NZ223913A - Percutaneous absorption promoting agent containing an anionic surfactant and a nitrogen-containing surfactant other than an anionic surfactant - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £23913 » 22 3 9 1 3 P rtorlty D ate (c y. .

CompVjte Spr.>;ifrc.a'o.on FiiecJ: Class: A.!...

Publication Date: P.O. Journal, No: /■<.'; A r NO Dr.V.VSIG8 No." Dale: NEW ZHA1.ANI) PATENTS ACT, 1953 COMPUTE SPECIFICATION PERCUTANEOUS ABSORPTION PROMOTING AGENT AND DERMATOLOGIC PREPARATION CONTAINING THE SAME SHISEIDO COMPANY LTD, a Japanese corporation, of 7-5-5, Ginza, Chuo-ku, Tokyo, Japan, hereby declare the invention for which >-/ we pray that a patent^mar j be granted to rrvc/us, and the method by which it is to be performed, ' f V' F to be particularly described in and by the following statement: - (follov/ed by page la) r* - la- BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to a percuta neous absorption promoting agent and a dermatologic 5 preparation containing that percutaneous absorption promoting agent. More particularly, the inven tion relates to a percutaneous absorption promoting agent comprising (A) at least one anionic surfactant and one or two or more of surfactants having a nitrogen atom 10 in the molecule other than anionic surfactants, (B) one or two or more of anionic surfactants and one or two or more of nonionic surfactants not having a nitrogen atom in the molecule, (C) one or two or more of surfactants selected from the group consisting of amphoteric surfac-15 tants and semi-polar surfactants and at least one nonionic surfactant having a nitrogen atom in the molecule, (D) one or two or more of surfactants selected from the group consisting of nonionic surfactants, amphoteric surfactants, semi-polar surfactants and ' ^ 20 cationic surfactants having a nitrogen atom in the molecule, and one or two or more of nonionic surfactants not having a nitrogen atom in the molecule, or (E) an amine oxide as the active ingredient, and dermatological preparations containing these percutaneous absorption 25 promoting agents and drug components. 2. Description o'f the Related Art Heretofore, a drug component has been administered by oral administration, subcutaneous, intramuscular or intravenous administration by injection, administration to mucosa within the rectumor the mouth, etc.; Note, oral administration is most widely practiced. However, in the case of oral administration, drawbacks have occurred such that the concentration has become 2°d£l Dyl * •- r. O ,) i ,) temporarily higher than is necessary to ensure persistence of the effect and that side effects such as stomach disorder or lack of appetite may be caused. On —s the other hand, although absorption is rapid in administration by injection, this must be made by an expert such as a physician, etc.

Recently, dermatologic preparations by percutaneous administration have been developed to eliminate such side effects and drawbacks. However, even in such 10 dermatologic preparations, a sufficient percutaneous absorptivity has not been obtained in most cases, and therefore, they are not considered satisfactory.

Further, the surface of the skin, i.e., the stratum corneum, has in itself a physiological function 15 as a barrier for protection against the penetration of foreign matter from outside of the body, and therefore, a sufficient percutaneous absorptivity cannot be obtained by merely formulating a drug component in a base conventionally used in the prior art in a dermatologic 20 preparation.

To alleviate this factor, various percutaneous absorption promoting agents have been proposed in recent . ( years. For example, dimethyl sulfoxide, dimethyl- ' formamide, dimethylacetamide, methyldecyl sulfoxide, etc., are known, but are not considered to have a sufficient percutaneous absorption promoting effect and safety, or feeling upon use.

SUMMARY OF THE INVENTION s~-'" Accordingly, an object of the invention is to solve the problems of the prior art as mentioned above and provide a percutaneous absorption promoting agent having an excellent percutaneous absorption promoting effect of a drug component, and further, a satisfactory safety and feeling upon use. r Another object of the invention is to provide a dermatologic preparation comprising the percutaneous absorption promoting agent and a drug " r t .. r P t L component, which is an excellent percutaneous absorption agent promoting the effect of the drug component, and further, has a satisfactory safety and feeling upon use.

Other objects and advantages of the inven tion will be apparent from the following description.

In accordance with the present invention, there is provided a percutaneous absorption promoting agent for a drug component comprising at least one anionic surfactant and at least one surfactant having a nitrogen atom in the molecule other than the anionic surfactants as the active ingredients and a dermatologic preparation containing a desired drug component and the above-mentioned percutaneous absorption promoting agent.

In accordance with the invention there is provided a percutaneous absorption promoting agent for a drug component comprising at least one surfactant selected from the group consisting Of amphoteric surfactants and semi-polar surfactants and at least one nonionic surfactant having a nitrogen atom in the molecule as the active ingredients, and a dermatologic preparation containing a desired drug component and the above-mentioned percutaneous absorption promoting agent ingredients.

In accordance with the invention, there is further provided a percutaneous absorption promoting agent for a drug component comprising at least one anionic surfactant and at least one nonionic surfactant not having a nitrogen atom in the molecule as the active ingredients, and a dermatologic preparation containing a desired drug component and the above-mentioned percutaneous absorption promoting agent.

In accordance with the invention, there is further provided a percutaneous absorption promoting agent for a drug component comprising at least one surfactant selected from the group consisting of nonionic surfactants, amphoteric surfactants, semi-polar surfactants and cationic surfactants having a nitrogen , ' : r (followed by page 4a) atom in the molecule and at least one nonionic surfactant not having a nitrogen atom in the molecule as the active ingredients, and a dermatologic preparation containing a desired drug component and the above-mentioned percutaneous absorption promoting agent.

In accordance with the invention, there is further provided percutaneous absorption promoting acent for a drug component comprising an amine oxide as the active ingredient, and a dermatologic preparation containing a desired drug component and the above-mentioned percutaneous absorption promoting agent.

In a particular aspect, the subject of New Zealand Patent Specification No. 236497, the invention provides a dermatological preparation comprising (A) 0.001 to 10% by weight of a drug component selected from the group consisting of dexamethasone, indomethacin, hydroquinone, arbutin, minoxidil, kojic acid, naphthiomate, vitamin C, 8-methoxysolarene, vitamin C ester, swelthiamaline, and cephalantin; and (B) 0.001 to 10% by weight of a percutaneous absorption promoting agent selected from the group consisting of (a)(i) at least one anionic surfactant and (ii) at least one nonionic surfactant not having a nitrogen atom in the molecule, (b)(i) at least one surfactant selected from the group consisting of amphoteric surfactants and semi-polar surfactants and (ii) at least one nonionic surfactant having a nitrogen atom in the molecule, (c)(i) at least one surfactant selected from the group consisting of nonionic surfactants, amphoteric surfactants, semi-polar surfactants and cationic surfactants having a nitrogen atom in the molecule and (ii) at least one nonionic surfactant not having a nitrogen atom in the molecule, and (d) a water-insoluble or slightly water-soluble amine oxide.

DESCRIPTION! OF THE PREFERRED EMBODIMENT The above anionic surfactant may include anionic surfactants having one or two or more of carboxylic acid group, sulfonic acid group, sulfuric acid ester group, and phosphoric acid ester group, in the molecule. Those having a carboxylic acid group may include fatty acid soap, ether carboxylic acid and salts thereof, carboxylic acid salts such as condensates of amil acid and fatty acid, etc.; those having a sulfonic acid salt may include alkylsulfonic acid salts, sulfosuccinic acid, ester sulfonic acid salt, alkylallyl and alkyl-naphthalene sulfonic acid salts, N-acylsulfonic acid salt, formalin condensation type sulfonic acid salts, etc.; those having a sulfuric acid ester group, may include sulfated oil, ester sulfuric acid salt, alkyl-sulfuric acid salt, ether sulfuric acid salt, alkylallyl ether sulfuric acid salt, amidosulfuric acid salt, etc.; those having a phosphoric acid ester group may include alkylphosphoric acid salts, amidophosphoric acid salts, ether phosphoric acid salts, alkylallyl ether phosphoric acid salts, etc. One or two or more of these elements may be selected as desired.

On the other hand, as the surfactant having a nitrogen atom in the molecule other than the anionic surfactant, there may be included nonionic surfactants, amphoteric surfactants, semi-polar surfactants, cationic n'> < * '*"» , b i <_/ •-> surfactants, etc., having a nitrogen atom in the molecule.

Examples of the nonionic surfactant having a nitrogen atom in the molecule may include fatty acid alkanolamide, polyoxyethylene fatty acid amide, esters of alkanolamine, polyoxyethylene alkylamine, etc.

Examples of the amphoteric surfactant having a nitrogen atom in the molecule may include carboxy betaine such as N,N-d imethy1-N-lauryl-N-carboxymethy1-ammonium betaine, N,N-dimethyl-N-oleyl-N-carboxymethyl-ammonium betaine, etc.; imidazoline derivatives such as 2-lauryl-N-carboxyethyl-N-hydroxyethylimidazolinium betaine, 2-lauryl-N-carboxymethy1-N-hydroxyethyl-imidazolinium betaine, etc., aminocarboxylic acid salts such as N-cocoalkyl-B-aminopropionic acid sodium salt, N-cocoalkyl-B-iminodipropionic acid disodium salt, etc.; sulfobetaine; aminobetaine, etc. ' As the semi-polar surfactant having a nitrogen atom in the molecule, there may be included amine oxides such as lauryldimethylamine oxide, stearyldimethylamine oxide, bis-(2-hydroxyethyl)laurylamine oxide, etc.

As the cationic surfactant having a nitrogen atom in the molecule, there may be included aliphatic amine salts, alkyl quaternary ammonium salts, aromatic quaternary ammonium salts, pyridinium salts, imidazolium salts, etc. One or more of these elements can be selected and used as desired.

The ratio of the above anionic surfactant to the surfactant other than the anionic surfactant having a nitrogen atom in the molecule is preferably 20:1 to 1:20, more preferably 10:1 to 1:10, in terms of molar ratio.

The anionic surfactant to be used in the second embodiment of the present invention is as described above.

Examples of the nonionic surfactant not having a nitrogen atom in the molecule to be used in the second. n#*s embodiment of the present invention may include sorbitan fatty acid esters such as sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan 5 sesquioleate, sorbitan trioleate, penta-2-ethylhexy1 acid diglycerol sorbitan, tetra-2-ethylhexyl acid diglycerol sorbitan, etc.; glycerine fatty acids such as mono-cotton seed oil fatty acid glycerine, mono-erucic acid glycerine, sesauioleic acid glycerine, mono-stearic 10 acid glycerine, mono-stearic acid glycerine malic acid, etc.; propylene glycol fatty acid esters such as mono-stearic acid propylene glycol, etc.; lipophilic nonionic surfactants such as hardened castor oil derivatives, glycerine alkyl ethers, etc.; polyoxyethylene (i.e., 15 POE) sorbitan fatty acid esters such as POE sorbitan monooleate, sorbitan monostearate, POE sorbitan monooleate, POE sorbitan tetraoleate, etc.; POE sorbitol fatty acid esters such as POE sorbitol monolaurate, POE sorbitol monooleate, POE sorbitol pentaoleate, POE 20 sorbitol monostearate, etc.; POE glycerine fatty acid esters such as POE glycerine monostearate, POE glycerine monoisostearate, POE glycerine triisostearate, etc.; POE fatty acid esters such as POE monooleate, POE distearate, POE dioleate, distearic acid ethylene glycol, etc.; POE 25 alkyl ethers such as POE lauryl ether, POE oleyl ether, POE stearyl ether, POE behenyl ether, POE 2-octyldodecyl ether, POE cholestanol ether, etc.; POE alkylphenyl ethers such as POE octvlphenyl ether, POE nonylphenvl ether, POE dinonylphenyl ether, etc.; Pulronic type 30 surfactants such as Pulronic, etc.; POE-POP alkyl ethers such as POE-POP cetyl ether, POE-POP 2-decyltetradecyl ether, POE-POP monobutyl ether, POE-POP hydrogenated lanolin, POE-POP glycerine ether, etc.; fatty acid .esters of polyglycerol such as diglycerine monooleate, ^5 hexaglycerine stearate, decaglycerine monolaurate, etc.; ^ tetra POE-POP ethvlenediamine condensates such as Tetronic, etc.; POE castor oil hardened castor oil C'V derivatives such as POE castor oil, POE hardened castor oil, POE hardened castor oil monoisostearate, POE hardened castor oil triisostearate, POE hardened castor oil maleic acid, etc.; POE beeswax lanolin derivatives such as POE sorbitol beeswax, etc.; hydrophilic nonionic surfactants such as POE propylene glycol fatty acid esters, sucrose fatty acid esters, POE nonylphenyl-formaldehyde condensates, etc.

The ratio of the above anionic surfactant to the nonionic surfactant not having a nitrogen atom in the molecule is preferably 20:1 to 1:20, more preferably 10:1 to 1:10, in terms of molar ratio.

As the amphoteric surfactant to be used in the third embodiment of the present invention, there may be included carboxybetaine such as N,N-dimethyl-N-lauryl-N-carboxymethylammonium betaine, N,N-dimethyl-N-oleyl-N-carboxymethylammonium betaine, etc.; imidazoline derivatives such as 2-lauryl-N-carboxyethyl-N-hydroxy-ethylimidazolinium betaine, 2-laury1-N-carboxylmethyl-N-hydroxyethylimidazolinium betaine, etc.; amino-carboxylic acid salts such as N-cocoalkyl-&-amino-propionic acid sodium salt, N-cocoalkyl-B-imino-dipropionic acid disodium salt, etc.,; sulfobetaine, aminobetaine, etc. Examples of the above semi-polar surfactant may include amine oxides such as lauryl-dimethyla-mine oxide, stearyldimethylaffiine oxide, bis-(2-hydroxyethyl)laurylamine oxide, etc.

In the present invention, one or two or more selected from the group consisting of the above amphoteric surfactants and the above semi-polar surfactants may be used as desired.

As the nonionic surfactant having a nitrogen atom in the molecule, fatty acid alkanol amide, polyoxyethylene fatty acid amide, esters of alkanolamine, polyoxy-ethylenealkylamine, etc. may be included, and one or two or more may be selected as desired from thereamong.

The ratio of the above amphoteric surfactant and r; «./ the semi-polar surfactant to the nonionic surfactant having a nitrogen atom in the molecule is preferably 20:1 to 1:20, more preferably 10:1 to 1:10, in terms of molar ratio.

In the fourth embodiment of the present invention, the nonionic surfactant, the amphoteric surfactant, the semi-polar surfactant and/or the cationic surfactant having a nitrogen atom in the molecule are used in combination with a nonionic surfactant not having a 10 nitrogen atom in the molecule as described above.

The ratio of one or two or more selected from the group consisting of the nonionic surfactants, the amphoteric surfactants, the semi-polar surfactants and cationic surfactants having a nitrogen atom in the 15 molecule to the nonionic surfactant not having a nitrogen atom in the molecule is preferably 20:1 to 1:20, preferably 10:1 to 1:10, in terms of molar ratio.

As the amine oxide to be used in the fifth embodiment of the present invention, there may be 20 included those shown below. (1) Amine oxide represented by the formula (I) R, X1 1 R.

R_ - N 0 (I) I I 3 (wherein R^ , R2 and R^ represent straight or branched alkyl group or alkenyl group having 1 to 24 carbon atoms, and at least one of , R^ and R^ represent straight or branched alkyl group or alkenyl group having 8 or more carbon atoms).

Specific examples of the amine oxide represented by the formula (I) may include dimethyllaurylamine oxide, dimethylmyristylamine oxide, dimethylcetylamine oxide, dimethylstearylamine oxide, dimethyloleylamine oxide, dimethylbehenylaraine oxide, methyldilaurylamine oxide and the like. (2) Dihydroxyethylalkylamine oxide represented by the formula (II) '2 9 SEP 1988' O 9 < ■ p ! O J. c CH-CHo0H | £ <£ R - N * 0 (II) i CH2CH2OH (wherein R represents straight or branched alkyl group or alkenyl group having 8 to 24 carbon atoms). (3) Dimethylalkylpolyoxyethyleneamine oxide represented by the formula (III) C!I.

R - (OCH-CH-) - N -v 0 (III) /. z. n i 3 CH. 3 (wherein R represents a straight or branched alkyl group or alkenyl group having 8 to 2 4 carbon atoms, and n represents an integer of 1 to 5) .

One or two or more of the above amine oxides may be used.

As the drug component, the pharmecological effect of which can be increased by utilization of the above percutaneous absorption promoting agent, the following drugs may be exemplified.

For example, steroid type anti-inflammatory agents such as predonizolone, dexamethasone, etc.; non-steroid type anti-inflammatory agent such as indomethacin, fluphenamic acid, mephenaraic acid, etc.; anti-histamic agents such as chlorophenylamine, diphenehydramine, 25 promethazin, etc.; sulfur agents such as sulfur monomethoxicin, sulfur methizole, etc.; antibiotics such as penicillin, cephalosporin, chloramphenicol, streptomycin, etc.; antifungal agents such as naphthiomate, chlotrimazole, etc.; anti-malignant tumor 30 agents such as cyclophosphamide, busulfan, actinomycin, etc.; analogesics such as morphine, codeine, nalorufin, pentazocin, aspirin, acetanilide, aminopyrin, etc.; narcotics and tranquilizers such as prostaglandins preparations, barbital, thiopental, etc.; phychophaxma-ceuticals such as chloroproma-zine, recerpine, chloro-diazeboxide, etc.; anti-Perkinson's disease agents such as chlorozoquisazone, levodopa, etc.; cardiacs such as dikitoxicin, digoxin, etc.; antiarrythmic agents such as hydrochloric acid procainamide, etc.; anti-stenocardia agents such as dipiridamol, amilnitrite, etc.; antihypertensives such as diazokiside, minoxyzyl, recerpine, 5 quanitizine nitrate; UV-ray inhibitors such as para- aminobenzoate ester, etc.; melanin formation inhibitors such as hydroquinone, arbutin, kojic acid, Vitamin C ^ esters, para-hydroxycinnamate, etc.; psoriasis PUVA therapeutics such as 8-methoxysolarene, etc.; Vitamins 10 such as Vitamin A, Vitamin E, Vitamin C, coenzyme Q10, (Vitamin Q), etc.; hair growing agents such as cephal-antin, swelthiamaline, okisendoron, etc.; hormones such as insulin, estradiol, methylteststeron, etc.; diagnostics; allergen for patch test; insecticides; secticides; 15 humectants; corneum emoliient; hairdyes, and other drug components. Particularly, as the drug component, water-soluble drug components such as indomethacin, minoxidil, hydroquinone, arbutin, kojic acid, Vitamin C, Vitamin C ester, swelthiamaline, cephalantin, etc. can be particu-20 larly rapidly absorbed into the skin.

These drug components can be absorbed rapidly into the skin by coating on the skin when mixed with the percutaneous absorption promoting' agent of the present invention. In the case of a drug component to be used 25 for topical action, an excellent deep penetration of the skin can be exhibited, and in the case of drug component to be used for systemic action, this can also exhibit a '/"■ similarly excellent effect because the drug component is migrated into the blood.

The subject to which these ingredients are applied is of course a human being, but they can be also effectively used for other animals.

The amount of the drug component formulated may be sufficient to bring about the desired pharmacological effect, which depends also on the kind of the drug ^fov- component, body weight of the patient, severity of the . ^disease, etc., but is preferably 0.001 to 50 parts by jun1992 f*s --...35 T, (* * $29^" ''' O r n < , p j ^ o tj j_ weight of the percutaneous absorption promoting agent, more preferably 0.01 to 30 parts by weight, per 1 part by weight of the drug component.

The above percutaneous absorption promoting agent may be used by suitably mixing the drug component as such, but is generally used by mixing the constituents in a base for dermatologic preparation such as cream preparation, ointment preparation, gel preparation, lotion preparation, emulsion, adhesive tape, etc.

The amount of the respective constituents in that case may differ depending on the kind of the drug component, but generally the following ranges are the preferred ranges of the amount formulated. That is, the total amount of the anionic surfactant and the surfactant other than the anionic surfactant having a nitrogen atom in the molecule may be 0.001 to 10% by weight, more preferably 0.01 to 5% by weight in the dermatologic preparation, and the drug component may be 0.001 to 10% by weight, more preferably 0.01 to 5% by weight. On the other hand, for the ratio of the anionic surfactant to the surfactant having a nitrogen atom in the molecule other than anionic surfactants, the ratio as mentioned above, namely 20:1 to 1:20, preferably 10:1 to 1:10, may be applied as such.

The total amount formulated of the amphoteric surfactant and the semi-polar, surfactant and the nonionic surfactant having a nitrogen atom in the molecule may be 0.001 to 10% by weight, more preferably 0.01 to 5% by weight in the dermatologic preparation, and the drug component may be 0.001 to 10% by weight, more preferably 0.01 to 5% by weight. For the ratio of the amphoteric surfactant and the semi-polar surfactant to the nonionic surfactant having a nitrogen atom in the molecule, the ratio as described above, namely 20:1 to 1:20, preferably 10:1 to 1:10 in terms of molar ratio, may be applied as such.

The total amount of the anionic surfactant, and the o > • • Tv : S.' <J J """"N nonionic surfactant not having a nitrogen atom in the molecule may be 0.001 to 10% by weight, more preferably 0.01 to 5% by weight in the dermatologic preparation, while the drug component may be 0.001 to 10% by weight, 5 more preferably 0.01 to 5% by weight. For the ratio of the anionic surfactant to the nonionic surfactant not having a nitrogen atom in the molecule, the ratio as described above, namely 20:1 to 1:20, preferably 10:1 to 1:10 in terms of molar ratio, may be applied as such. 10 Further, the total amount formulated of one or more selected from the group consisting of nonionic surfactants, amphoteric surfactants, semi-polar surfactants and cationic surfactants having a nitrogen atom in the molecule and one or more of nonionic surfactants not 15 having a nitrogen atom in the molecule may be 0.001 to 10% by weight, more preferably 0.01 to 5% by weight in the dermatologic preparation, and the drug component may be 0.001 to 10% by weight, more preferably 0.01 to 5% by weight. For the ratio of one or two or more selected 20 from the group consisting of nonionic surfactants, amphoteric surfactants, semi-polar surfactants and cationic surfactants having a nitrogen atom in the molecule to one or two or more of nonionic surfactants not having a nitrogen atom in the molecule, the ratio as 25 mentioned above, namely 20:1 to 1:20, preferably 10:1 to 1:10 in terms of molar ratio, may be applied as such.

Further, the amount of amine oxide formulated may be 0.0001 to 10% by weight, more preferably 0.01 to 5% by weight in the dermatologic preparation. The amount 30 of the drug component may be 0.001 to 10% by weight, more preferably 0.01 to 5% by weight.

In the dermatologic preparation promoting the percutaneous absorption of drug component according to the present invention, it is also possible to formulate 35 components as generally formulated in drugs, quasi drugs, cosmetic, etc. Examples of such components may include polyhydric alcohol, oil component, wax, acid, O O ' ■ p ■ ■ *>• «J ./ f alkali, cationic surfactant, nonionic surfactant, anionic surfactant, amphoteric surfactant, powder, pigment, dye, preservative antifungal agent, antio-xident, UV-ray absorber, chelating agent, water-soluble 5 polymer, montmorilonite, alcohol, solvent, flavor, etc.

More specifically, there may be included polyhydric alcohols such as glycerine, propylene glycol, etc.; oil components such as fluid paraffin, squalane, higher -»*\ fatty acid, higher alcohol, etc.; organic acids such as citric acid, lactic acid, etc.; alkalis such as caustic soda, triethanolamine, etc.; anionic surfactants such as higher alkylsulfuric acid ester salts, higher alkyl-ethersulfuric acid ester salts, higher fatty acid amide sulfonic acid salts, higher alkvlsulfosuccinic acid 15 salts, alkylbenzenesulfonic acid salts, acylglutamic acid salts, higher alkylphosphoric acid salts, etc.; cationic surfactants such as higher alkyl quaternary ammonium salts, fatty amine salts, alkylpyridinium salts, etc.; amphoteric surfactants such as carboxy-20 betaine, sulfobetaine, imidazoline derivatives, etc.; polyoxyethylene alkyl ether, polyoxyethylene fatty acid amide, sorbitan fatty acid esters, fatty acid alkanol-amide, polyglycerine fatty acid ester, etc.

The percutaneous absorption promoting agent and the 25 dermatologic preparation according to the present invention have an excellent effect of promoting the percutaneous absorption of a drug component, and further, are percutaneous absorption promoters with a good safety and feeling upon use.

EXAMPLES The present invention will now be further illustrated by, but is by no means limited to, the following Examples, wherein "%" represents "% by weight", unless otherwise specified.

Example 1-1: Cream ' . r,'' ! ^ (1) Dexamethasone 0 .025% (2) Propylene glycol 8.0 ' • * i V 2 9 St - 14 Ky ' _> j (3) Glycerine 5.0 (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Sodium dodecylsulfate 0.08 (7) Dodecyldimethylamine oxide 0.16 (8) Glycerine monofatty acid ester 1.5 (9) Preservative q.s. (10) Clay mineral (bentonite) 6.0 (11) Purified water balance 10 [Preparation Method] To (5) were added (1), (4), (8) and (9) and these components were dissolved and mixed by heating to 70°C. This was called composition (A). The components (6) and (7) were added to a part of (11) to be dissolved 15 therein, followed further by an addition and mixing of the components (2) and (3). This was called composition (B). While composition (B) was stirred at a temperature maintained at 70°C, composition (A) was gradually added to effect preliminary emulsification, 20 followed by emulsification by a homomixer.

The resultant emulsion was added to a dispersion having added and dispersed (10) in the remainder of (11) under stirring, and cooled to obtain a cream.

Comparative Example 1-1: Cream (1} Dexamethasone 0.025% (2) Propylene glycol 8.0 (3) Glycerine .0 (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Glycerine monofatty acid ester 1.5 (7) Preservative q.s. (8) Clay mineral (bentonite) 6.0 (9) Purified water balance [Preparation Method] According to Example 1-1.

Text Example 1-1 \ For the creams prepared in Example 1-1 and Compara- O O ' ' bj tJ - 15 tive Example 1-1, the vasoconstrictive action was compared.

More specifically, on the upper backs of 10 healthy human males, creams prepared in Example 1-1 and Comparative Example 1-1, and further creams of the above two kinds of creams not containing dexamethasone were respectively and randomly apportioned, applied by using an adhesive plaster for patch test (produced by Torii Yakuhin), and plastered under sealing. After 4 hours, the adhesive plaster was peeled off, the sample removed, and judgement was conducted after further standing for 4 hours. Judgement was conducted according to the standards of achromasia phenomenon accompanied with vasoconstrictive action of steroids as "remarkable achromasia phenomenon" (score 2), "clear achromasia phenomenon" (score 1), "faint achromasia phenomenon" (score 0.5), "no change" (score 0), and an average score was determined for each base.

The results are shown in Table 1-1.

Table 1-1 Base Average score after 4 hours Example 1.7 Comparative Example 1.0 System of Example from which dexamethasone is removed 0 System of Comparative Example from which dexamethasone is 0 removed As apparent from Table 1-1, it can be seen that the cream of Example 1-1 had an excellent vasoconstrictive action.

O f » f .• p • c/ J Example 1-2: Gel (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) Polyoxyethylene 1.5 (hereinafter called POE: 40 mole) hardened caster oil (5) Sodium dodecylsulfate 0.5 (6) Sodium dodecylphosphate 0.6 (7) Sodium laurylisothionate 0.2 (8) Dodecyldimethylamine oxide 1.14 (9) Laurie acid diethanolamide 0.2 (10) Diisopropanolamine 0.35 (11) Purified water balance 15 [Preparation Method] After (5), (6), (7), (8) and (9) were dissolved in (11), (3) was dispersed in the solution. The dispersion was added to a solution of (1) and (4) added and dissolved in (2) , followed by thorough mixing. Further, to 20 this mixture was added (10) and the mixture was stirred and mixed to obtain a gel.

Comparative Example 1-2 (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) POE hardened caster oil 1.5 (5) Diisopropanolamine 0.35 (6) Purified water balance [Preparation Method] According to Example 1-2.

Comparative Example 1-3 Commercially available ointinent containing 1% indomethacin (gel-like external agent).

Text Example 1-2 35 For the above gel bases, the pharmacological effects were examined and compared according to the carageenin edema inhibition test. n n ■ • r , 'J j- More specifically, using 5 Wooster-strain male rats 6 weeks of age, as one group, first the right rear leg volume of the rat in each group was measured by a rat rear leg footpad edema volume measuring device 5 KM-357 (produced by Natsume Seisakusho), and then 0.2 g of a sample was applied on the right rear leg of rat. Two hours later, 0.05 ml of 1% carageenin sodium salt was subscutaneously injected at the same site, and 3 hours after the carageenin sodium salt injection, the 10 right rear leg volume was measured to calculate foot edema inhibition according to the following formula, with the difference in the right rear leg volume before coating of the sample being the foot edema volume.

Foot edema inhibition (%) = Vc ~ >: 100 Vc wherein Vc and Vt represent average edema volumes of the control group (coated with no test sample), and the group coated with test sample, respectively.

The above test results are shown in Table 1-2.

Table 1-2 Carageenin food edema inhibition (%) Example 1-2 53.9 Comparative Example 1-2 11.2 Comparative Example 1-3 8.5 As apparent from the table, it can be seen that the gel base of Example had an excellent carageenin edema inhibition action.

Example 1-3 rl4 7" (1) C Cj Hydroquinone 1.0% (2) Sodium dodecylsulfate 0.2 (3) Dodecyldimethylamine oxide 0.7 fv "2| ! Z o! 12 9 sep rasa*/ \pc,^ C)o.)r . 1 . (4) Purified water balance [Preparation Method] After (2) and (3) were dissolved in (4), (1) was added and the mixture stirred and dissolved to provide a 5 sample.

Comparative Example 1-4 (1) [^c] Hydroquinone 1.0% (2) Purified water balance [.Preparation Method] According to Example 1-3.

Comparative Example 1-5 (1) [^c] Hydroquinone 1.0% (2) Urea 5.0 (3) Purified water balance 15 [Preparation Method! According to Example 1-3.

Text Example 1-3 On the back skins of hairless mice, 3 mice in one group, 100 microliters of a sample was plastered with 20 Torii adhesive plaster for patch test (diameter: 1.6 cm). On the adhesive plaster was placed a sponge, which was further coated with a thin film of a rubber so as to adhere the plaster to the skin.. After coating, each mouse was placed in a sealed vessel made of a 25 plastic, with a delivery of air, and carbon dioxide discharged by breathing absorbed in a 50% methanolic solution of monoethanolamine.

After coating, the adhesive plaster at the coated portion was removed at 24 and 4 8 hours for measurement 30 of the radio activity in the adhesive plaster. Next, the coated portion was subjected to stripping with cellophane tape for 8 times, and the activity in corneum adhered to cellophane tape was measured. Then the animals were sacrificed, the skin at the coated portion 35 peeled off, and the activity in the skin measured. The remaining whole body was homogenated by a blender wit|> an addition of 30 g of 0. 5N aqueous sodium hydroxid^^ th 2 9 SEP 1988 ^ . N S» O J and a certain amount of the homogenate sampled for a measurement of the activity. Also, fetus and urine discharged up to a predetermined time were recovered for a measurement of the activity.

Here, the sum of the amount discharged by breathing, the amounts of fetus and urine discharged, and the amount stored in the body was defined as the percutaneous absorption amount in body. The above test results are shown in Table 1-3.

Table 1-3 Percutaneous absorption amount in body Example 1-3 2 8.8% Comparative Example 1-4 4.9 Comparative Example 1-5 4.6 (after 48 hours) Example 2-1: Cream (1) Dexamethasone 0.025% (2) Propylene glycol 8.0 (3) Glycerine 5.0 (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Laurie acid diethanolamide 0.6 (7) N,N-dimethyl-N-lauryl-N- 0.3 carboxymethylammonium betaine (8) Glycerine monofatty acid ester 1.5 (9) Preservative q.s. (10) Clay mineral (bentonite) 6.0 (11) Purified water balance [Preparation Methodl To (5) were added (1), (4), (8) and (9) and these=-— ig \ 2 9 sep 1988 *-■ ** <-* o j components were dissolved and mixed by heating to 70°C.

This was called composition (A).

The components (6) and (7) are added to a part of (11) to be dissolved therein, followed further by an 5 addition and mixing of the components (2) and (3) . This was called composition (B).

While composition (B) was stirred at a temperature maintained at 70°C, composition (A) was gradually added to effect preliminary emulsification, followed by 10 emulsification by a homomixer.

The resultant emulsion was added to a dispersion having added and dispersed (10) in the remainder of (11) under stirring, and cooled to obtain a cream.

Comparative Example 2-1: Cream (1) Dexamethasone 0.025% (2) Propylene glycol 8.0 (3) Glycerine .0 (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Glycerine monofatty acid ester 1.5 (7) Preservative q.s. (8) Clay mineral (bentonite) 6. 0 (9) Purified water balance [Preparation Method] According to Example 2-1.

Text Example 2-1 For the creams prepared in Example 2-1 and Comparative Example 2-1, the vasoconstrictive action was compared as in Test Example 1-1.

The results are shown in Table 2-1. "2 9 sep ma ^ i O 9 <) -> O tj Table 2-1 Average score after 4 hours Example 2-1 1.5 Comparative Example 2-1 1.0 System of Example 2-1 from which dexamethasone is removed 0 System of Comparative Example 2-1 from which dexamethasone is 0 removed As apparent from Table 2-1, it can be seen that the cream of Example 2-1 had an excellent vasoconstrictive action.

Example 2-2: Gel (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) carboxy'vinyl polymer 1.2 (4) POE 1.5 hardened caster oil (5) Lauryldimethylamine oxide 0.6 (6) P.O.E. (15 mole) oleyl amine 0.8 (7) N,N-dimethyl-N-lauryl-N- 1.0 sulfomethylammonium betaine (8) Laurie acid diethanolamide 0.35 (9) Diisopropanolamine 0.35 (10) Purified water balance [Preparation Method! After (5), (6), (7) and (8) were dissolved in (10), (3) was well dispersed in the solution. The dispersion was added to a solution of (1) and (4) added and dissolved in (2) , followed by thorough mixing. Further, to this mixture was added (9) and the mixture stirred and. mixed to obtain a gel. b 29sep ;"■> r> ' • p ; ■- '•J i« o t Comparative Example 2-2 (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) POE hardened caster oil 1.5 (5) Diisopropanolamine 0.35 (10) Purified water balance [Preparation Method] According to Example 2-2.

Comparative Example 2-3 Commercially available ointment containing 1% indomethacin (gel-like external agent).

Test Example 2-2 For the above gel-like bases, the pharmacological 15 effects were examined and compared as in Test Example 1-2 according to the carageenin edema inhibition test.

The above test results are shown in Table 2-2.

Table 2-2 Carageenin foot edema inhibition (%) Example 2-2 50.8 Comparative Example 2-2 11.2 Comparative Example 2-3 8.5 As apparent from the table, it can be seen that the gel base of Example had an excellent carageenin edema inhibition action.

Example 2-3 35 f1) '-14 cJ Hydroquinone (2) Coconut fatty acid diethanolamide (3) Dodecyldimethylamine oxide //V 12 ° I 2 9 SEP my W ,cV \xe e, vj 0* O o <■_ p / -'<j o ij J. i (4) Purified water balance [Preparation Method] After (2) and (3) were dissolved in (4), (1) was added, and the mixture stirred and dissolved to provide 5 a sample.

Comparative Example 2-4 (1) t14cJ Hydroquinone 1.0% (2) Purified water balance [Preparation Method] According to Example 2-3.

Comparative Example 2-4 (1) t^c3 Hydroquinone 1.0% (2) Urea 5.0 (3) Purified water balance 15 [Preparation Method] According to Example 2-3.

Test Example 2-3 For the samples obtained above, the percutaneous absorption amounts were determined as in Test 20 Example 1-3.

The above test results are shown in Table 2-3.

Table 2-3 Percutaneous absorption amount Example 2-3 26.8% Comparative Example 2-4 4.9 Comparative Example 2-5 4 . 6 (after 48 hours) Example 3-1: Cream (1) Dexamethasone (2) Propylene glycol O O ' - P . j. (3) Glycerine .0 (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Sodium myristylsulfate 2.5 (7) Sorbitan monooleate 1.0 (8) Glycerine monofatty acid ester 1.5 (9) Preservative q.s. (10) Clay mineral (bentonite) 6 . 0 (11) Purified water balance Preparation Method To (5) were added (1), (4), (8) and (9) and these components were dissolved and mixed by heating to 70°C. This was called composition (A). The components (6) and (7) were added to a part of (11) to be dissolved 15 therein, followed further by an addition and mixing of components (2) and (3) . This was called composition (B). While composition (B) was stirred at a temperature maintained at 70°C, composition (A) was gradually added to effect preliminary emulsification, 20 followed by emulsification by a homomixer.

The resultant emulsion was added to a dispersion having added and dispersed (10) in the remainder of (11) under stirring, and cooled to obtain a cream. Comparative Example 3-1: Cream (1) Dexamethasone 0.025% (2) Propylene glycol 8 . 0 (3) Glycerine .0 (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Glycerine monofatty acid ester 1.5 (7) Preservative q.s. (8) Clay mineral (bentonite) 6.0 (9) Purified water balance [Preparation Method] According to Example 3-1.

Test Example 3-1 For the creams prepared in Example 3-1 and Compara tive Example 3-1, the vasoconstrictive action was compared as in Test Example 1-1.

The results are shown in Table 3-1.

Table 3-1 Average score after 4 hours Example 3-1 1.4 Comparative Example 3-1 1.0 System of Example 3-1 0 from which dexamethasone is removed System of Comparative 0 Example 3-1 from which dexamethasone is removed As apparent from the table, it can be seen that the cream of Example 3-1 had an excellent vasoconstrictive action.

Example 3-2: Gel (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) Polyoxyethylene 1.5 (40 mole addition) hardened caster oil (5) Sodium dodecylsulfate 0.7 (6) Sodium monOlaurylphosphate 0.6 (7) Sodium laurylisothionate 0.7 (8) POE sorbitan monostearate 2.3 (9) Sucrose fatty acid ester 1.5 (10) Diisopropanolamine 0.35 (11) Purified water balance [Preparation Method] After (5) , (6) , (7) , (8) and (9) were dissolved in (11) , (3) was dispersed in the solution. The dispersion ^ <1 <J 26 was added to a solution of (1) and (4) added and dissolved in (2), followed by thorough mixing. Further, to this mixture was added (10) and the mixture was stirred and mixed to obtain a gel.

Comparative Example 3-2 (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) Polyoxyethylene 1.5 [Preparation Method] According to Example 3-2.

Comparative Example 3-2 Commercially available ointment containing 1% indomethacin (gel-like external agent).

Test Example 3-2 For the above gel bases, the pharmacological effects were examined and compared as in Test Example 1-2 according to the carageenin edema inhibition test.

The above test results are shown in Table 3-2. (40 mole addition) hardened caster oil (5) Diisopropanolamine (6) Purified water balance 0.35 Table 3-2 Carageenin foot edema inhibition (%) Example 3-2 48.3% Comparative Example 3-2 Comparative Example 3-3 11. 2 8.5 As apparent from the table, it can be seen that the gel base of Example 3-2 had an excellent carageenin 9 O 11 o * " ** »J O j. r edema inhibition action.

Example 3-3 (1) L14C ] Hydroquinone 1.0% (2) Sodium N-lauroyl glutamate 1.2 (3) Polyoxyethylene 1.6 (15 mole addition) stearyl ether (4) Purified water balance [Preparation Method] After (2) and (3) were dissolved in (4), (1) was added and the mixture stirred and dissolved to provide a sample.

Comparative Example 3-4 (1) [^C] Hydroquinone 1.0% (2) Purified water balance 15 Preparation Method According to Example 3-3.

Comparative Example 3-5 (1) [^c] Hydroquinone 1.0% (2) Urea 5.0 (3) Purified water balance preparation Method According to Example 3-3.

Test Example 3-3 For the samples obtained above, the percutaneous 25 absorption amounts were determined as in Test Example 1-3.

The above test results are shown in Table 3-3. o >')1> C : WwOi/J.' Table 3-3 ' *^\ L*4 OV fm SEP 1988 ^ \ - ' Percutaneous absorption amount Example 3-3 21 .8% Comparative Example 3-4 4 . 9 Comparative Example 3-5 4 .6 (after 48 hours) Example 4-1: Cream (1) Dexamethasone 0.025% (2) Propylene glycol 8.0 (3) Glycerine .0 (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Fatty acid alkanolamide 1.8 (7) Sorbitan monooleate 1,0 (8) Glycerine monofatty acid ester 1.5 (9) Preservative g. s. (10) Clay mineral (bentonite) 6 . 0 (11) Purified water balance [Preparation Method] To (5) were added (1), (4), (8) and (9) and these components were dissolved and mixed by heating to 70°C. This was called composition (A). The components (6) and (7) were added to a part of (11) to be dissolved therein, followed further by an addition and mixing of components (2) and (3). This was called composition (B). While composition (B) was stirred at a temperature maintained at 70°C, composition (A) was gradually added to effect preliminary emulsification, followed by emulsification by a homomixer.

The resultant emulsion was added to a dispersion having added and dispersed (10) in the remainder of (11) O ' • p f O SJ t./ J_ I under stirring, and cooled to obtain a cream. Comparative Example 4-1: Cream (1) Dexamethasone 0.025% (2) Propylene glycol 8.0 (3) Glycerine .0 (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Glycerine monofatty acid ester 1.5 (7) Preservat ive q.s. (8) Clay mineral (bentonite) 6.0 (9) Purified water balance [Preparation Method] According to Example 4-1.

Test Example 4-1 15 For the creams prepared in Example 4-1 and Compara tive Example 4-1, the vasoconstrictive action was compared as in Test Example 1-1. • The results are shown in Table 4-1.

Table 4-1 Base kltXaqeA lCOre after 4 hours Example 4-1 1.5 Comparative Example 4-1 1.0 System of Example 4-1 0 from which dexamethasone is removed System of Comparative 0 Example 4-1 from which dexamethasone is removed As apparent from the table, it can be seen that the 35 cream of Example 4-1 had an excellent vasoconstrictive ■„ , action.

'•;T Example 4-2: Gel <\i j?29SEPW>o\; ■ <? o e: •„ < * •' Or.. f. ■ -'V t*J O <J J. I (1) Indomethacin (2) Ethyl alcohol (3) Carboxy vinyl polymer (4) Polyoxyethylene 1.0% 50 . 0 1.2 1.5 (40 mole addition) hardened caster oil (5) Laurie acid diethanolamide (6) Lauryldimethylamine oxide (7) Lauryl betaine (8) POE sorbitan monostearate (9) Sucrose fatty acid ester (10) Diisopropanolamine (11) Purified water 0.5 1.14 0.2 0 . 35 balance 1.5 1.0 [Preparation Method] After (5), (6), (7), (8) and (9) were dissolved in (11), (3) was dispersed in the solution. The dispersion was added to a solution of (1) and (4) added and dissolved in (2), followed by thorough mixing. Further, to this mixture was added (10) and the mixture was stirred and mixed to obtain a gel.

Comparative Example 4-2 (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) Polyoxyethylene 1.5 [Preparation Method] According to Example 4-2.

Comparative Example 4-3 Commercially available ointment containing 1% indomethacin (gel-like external agent).

Test Example 4-2 For the above gel bases, the pharmacological effects were examined and compared as in Test ^=-J2xample 1-2 according to the carageenin edema inhibition (40 mole addition) hardened caster oil (5) Diisopropanolamine (6) Purified water 0 .35 balance ' - «_/ i The above test results are shown in Table 4-2.

Table 4-2 Carageenin foot edema inhibition (%) Example 4-2 49.1% Comparative Example 4-2 11.2 Comparative Example 4-3 8.5 As apparent from the table, it can be understood that the gel base of Example 4-2 had an excellent carageenin edema inhibition action.

Example 4-3 (1) Hydroquinone 1.0% (2) Distearyldimethyl ammonium 0.5 chloride (3) Triglycerine monolaurate 1.5 (4) Purified water balance [Preparation Method] After (2) and (3) were dissolved in (4), (1) was added and the mixture stirred and dissolved to provide a sample.

Comparative Example 4-4 (1) [^4C] Hydroquinone 1.0% (2) Purified water balance [Preparation Method] According to Example 4-3.

Comparative Example 4-5 (1) ["^cl Hydroquinone 1.0% (2) Urea 5.0 (3) Purified water balance [Preparation Method] According to Example 4-3. o.w 0 , .. i_/ JL, Test Example 4-3 For the samples obtained above, the percutaneous absorption amounts were determined as in Test Example 1-3.

The above test results are shown in Table 4-3.

Table 4-3 Percutaneous absorption amount Example 4-3 23.7% Comparative Example 4-4 4.9 Comparative Example 4-5 4.6 (after 48 hours) I, 4^29 sep v)88" Examples 5-1 - 5-5 Drug Permeability Test A drug permeability test was conducted for amine oxide, which is the product of the present invention.

Pharmaceutical samples comprising the following composition were prepared. (1) Hydroquinone 1.0% (2) Test substance 0.1 (3) Ethanol 20.0 (4) Purified water balance Preparation Method After (1) and (2) were dissolved in (3) , (4) was added and mixed to provide a sample.

Test Substance Tests were conducted for the following test substances.

(A) Amine oxide insoluble or slightly soluble in water Example 5-1: Dimethylstearylamine oxide O r>' f. .

«J J. ( Example 5-2: Dimethylbehenylamine oxide Example 5-3: Dihyaroxyethylstearylamine oxide (B) Water-soluble amine oxide Example 5-4: Dimethyllaurylamine oxide Example 5-5: Dimethylmilistylamine oxide Comparative Example 5-1 (1) Hydroquinone 1.0% (2) Ethanol 20.0 (3) Purified Water balance [Preparation Method] According to Examples 5-1 - 5-5.

Test Example 5-1 For an evaluation of the percutaneous absorption promoting effect of a drug with the test substance, a drug permeability test was conducted by using an in vitro diffusion cell, using the enucleated skin of a hairless mouse. As the diffusion cell device, a vertical film type 2-compartment cell with a diffusion 2 area of 2 cm was employed. The whole skin layer at the back of a 10 to 15 weeks old male hairless mouse was enucleated and mounted on the diffusion cell. In the cell compartment on the medicament sample side, 2 ml of a medicament sample was placed, and 2 ml of a phosphate buffer physiological saline (pH 7.2) was placed in the cell compartment on the receptor side, and the whole cell maintained at 32°C in a thermostat tank while gently stirring both phases. After 24 hours, the receptor solution was sampled and the amount of the drug permeated to the receptor side guantitated by high performance liquid chromatography. The results are represented in drug permeability (%). The results are shown in Table 5-1.

Table 5-1 Test substance Drug perme- Effect ability Example 5-1 Dime thy Istearylamine oxide Example 5-2 Dime thy Ibehenylamine oxide Example 5-3 Dihydroxye thy Istearylamine oxide Exanple 5-4 Dimethyllaurylamine oxide Example 5-5 Dimethylmilistylamine oxide Comparative Example 5-1 44.0 excellent 28.6 execellent .5 excellent 9.4 fair 11.8 fair 2.1 As apparent from the table, the percutaneous absorption promoting agent of the present invention had an excellent effect of promoting a skin permeability of a drug, and particularly, it can be understood that insoluble or slightly soluble amine oxides had excellent effects, Drug Percutaneous Absorption Test Example 5-6 (1) L^C] Hydroquinone 1.0% (2) Dimethylstearylamine oxide 0.1 (3) Ethanol 20.0 (4) Purified water balance [Preparation Method] After (1) and (2) were dissolved in (3) , (4) was added and mixed to provide a sample.

Comparative Example 5-2 (1) [■14cl Hydroquinone 1.0% (2) Ethanol 20.0 .<4 (3) Purified water balance [Preparation Method] According to Example 5-6.

Comparative Example 5-3 (1) [14c]Hydroquinone 1.0% (2) Urea 5.0 (3) Ethanol 20.0 (4) Purified water balance Preparation Method After (1) was dissolved in (3), a solution of (2) dissolved in (4) was added and mixed to provide a sample.

Test Example 5-2 For the samples obtained above, the percutaneous absorption amounts were determined as in Test Examples 1-3. The above test results are shown in Table 5-2.

Table 5-2 Percutaneous absorption amount in body Example 5-6 35.5% Comparative Example 5-2 4.1 Comparative Example 5-3 4.9 (after 48 hours) As apparent from the table, it can be seen that the percutaneous absorption promoting agent of the present invention had an excellent effect of promoting the absorption of a drug.

Example 5-7: Cream (1) Dexamethasone 0. 025 (2) Propylene glycol 8. 0 (3) Glycerine . 0 (4) Fluid paraffin 1. 0 (5) Diisopropyl adipate 3. 0 OO'.;0 K*' <J O U J_ * (6) Dimethylstearylamine oxide .0 (7) Glycerine monofatty acid ester 1.5 (8) Preservative q.s. (9) Clay mineral (bentonite) 6.0 (10) Purified water balance [Preparation Method] To (6) were added (1), (4), (5), (7) and (8) and these components were dissolved and mixed by heating to 70°C. This was called composition (A). The components (2) and (3) were added to a part of (10). This was called composition (B). While composition (B) was stirred at a temperature maintained at 70°C, composition (A) was gradually added to effect preliminary emulsification, followed by emulsification by a homomixer. The resultant emulsion was added to a dispersion having added and dispersed (9) in the remainder of (10) under stirring, and cooled to obtain a cream.

Comparative Example 5-4: Cream (1) Dexamethasone 0.025% (2) Propylene glycol 8.0 (3) Glycerine . Q (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 (6) Glycerine monofatty acid ester 1.5 (7) Preservative q.s. (8) Clay mineral (bentonite) 6.0 (9) Purified water balance [Preparation Method] According to Example 5-7.

Test Example 5-3 For the creams prepared in Example and Comparative Example, the vasoconstrictive action was compared as in Test Example 1-1.

The results are shown in Table 5-3. f* O I O'iC, i 1*4 u 1 Table 5-3 ~ „ Average score Base r^. A u after 4 hours Example 5-7 1.8 Comparative Example 5-4 0.9 System of Example 5-7 0 from which dexamethasone is removed System of Comparative 0 Example 5-4 from which dexamethasone is removed fc I1' f *-\s ' p- O \ / -A ilN z2 9 sep 19887 \ As apparent from the table, it can be seen that the cream of Example 5-7 had an excellent vasoconstrictive action.

Example 5-8: Gel (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) Polyoxyethylene (40) 1.5 hardened caster oil (5) Dimethylbehenylamine oxide 1.0 (10) Diisopropanolamine 0.35 (11) Purified water balance [Preparation Method] After (1), (4) and (5) were dissolved in (2), (3) dissolved in (7) was added, followed by thorough mixing.

Further, to this mixture was added (6) and the mixture stirred and mixed to obtain a gel.

Comparative Example 5-5 (1) Indomethacin 1.0% (2) Ethyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) Polyoxyethylene (40) 1.5 hardened caster oil 9 0 V O il' (5) Diisopropanolamine 0.35 (6) Purified water balance [Preparation Method] According to Example 5-8.

Comparative Example 5-6 Commercially available ointment containing 1% indomethacin (gel-like external agent).

Test Example 5-4 For the above gel bases, the pharmacological 10 effects were examined and compared as in Test Example 1-2 according to the carageenin edema inhibition test.

The above test results are shown in Table 5-4.

Table 5-4 Carageenin foot edema inhibition (%) Example 5-8 Comparative Example 5-5 Comparative Example 5-6 56.1 12.0 10.8 As apparent from the table, it can be seen that the gel base of Example 5-8 had an excellent carageenin edema inhibition action.

Test Example 6-1 30 The effect of the promotion of a percutaneous absorption of drugs with the test substances shown in Table 6-1 were evaluated as in Test Example 5-1.

V* v 29 SEP 1988 * % A Test substance Drug Drug permeability (%) Example 6-1 Sodium dodecylsulfate 0. 2% Arbutin 0.3% 39% Dodecylaminoacetic acid betaine 0.

% Example 6-2 Sodium dodecylsulfate 0. 2% Minoxidil 0.3% 32% Dodecylaminoacetic acid betaine 0.

% Example 6-3 Sodium dodecylsulfate 0. 2% Kojic acid 0.3% 40% Dodecylaminoacetic acid betaine 0.

% Example 6-4 Laurylimidazoliniumbetaine 0. 1% Arbutin 0.3% 27% LauryIdiethanolamide 0.

% Example 6-5 Stearyldimethylamine oxide 0.

% Arbutin 0.3% 34% Comparative - Arbutin 0.3% 1% Example 6-1 O ' p 'J O . 40 In the table, numerical values (%) in the column of test substance and drug show the concentrations in aqueous solution.

As apparent from the results in the above table, it 5 can be understood that the test substances (percutaneous absorption promoting agent) of Examples 6-1 - 6-5 according to the present invention have a remarkable effect of promoting an excellent skin permeability of drugs. ill

Claims (13)

WHAT WE CLAIM IS

1. A percutaneous absorption promoting agent for a drug component, comprising at least one anionic surfactant and at least one surfactant having a nitrogen atom in the molecule other than anionic surfactants as the active ingredients.

2 A percutaneous absorption promoting agent as claimed in Claim 1, wherein the molar ratio of said anionic surfactant to said surfactant having a nitrogen atom in the molecule is between 20:1 and 1:20.

3. A percutanteous absorption promoting agent as claimed in Claim 2, wherein the molar ratio is between 10:1 and 1:10.

4. A percutaneous absorption promoting agent as claimed in any one of Claims 1 to 3, wherein said surfactant having a nitrogen atom in the molecule is at least one surfactant selected from the group consisting of nonionic surfactants, amphoteric surfactants and semi-polar surfactants. ; j ■fflP

5. A percutaneous absorption promoting agent as claimed in any one of Claims 1 to 4, wherein said anionic surfactant is at least one surfactant selected from the group consisting of those having at least one carboxylic acid sulfonic acid group, sulfuric acid ester group, and phosphoric acid c\ ter group, in the molecule. / 20 dec 1990*;*

6. A percutaneous absorption promoting agent as claimed in Claim 4, wherein »»•' ~ said nonionic surfactant is at least one surfactant selected from the group consisting of fatty acid alkanolamides, polyoxyethylene fatty acid amides, esters of alkanolamine, and polyoxyethylene alkylamines. - 42 - i

7. A percutaneous absorption promoting agent as claimed in Claim 4, wherein said amphoteric surfactant is at least one surfactant selected from the group consisting of carboxy betaines, imidazoline derivatives, aminocarboxylic acid salts, sulfobetaines and aminobetaines.

8. A percutaneous absorption promoting agent as claimed in Claim 4, wherein said semi-polar surfactant is at least one surfactant selected from the group consisting of amine oxides.

9. A dermatological preparation, comprising a drug component and a percutaneous absorption promoting agent according to any one of Claims 1-8.

10. A dermatological preparation as claimed in Claim 9, wherein the drug component is from 0.001 to 50 parts by weight of the percutaneous absorption promoting agent.

11. A dermatological preparation as claimed in Claim 10, wherein the drug component is from 0.01 to 30 parts by weight of the percutaneous absorption promoting agent.

12. A dermatological preparation according to any one of Claims 9 to 11, substantially as herein described with reference to the examples.

13. A percutaneous absorption promoting agent according to any one of Claims 1 to 8, substantially as herein described with reference to the examples. v "S<£ Jz '■'W Hlsfthelr authorised AgeRta., . J. PARK & SON.