium, magnesium, etc., and 2 is preferably 0, that is, one containing substantially no water.

Carbon dioxide, hydrogen sulfide, or radon can be used by being dissolved in a skin preparation for external use under normal pressure or under pressure, but it is preferable to use these gas components by adsorbing them on zeolite.

Carbon dioxide, hydrogen sulfide or radon can be adsorbed onto zeolite by, for example, bringing these gases into contact with zeolite. The adsorption is preferably carried out under pressure under anhydrous conditions.

For example, in the case of carbon dioxide gas, it is preferable that 52 or more of these gases be adsorbed per 100 f of zeolite at room temperature.

For example, in the case of carbon dioxide gas, a combination of carbonate and acid is preferred as the gas generating substance. In this case, the carbonate is
For example, hydrogen carbonate) IJum, sodium carbonate, sodium sesquicarbonate, potassium hydrogen carbonate, potassium carbonate,
Potassium sesquicarbonate, ammonium bicarbonate salt, ammonium carbonate salt, ammonium sesquicarbonate salt, etc. are mentioned, and these can be used alone or in combination of two or more kinds.

Further, as the acid, both organic acids and inorganic acids can be used, but water-soluble and solid acids are preferred.

Examples of organic acids include straight chain fatty acids such as formic acid, acetic acid, propionic acid, butyric acid, and valeric acid; oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid, maleic acid, phthalic acid, (Dicarboxylic acids such as phthalic acid and terephthalic acid; acidic amino acids such as curtamic acid and aspartic acid; glycolic acid, lactic acid, hydroxyacrylic acid, a-oxybutyric acid, glyceric acid, tartronic acid, malic acid, tartaric acid, citric acid, salicylic acid) (o,tn
.

p), oxyacids such as gallic acid, mandelic acid, tropic acid, ascorbic acid, gluconic acid; cinnamic acid, benzoic acid, phenylacetic acid, nicotinic acid, kainic acid, rubic acid, pyrrolidonecarboxylic acid, trimellitic acid, benzenesulfone acid, toluenesulfonic acid, and acid salts of these organic acids. Examples of inorganic acids include phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium sulfite, potassium sulfite, sodium pyrosulfite (sodium metabisulfite), potassium pyrosulfite (potassium metabisulfite), acidic Examples include sodium xametaphosphate, acidic potassium hexametaphosphate, acidic sodium pyrophosphate, acidic potassium pyrophosphate, and sulfamic acid. Among these, carboxylic acids such as succinic acid, tartaric acid, malic acid, and citric acid are preferred.

The amount of zeolite blended into the external skin preparation of the present invention varies depending on the dosage form of the external preparation, but is preferably 0.1 to 50% by weight. In the case of a gas, it is preferable to contain 50 to 5.040 pI)m, although it varies depending on the type. In the case of gaseous products, the gas is 50 to 5.0001
)I)m is preferably generated.

The medicinal ingredients whose absorption is promoted and drug efficacy is enhanced according to the present invention are not particularly limited as long as they can be administered transdermally, but suitable examples include the following drugs.

For example, ethyl aminobenzoate, dibucaine hydrochloride, tetracaine hydrochloride, procaine hydrochloride, lidocaine, methyl salicylate, guaiazulene, sodium guaiazulene sulfonate, aluminum chlorohydroxyallantoinate, pendazac, indomethacin, glycyrrhetinic acid, glycyrrhizic acid, Bufexamac, dextran sulfate Analgesic and anti-inflammatory agents such as sodium, crotamiton, butyl flufenamate, allantoin, aloe powder, ictamol, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, β-glycyrrhetinic acid, glycyrrhetinyl stearate, stearyl glycyrrhetinate, hinokitiol; hydrocortisone, hydrocortisone acetate, butyric acid Hydrocortisone, fluocinolone acetonide, flumethacin pivalate, fluocinonide, fluoromenlone, beclomethasone propionate, dexamethacin, dexamethacin sodium phosphate, dexamethacin acetate, fludroxycorted, betamethacin valerate, betamethacin dipropionate, triamcinolone acetonide , prednisolone, methylprednisolone, methylprednisolone acetate, diflucortolone valerate, clobetasol fropionate, amcinonide, haldinonide, prednisolone acetate valerate, hydrocortisone propionate butyrate, and other corticosteroids; estradiol, estrone, ethinylestradiol, shetelsterbestol , hormonal agents such as hexestrol; phenol, resorcinol, salicylic acid, hexachlorophene, merculochrome, thimerosal, acrinol, iodine, benzalkonium chloride, benzethonium chloride, penicillin v1, benzapenicillin G1, streftomycin,
Chloramphenicol, tetracycline, tetracycline hydrochloride, erythromycin, frasiomycin, saradiomycin sulfate, bacitracin, oxytetracycline hydrochloride, kanamycin sulfate, kanamycin, chloromycetin, polymyxin B1 nitro7razone, potassium permanganate, boric acid, borax , benzoic acid, sodium benzoate, sodium salicylate, nrubic acid, potassium nrubate, dehydroacetic acid, sodium dehydroacetate, ethyl parabenzoate, butyl parabenzoate, propyl parabenzoate, methyl parabenzoate, isopropylmethylphenol, cresol , Chlorxylenol, Thymol, Parachlorophenol, Photosensor No. 101, Photosensor No. 201, Chloramine T,
Disinfectants and disinfectants such as thianthol, lysozyme chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, trichlorocarbanilide, 3-trifluoromethyl-4,4'-dichlororuvanilide, hexachlorophene; isotependyl hydrochloride, diphenylimitaso-/L /, antihistamines such as clemizole sulfate, diphenhydramine lauryl sulfate, chlorpheniramine maleate; chrysalobin, undecylenic acid, zinc undecylenate, pentachlorophenol, phenylmercuric acetate, fmerosal, trifumycin, tolnaftate,
Phenyl iodo undiginoate, clotrimazole,
Haloprozin, variotin, pyrrolnidoline, cytucanin, niscutin, exalamide, ciclopirox.
Antifungal agents such as olamine, miconazole nitrate, econazole nitrate, and inconazole nitrate; retinol, retinol acetate, retinol palmitate, tehydroretenol,
ergocalciferol, dt-a-tocopherol,
dt-α-tocopherol acetate, dL-a-succinate)
Coferol calcium, ubiquinone, butonadione, menaquinone, menadione, thiamine hydrochloride, thiamine nitrate, thiamine phosphate, riboflavin, flavin mononucleotide, riboflavin butyrate, pyridoxine hydrochloride, pyridoxal 5'-phosphate, pyridoxine caprilate, civalmitenic acid Pyridoxine, pyridoxine tripalmitate, dianocobalamin, hydroxycobalamin, deoxyadenosylcobalamin, methylcobalamin, nicotinic acid, nicotinamide, hensyl nicotinate, calcium pantothenate, sodium bantothenate, bantothenyl alcohol, dicarboethoxypantothenic acid Vitamins such as ethyl ester/propylene glycol liquid, acetyl bantothenyl ether ether, bantothenyl ethyl ether, biotin, folic acid, choline, inositol, ascorbic acid, sodium ascorbate, ascorbyl stearate, ascorbyl palmitate, ascorbyl civalmitate; oxidation zinc,
Calamine, aluminum sulfate, lead acetate, bismuth subnitrate, bismuth subgallate, tannic acid, zirconium chloride oxide, allantoin chlorhydroxyaluminum, allantoin dihydroxyaluminum, aluminum hydroxychloride, zinc chloride, aluminum chloride, ferric chloride, calamine, Astringents such as chlorinated aluminum bromide, aluminum phenolsulfonic acid, aluminum naphthalene sulfonic acid, dry potassium aluminum sulfate, zinc paraphenolsulfonate; urocanic acid, 2-ethoxyethyl 4-methoxycinnamate, para-aminobenzoic acid UV absorbers such as ether, 2-(2-hydroxy-5-methylphenyl)benzotriazole, 2-hydroxy-4-methoxybenzophenone;
Sequestering agents such as IJum, sodium citrate, sodium polyphosphate, sodium metaphosphate, and gluconic acid; Hypnotic and sedative agents such as barbital, thiobental, chloral hydrate, and potassium bromide; Chlorpromazine,
Psychotropic drugs and antiepileptic drugs such as reserpine and chlordiazepoxide; antiparkinsonian drugs such as chlorzoxazone and levodopa; cardiotonic drugs such as digitoxin and digoxin; antiarrhythmic drugs such as propyroinamide hydrochloride, propranol hydrochloride, lidocaine hydrochloride, and indenolol hydrochloride; Antianginal agents such as diviridamol, amyl nitrite, nitroglycerin, and inrubid nitrate; antihypertensive agents such as reserpine and guanethidine sulfate; ictamol, moctal, camphor,
Thymol, diphenhydramine, chlorpheniramine,
[A drug such as acid flomethacin, N-ethyl-〇-crotonotoluidine, etc.; red foaming agents such as Cantharis, capsicum tincture, ictamol, turpentine oil, bismuth subgallate; purified sulfur, precipitated sulfur, salicylic acid, urea, etc. Emollients; antiperspirants and deodorants such as aluminum chloride, aluminum sulfate, aluminum acetate, aluminum phenolsulfonate, and sodium perborate; selenium disulfide,
Hair preparations such as alkylinquinolinium bromide, zinc pyrithione, biphenamine, thianthol, cantharis tincture, ginger tincture, capsicum tincture, potassium bromate, sodium bromate, carpronium chloride, acetylcholine chloride, pilocarpine chloride, vitamin oil, etc.;
Other examples include prostaglandins and the like.

Various types of non-aqueous bases commonly used can be used in the skin external preparation of the present invention, if necessary. For example, various materials such as inorganic powders such as talc and bentonite, liquid paraffin, petrolatum, silicone oil, aliphatic higher alcohols, higher fatty acids, fatty acid esters, vegetable oils, lanolin and its derivatives, squalene, squalane, and polyethylene are used. It is available for use.

Examples of dosage forms include ointments, lotions, sprays, liniments, pastes, poultices, powders, granules, and tablets.

[Action and effect of invention]

In the skin external preparation of the present invention, transdermal absorption of the medicinal ingredients contained therein is significantly promoted, and the medicinal ingredients exhibit sufficient medicinal efficacy.

Its mechanism of action is that carbon dioxide, hydrogen sulfide, and radon contained together with zeolite promote skin blood flow and skin absorption of medicinal ingredients, and that heat of adsorption is generated when zeolite comes into contact with water. It is presumed that this is a synergistic effect with the gas component.

〔Example〕

Next, the present invention will be explained with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Example 1 Ointment Purified lanolin 5 (parts by weight) White beeswax 4 White petrolatum 81 Zeolite containing carbon dioxide 5 Total 100 (parts by weight→) An ointment was prepared by kneading the above composition.

*The carbon dioxide-containing zeolite used was one obtained by dehydrating zeolite (trade name Zeolum 4-A, manufactured by Toyo Soda Co., Ltd.) at about 300°C and adsorbing carbon dioxide gas at a pressure of 5 kg/cm''.

Example 2 Liniment *Zeolite containing carbon dioxide 50? Menthol 451 Camphor oil 2001 Olive oil 6952 The total amount is 1.0OOr.

The above composition was mixed and stirred to form a liniment.

Note that the same carbon dioxide-containing zeolite as in Example 1 was used.

Example 3 Poultice Kaolin collection 501 *Zeolite containing carbon dioxide 5F Boric acid 41 Concentrated glycerin 402 Indomethacin 12 Total #xoor Glycerin was heated to 100 to 110° C. for about 2 hours to dehydrate. The hot glycerin was transferred to a crusher, and while stirring, boric acid was added little by little to dissolve it. Next, dry for about 2 hours, add 9 fine kaolin powder little by little, and stir. It was cooled down.

Furthermore, carbon dioxide gas-containing zeolite and indomethacin were kneaded, and this was applied to a nonwoven fabric.

Note that the same carbon dioxide-containing zeolite as in Example 1 was used.

Comparative Example 1 Ointment Example 1 was repeated except that the carbon dioxide-containing zeolite was replaced with zeolite only.

Comparative Example 2 Ointment An ointment with the same formula as Example 1 except for the carbon dioxide-containing zeolite was prepared, placed in a pressure-resistant container, and carbonated at 3K.
After blowing at g/α2 and keeping it for 3 hours, it was divided into small pieces and used as a product.

Example 4 The effects of the skin external preparation of the present invention were evaluated as follows.

Method: A male white rabbit weighing 2.5 K4 was fixed in the dorsal position, and the abdomen was carefully pricked with hair clippers, and sample 1 of Example 1 was prepared. (
Methyl salicylate content: 50 ■) on unblemished skin approximately 48
It was applied to cm2. After application 0.5°1.0, 1.5
, 2.0, 3.0, and 5.0 hours.

The blood methyl salicylate content was measured by a conventional method using high performance liquid chromatography after converting the methyl salicylate into salicylic acid. The results are shown in FIG.

In addition, Sample 12 of Comparative Example 1 (methyl salicylate content: 50 to 50) and Sample IV of Comparative Example 2 (methyl salicylate content: approximately som 9) were used as controls.

Results: As shown in Figure 1, when the product of the present invention was applied,
Blood salicylic acid concentrations were higher than in controls.

[Brief explanation of drawings]

FIG. 1 is a drawing showing the relationship between the time after application and the blood salicylic acid concentration when the ointments of the present invention, Comparative Example 1, or Comparative Example 2 are applied to domestic rabbits. that's all

Claims (1)

[Scope of Claims] 1. An external skin preparation characterized by containing one or more gases or gas generating substances selected from carbon dioxide, hydrogen sulfide, and radon, zeolite, and medicinal ingredients. 2. The skin external preparation according to claim 1, wherein carbon dioxide gas, hydrogen sulfide, or radon is adsorbed on zeolite.