CA1326820C - Percutaneous absorption promoting agent and dermatologic preparation containing the same - Google Patents

Abstract

PERCUTANEOUS ABSORPTION PROMOTING AGENT
AND DERMATOLOGIC PREPARATION CONTAINING THE SAME

ABSTRACT OF THE DISCLOSURE
A percutaneous absorption promoting agent comprising (A) at least one anionic surfactant and one or two or more of surfactants having a nitrogen atom in the molecule other than anionic surfactants, (B) one or two or more of and 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-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 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 a dermatological preparation containing these percutaneous absorption promoting agent and drug components.

Description

P~CUTANEOUS ABSORPTION PRO~OTIN~ AGENT AND
DERMATOLOGIC P~EPARATXON CONTAINING THE SAME

3ACKGROUND OF THE I~VEN~ION
l Field of the Invention The preseAt invention relates to a percuta-neous absorption promoting agent and a ~ermatolo~ic preparat~on containing that per~utaneou~ absorption promoting agent More particularly, the present ~nven-tion relates to a percu~zneous absorption promotin~
a~ent compxi~ing ~A1 at least one anionic surfactant and one or two or more o~ sur~act~nts having a nitrogen atom ln the molecule other than an~onic surfactants, (B) one or ~wo o~ more of anlonic surfactants and one or ~wo or more of nonionic surfac~ants not hav$ng a nitrogen atom in the molecule, ~C) one or two or more of ~urfactants selected ~xom the group consisting of ~mp~oteri~ sur~ac-tant- and scmi-polar surfsctant~ and at lea~t one nonionic sur~actart having a nitrogen atom ~n the molecule, ~) one or two or more of surfactants selected ~rom the ~Xoup ~onsl~tlng of nonionlc ~urfactants, amphoteric surfactant~, semi-polar sux~actants and cationic 9urfactant~ ha~ing a nitrogen atom in the molecule, and one or two or more of nonioni~ surfactants not having a ni~rogsn atom in the molecule, or ~E) an amine oxide as the active ingredient, and dermatolo~ical preparaticn containing these percutaneous absorption 5 promotin~ agent and drug components 2 Description o~f the Related Art Hereto~ore, a drug component has been admin-istered by oxal administration, subcutaneous, intramuscular or intxavenous administrat~on by i~ject~on, administration to mucosa within the rectumor the mouth, etc ~ Note, oral ~dministration is most widely practiced However, in the case o~ oral administration, dxaw~acks have occuxxed ~uch that the concentratlon has become ~ 2 - 1 3~6820 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 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 percu-taneous administration have been developed to eliminate such side effects and drawbacks. However, even in such 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 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
Accordingly, an object of the present invention is 3~ 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.
Another object of the present invention is to provide a dermatologic preparation comprising the percutaneous absorption promoting agent and a drug .. , .. . . ~

~ . . . . .

- 3 ~ 1 32 68 ~0 component, which is an excellent percutaneous absorption agent promoting the ef~ect of the dxug component, and fur~her, has a satisfactory ~g~ety and fe~ling upon use.
Other objects and advantages of the presen~ inven-tion will be apparent from the following description.
In accordance wlth the present invention, there are prov~ded a percutaneou~ absorp~ion promoting agent for a drug component comprising at least one anionic sur~ac-tant and at least one ~urfactant havin~ a nitrogen atom in the molecule other than the anionic ~ur~actants as the active ingredlents and a dermatologic preparation containing a des~ red ~rug component and the above~
mentioned percutaneo~ absorption promoting agent.
In accordance with the pro~ent lnvon~lon~ there are also pxov~ded a perautaneoUS absorption promot~ng agent for a dru~ componen~ comprising ~t lea~t one surfactant selected from th~ gro~p con6i~ting of amphoterio sur~actants and semi-polar sux~actants and ~t leas~ one nonionic su~aotant hav~ng a nitrogen atom ln the molecule as the active lngredient~, and a dermatologic preparation con~ain~ng a ds~ixed drug oomponent and the above-mentioned percutan-ou~ ab~orptlon promoting ag-nt i ngredients .
In accordance wlth the prQsent invention, there are further provide~ a perautaneous a~soxption promoting agent or a drug compon~nt oomprising at least one anionic surfactant and at least one nonionic surfactant not having a nitroqen atom in the molecule as the active ingredients, and a dermatologic preparation containing a desired drug component and the a~ove-mentioned percuta-neous absorption promoting agent.
In accordance with the present invention, there are further proviaed a percutaneous absorption promoting agent or a drug component comprising at least one surfactant selected from the group consisting of nonionic ~ur~a~tants, amphoteric 6urfactants, s~mi-polar suxfactants and c~t~onic surfactants having a nitrogen - . . ~. . .

_ 4 _ 1 3268 2 0 atom in the molecule and at least one nonionic surfac-tant 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 present invention, there are further provided percutaneous absorption promoting agent 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.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The above anionic surfactant may include anionic surfactants having one or two or more of carboxylic acid ,is 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 ~ulfonic 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 alkylphos~horic 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 X

~ 5 ~ l 32 682 0 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-dimethyl-N-lauryl-N-carboxymethyl-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-carboxymethyl-N-hydroxyethyl-imidazolinium betaine, etc., aminocarboxylic acid salts ~15 such as N-cocoalkyl-~-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 !, ': '' ' , ' ., ', ' . . : .

- 6 - l 32 6820 embodiment of the present inventio~ may include sorbitan atty acid e6ters such ac ~orbitar. monooleate, sorkitan mono~sostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monos~earate, sorbitan S sesquioleate, 60rbitan tr~oleate, penta-2-ethylhexyl acid diglycerol sorbitan, tetra-2-ethylhexyl acid diglycerol ~or~itan, etC.t glycerlne fatty acids ~uch as mono-cotton seed oil fatty acid gly~erine, mono-erucic acid ~lycerine, ses~uioleic acld glycerine, mono-~tear~c acid glycerine, mono-~tearic acid glycerine malic acid, etc.; propylen~ glycol iatty acid estexs such as mono-stearic acid propylene glycol, etc.: lipophillc nonionic surfa~tantY ~uch as hardened ca~ter oil derivatives, glycerine alkyl ether8, etc.; polyoxyethylene ~l.e"
PO~) sorbitan fatty acid esters Such as POE ~orbitan monooleate, sorbitan mono~tearate, POS sorbltan monooleate, POE sorbitan tetraoleate, etc .; POE sorbi~ol fatty acid esters such as POE sorb~tol monolaurate, POE
sorbitol monoolea~e, POE sorbitol pen~aoleate, POE
sarbltol mono~toar~te, etc.~ POE glycerine fatty acid esters ~uch a6 paE glycerine mono~tearate, POE glycerine monoi60stearat~, POE glycerine tr~isostearat-, etc.s POE
fatty acid e~ters ~uch a~ PO~ monooloate, PO~ ~lstearat-, POE d~oloate, distearic acid ethylene glycol, otc.s POE
2S alkyl ether~ ~uch as POE lauryl ether, POE oleyl ether, POE stearyl ether, POE behenyl ether, POE 2-octyldodecyl ether, POE cho~e~tanol ether, etc.; POE al~ylphenyl ethers such as POE octylphenyl ether, PO~ nonylphenyl ethe~, POE dinonylphenyl ether, etc.; Pulronic type s~actants such as Pulronic, etc ,; POE-POP alkyl ethers such as POE-POP cetyl ether, POE-POP ~-decyltetradecyl ethe~, POE-PO~ monobutyl ether, POE-POP hydrogenated lanolln, POE-POP glycerlne ether, etc. atty acid esters of polyglycerol ~uch as di~lycerine monooleate, hexaglycer~ne stearat-, decaglycerine monolaurate, etc.S
tetra PO~-POP ethyl-nediamine conden~ates such as Tetronic, etc.S POE caster oil hardened ca6t-r oll : ~ - . .

: . , .

~ 7 ~ 1 32 682 0 derivatives such as POE ea4ter oil, POE hardened caster oil, PO~ hardene~ caster oil monoiso~tearate, POE
hardened caster oil triisostearate, PO~ harde~ed caster oil maleic acid, etc. POE beeswax lanolin derivatives such as PO~ sorbitol beeswax, etc.; hydrophilic nonionic surfactants ~uch as POS p~opylene glycol fat~y aoid esters, ~ucrose fatty aaid ester6, POE nonylphenyl-formaldehyde condensates, etc.
The ~atio of the above anlon~c surfactant to the nonionio surfactant not having a nitrogen atom in the molecule i9 preferably 20-1 to 1:20, more prefe~ably 10;1 to 1:10, in terms of molar ratio.
As the amphoteric ~u~actant to be used in the third embodiment of the present in~ention, there may be lncluded carboxybeta~ne such a~ N,~-dimethyl-~-lauryl-N-carboxymethylammonium betaine, N,N-dimethyl-N-oleyl-N-ca~boxymethylammor.ium be~aine, etc. i~ldazoline deriva~ives suoh as 2-lauryl-N-carboxye~hyl-~-hydxox~-ethylimidazolinium betaine, 2-lauryl-N-carboxylmethyl-N-hydroxyethylimidazolinium betaine~ etc.t amino-ca~bo~ylic acld salts such as N-cocoalkyl-B-amino-propionic acid sodlum ~alt, ~-cocoalkyl-~-imino-dipropionic ac~d dl~od~um salt, eta.; sulfo~2taine, am~nobota~n2, etc, ~xample~ of the above semi-polar surfactant may include amine oxides such as lauryl-dlmethylamlne oxide, stearyldimethy'amine oxide, bis-~2-hydroxyethyl)laurylamine oxide, etc.
In ~he present invention, one or two or more selected f~om the gro~p consisting o~ the above amphoteric surfactants and the above semi~polar surfac-tants may be used as desired.
As the nonionic 3~ractant having a nitrogen atom in t~e mole¢ule, fatty acld alkanol amide, polyoxyethylene fatty acid amide, esters of alkanolamine, polyoxy-ethylenealkylamine, etc. may be included, and one or twoo~ more may be selected as deRlred from thereamon~.
The ratio of the above amphoteric surfactant and . , the semi-pol~r s~r~actant to the nonionio surfactant having a nitrogen atom in ~he molecule i~ preferably 20:1 to 1:20, more preferably 10:1 to 1~10, in termY of molar rat~o.
~n the fourth em~odiment of the present invention, the nonionlc surfactant ~ the amphoteric surfactant, the semi-polar-surfactant and/o~ the cat~onlc sur~actant having a nltrogen atom in the molecule are used in combination with a nonionic surfactant not having a nitroge~ atom ~n the molecule a~ described a~ove, ~ he ratio o~ one or two or more ~eleoted from the group consisting of the nonlonlc ~ur~actant~, the amphoteric surfaotants, the 6-mi-polar sur~actants and cationlc sur~actants havlng a nitrogen atom ln the lS molecule to the nonLonic surfactant not having a nitrogen atom in th~ molecule i8 preferably 20:1 to 1~20, preferabl~ 10:1 to 1:10, in terms of molar ra~io.
As the amlno oxido to be u8ed ~n the fi~th embodiment of the pre~ent invention, tho~e may be 20 inclu~ed tho~- ~hown below.
~1~ Amine oxlde repr-~-nt-d by the ~ormul~
~1 R2 ~ N ~ O ~I) (wherein Rl , R2 and R3 represent straight or branched alkyl group or alkenyl group having 1 to 24 carbon atom~, and at least one of Rl , R2 and R3 represent st~aight or branched alkyl group or al~enyl group having ~ or more carbon atoms).
Speci~ic examples of the amine oxide represented by the ormula (I~ may include dimethyllaurylamine oxide, dimethylm~ristylamine oxide, dimethylcetyl~mine oxide, dimethylstearylAmine oxide, dimeth~loleylamine oxide, dimethylbehenylamine oxide, methyldilaurylamine oxide and the l~ke.
(2) Dihydroxyethylal~ylamine oxide represented by the formula ~

.. . . . .

.
:' - ,, . ~, ~ :

- . ~. : . , . :: .

_ 9 _ 1 32 68~0 C:H2CH;~OH
R - N ~ O ~II) C:H2CH20H
~wherein R repre~ents straight or branched alkyl ~roup or al~enyl group having ~ to 24 carbon atoms).
~ 3~ Dimethylalkylpolyoxyethyleneamine oxide represented by the formula (~II) C~3 R - ~OCH2CH2)n - N ~ O ~III) (wherein P represents a straight ox ~ranched alkyl group oX alkenyl group having 8 to 24 ~arbon atoms, and n represents an ln~eger o 1 ~o 5).
On~ ox two or more of the above amine oxides may be u~ed, As the drug component, the pharmecolog~cal effect of which can be increase~ by utiliz~tion o the above per¢u~aneous absorptlon pxomo~ing agent, the fol~owing dr~lgs may be exemplified.
For example, sterold ~ype anti-~nflammatory agents such a~ predonizolone, dexamethasone, etc.S non-steroid type anti-infl~mmato~y agen~ ~uch as indom~thacln, fluphenamic 4Cid~ mephenamic acid, e~c.S ~nti~hi~tamic agents such a~ chlorophenylamine, diphenehydramine, prometha~in, etc. ~ sulfur agents suoh as sulfur monomethoxic~n, sulfur methizole, etc. ant~biotics such as penlclllin, cephalo~poxin, chloramphenicol, streptomycin, etc ; antifungal a~ents ~uch as naphth~omate, ahlotrimazole, etc.S ant$-malignant tumor agents such as cyclophosphamide, busul~an, aat~nomycin, etC.s analogesios such a~ morphine, codeine, nalorufin, pentazocin, asplrin, acetanllide, aminopyxin, etc ;
narcotios ~nd ~ranquilizers sucn a~ prostaglanains preparations, barbital, thiopental, etc ; phychopharma-3S ceuticals such a~ chloropromazine, recerpine, chloro-diaæe~oxide, e~a, ~ anti-Perkinson's disesse agent~ such as chlorozoquisazone, levodopa, etc. card~acs such as ;' ' ~ . . ~ . , ' .. . .

~ .
.

- ~ 32682o dikitoxicin, digoxin, etc.; antiarrythmic agents such as hydrochloric acid procainamide, etc.; anti-stenocardia agents such as dipiridamol, amilnitrite, etc.; anti-hypertensives such as diazokiside, minoxyzyl, recerpine, 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 P WA
therapeutics such as 8-methoxysolarene, etc.: Vitamins such as Vitamin A, Vitamin E, Vitamin C, coenzyme QlO, ~Vitamin Q), etc.; hair growing agents such as cephal-antin, swelthiamaline, okisendoron, etc. hormones such as insulin, estradiol, methylteststeron, etc.~ diagnos-, tics; allergen for patch test; insecticides; secticides;
~15 humectants; corneum emoliient; hairdyes, and other drugcomponents. Particularly, as the drug component, water-soluble drug components such as indomethacin, minoxidyl, hydroquinone, arbutin, kojic acid, Vitamin C, Vitamin C
ester, swelthiamaline, cephalantin, etc. can be particu-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 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 effec-tively 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 component, body weight of the patient, severity of the disease, etc., but is preferably O.OOl to 50 parts by /
X

, ~ , - .

; - ~ , : .

weight of the percutaneous a~sorp~ion promoting -gent, more preferably 0.01 to 30 parts ~y welght, per 1 part ~y weight of the drug component.
The above percutaneous absorption promoting agent may be used by _uitably mixing the drug component as such, but ls generally used by mlxlng the constituents in a base for dermatolo~lc preparation 8UCh as cream p~eparation, ointment preparation, gel preparation, lotion preparation, emulslon, adhesive tape, e~c.
The amo~nt o the respective aonstituents in that case may differ dcpendin~ on the kind of the drug component, but generally the following range~ are the preferred ranges oP the amount fo~mulatod. That i~, the total amoun~ of the anionic surfActan~ and the 1~ ~urfactan~ other than the anionic ~ur~actant having a nitrogen atom in the molecule may be 0.001 to 10~ by wei~ht, more prefer~ly 0.01 to S~ by w~igh~ in the dermatologic preparation, an~ the drug component may be O.OOl to 104 by weight, more preferably 0.01 ~o 5~ b~
weight. On the other hand, for the ratio of the anionic su~ctant to the surfactant having a nitrogen atom ln the molecule other than anionic sur~actant4, ~he r~tio as mentioned above, namely 20~1 to 1~20, prefexably lO:l to l:lO~ may be applied A9 such.
The total amount formulated of ~he amphoteric Qurfactant and tho semi-polar surfac~ant and the nonlonlc surfactant havLng a nitxogen atom in the molecule may be 0.001 to lO~ ~y weight, more pre~erably 0.01 to 5~ by weight in the dermatologlc preparation, and the dru~
component may be 0.001 to lO~ by weight, more preferably 0.01 to 5% by weight. For the ratio of the amphote~ic surfactant and the 6~mi-polar surfactant ~o the nonionic surfactant havlng a nitrogen atom in the molecule, the ratio as described above, namely 20:1 to 1:20, prefera~ly 1~:1 to 1:10 in term8 of molar ratio, may be applied a~
~uch.
The total amount of the anionic ~ur~actant and the ., , . , ~,~, j . . .

: , .

-` 1 326820 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, 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.
Further, the total amount formulated of one or more selected from the group consisting of nonionic surfac-tants, 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 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 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 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 components as generally formulated in drugs, quasi drugs, cosmetic, etc. Examples of such components may include polyhydric alcohol, oil component, wax, acid, A

s . .. . . ...
; . . . .
:

.

- 13 _ 1 32 6820 alkali, cationic surfactant, nonionic suractant, anionic cu~actant, ampho~eric ~urfactant, pow~ex, pigment, dye, preservative ~ntifu~gal agent, antio-xi~ent, UV-ray absorber, chelating agent, water-solu~le polymer, montmorilonite, alcohol, solvent, ~la~or, etc.
More spec~fically, there may be included polyhyd~lc alcohols such a~ glycerine, propylene glycol, etc.; oil components uch as ~l~id paraffin, ~q~alane, higher fatty acid, higher alcohol, eto.) organJc aci~ such as Citrio acid, lact~c acld, etc.s alkali~ such aS caustlc soda, triethanolam~ne, etc.; anionic surfactants such a~
hlgher alkyl6~1furic acid e~t-r ~alt8, higher alkyl-eth-r~ulfuric acid ~ter Qalts, h$gher fatty acid amide ~ul~onic ~Cid ~lts, higher ~lkylsul~osu~cinic acid ~alts, alkylbenzene~ulfonlc ~cid galt~, acylglUtAmlC
acid salt~, higher alkylpho~phorlc acid salt4, etc.
catlon~c surf~ct~n~s cuch as h~gher ~lkyl quat~rnary ammonium sal~s, atty amine salts, alkylpyrid~nium salts, etc.~ ampho~erlc sur~actants ouch a~ carboxy-betaine, sulobeta~no, imidazolin- d-rivat~vo~, etc.;
polyoxyethyl-n- alkyl ether, polyoxy-thylene P~tty ac~ d amid-, sorbitan fatty ac~d e~ters, ~atty acld alkanol-amid-, polyqlycerine ~atty acld osteX, etc, ~he Dercuta~eou~ absor~tion Dromot~n~ aaent and th-derma~ologic preparation according to ~he present lnv-ntion have an excellet~t e~fect Of promoting the percutaneous ab~o~ption of a drug co~ponent, and further, are Percutaneous ab~orption promoters with a good safety - and feel;ng upon U5- .
~XA~PLES
.
The present ~nvention will now be furthex illus-trated by, b~t is by no means l~mited to, the followin~
Examples, wherein "~" xepre~ents "% b~ weight", unless otherwi~e spec ~ f ~ ea .
3~ Example 1-1: Cream ~ examethasone 0.025%
(2) Prop~lene glycol 8.0 .,, , . . , . . , . - . -,, . . ,. .. :,- ~ ; . .

. . .

- 14 _ 1326820 ~3~ Glycerine 5 0 ~4) Fluid paraffin 1 0 (5) Diisopropyl adipate 3 0 ~6) Sodiwm dodecylsul~te 0,08 (7) Dodecyldimethylamlne oxide 0 16 ~8) Glycerine monofatty acid ester 1 5 t9) Preservat$ve q,e ~10) Clay mineral (bentonite) 6 0 ~11) Pur~f~ed water balance ~Prep~rat$on M-thod~
~o ~S~ wer- added (13, ~4) " 8) and ~g1 and these componantt wer- dis~olved An~ mixed by heating ~o 70C
This wa~ called compo~lt$on ~A) The components ~6) and ~7) were added to a part of tll) to be dis~olved 15 therein, o~10w d further by an addition and mixlng o~
the component~ ~2) ana ~3) This was ~alled compo~i-ti~n ~B) While compo~it~on t~) wa~ stirred at a temperature malntained at 70C, composition ~A) was gradually add-d to effect preliminary ~mul~iflaation, 20 ~ollowed by mul~ification by a homomixer.
Tha re~ultant emul~ion wa~ added to a disper6ion having added and di8per~ed (10) in th- r-ma~nder of un~er ~tlrr$n~, and cooled to obtaln a cream ComParative Examplo 1-1 Cream 1) Dexam thasone 0 02S~
(a~ Propylane glycol 8 0 ~3~ Glycer$ne 5,0 4) Fluid paraffin 1 0 ~5) Oii~opropyl adipate 3,0 ~6) Glycerine monofatty acid ester 1 5 ~7) Pres-rvative q s 8) C14y mineral (bentonite) 6 0 9~ Purified wate~ balance ; ~Prepara~ion Method~
Accord~ng to Example 1-1 For the creams prepared in Example 1-1 and ~ompara-~ :

~. ,. .. .. . ~ ~ . - ; -- 15 - l 32 6820 tive Example l-l, the vasoconstrictive action was compared.
More specifically, on the upper backs of 10 healthy human males, creams prepared in Example l-l and Compara-tive Example l-l, 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 aftex 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 l-l.
Table l-l Base Average score after 4 hours Example 1.7 Comparative Example l.O
System of Example from which dexamethasone is removed O
System of Comparative Example from which dexamethasone is O
removed As apparent from Table l-l, it can be seen that the cream of Example l-l had an excellent vasoconstrictive action.

~; .

:

- ~ 3268~

ExamPle 1-2: Gel ~l) Indo~ethacin 1,0 ~2) Ethyl alcohol 50,0 ( 3 ) Carboxy vinyl polymer l . 2 ~4) Polyox~ethylene 1. 5 (herelna~ter oalled POE~ 40 mole) hArdene~ ca~ter o~ l (5~ Sodium dodecyl~ulfate 0.5 t6) SodLum dode~ylpho~pha4e 0. 6 ~7) ~odium lauryli~othionate 0 . 2 ( 8 ) Do~cyldlmethylamino oxlde 1,1 4 ~9) Laur~c acid diethAnolamide 0.2 (10~ Dl$~opropAnolamln- 0.35 (11) Pur~ied wa~er balance ~Prep~xation Method~
After ~S), ~6) ~ ~7) ~ (e) and (9) were dissolved in (ll), (31 was d~spersed in the solut~on. The disper~ion wa~ Added to A ~olut~on o~ nd ~4) added and di3-801v-d in ~2), ~ollowed by thorough mixing. Further, to 2~ thi~ mixture WA~ added ~10) and the m~xture was ~tirred and mlxea to obtaln a ~ol, Compar~t~v- ExamPle 1-2 ~1) Indomethac~n 1.0 t2) Ethyl alcohol 50,0 (3) Carboxy vlnyl poly~ex 1.2 (4) POE hardenod castex oil 1.5 ~5) Dii~opropanolAmine 0.35 t6) Purified water balance LPreparat~on Method~
According to Example 1-2.
comParative ~xample 1-3 Comm~rcially available ointment containing 1 indomethaaln ~gel~ e external agent).
Text Example 1-2 For the above gel baseY~ the pharmacological effects were xamined and compared accoxdinq to the carageenln edema lnhibition tes~.

~:

~ 3~68~0 .~

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 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 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 VcVt x 100 '15 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 C~rageenin 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 (1) [14C] Hydroquinone 1.0%
(2) Sodium dodecylsulfate 0.2 (3) Dodecyldimethylamine oxide 0.7 .
~;

~$
,~ ,: .. .. , . :: . :

,, . ~ .. , . . : ~ .

- 19 _ 1 3~68~0 (4) Purified water balance ~Preparation Method]
Ater (2) and (3) were dissolved in (4), (1) was a~ded and ~he mixtUre gtirred and dissolved to provide a sample.
Comparativo Example 1~4 4C~ Hydroquino~e 1.0%
~2) Pur$~ied water balance -~Preparation Method]
Aacording to ~xample 1-3.
Com~arativ~ ~xample l-S
4C~ Hydroqulnone 1.0 ~2) Urea 5.~
(31 Purifie~ water balance ~Preparation Metho~
Accord~ng to Example 1-3.
Text Example 1-3 On the back ~klns of hairles~ m~ce, 3 miae in one group, 100 microliters of a ~ample wa~ plastered with Torii adhe3ive pl~ster ~or patoh test ~aiameters .6 Cm). On the adho~ive plaster wa~ placed a sponge, which wa~ f~rther coate~ wlth a thin ~ilm o~ a rubb~ BO
a~ to adherQ the plaster to tho ~kin. After coating, each mouEe was placod in a sealed vess~l m~de of a plastic, ~ith a delivery o zir, and carbon dioxide I discharged by breathing ab~orbed in a SO~ methanolic I solution of monoethanolamlne.
I After coating, the adhesive pla~ter at the coated portiQn was removed at 24 and 48 ho~rs for measuremen~
1 30 of the radio activity in the adheslve plaster. Next, i the coated portion was subjected to stripping with ' cellophane tape for ~ times~ and the activity in corneum ¦ adhered to cellophane tape wa~ mea~ured. ~hen ~he ~ animals were ~acri~lced, the skin at the coated portlon 1 35 peeled off, and the activity in the skin mea~red. The remainin~ whole body was homo~enated b~ a blender with an addition o~ ~0 g of ~,5N aqueous sodium hydroxide, ,, :, : ~ . . ,, :

s' ' ~

.. . . - . , - i9 _ ~ 3268~0 and a certain amount of the homogena~e sampled for a measurement o~ the activity. Also, ~etus and urine d$~oharged up to a predeter~ined time were recovered for a mea~urement of the activity.
Here, the ~um of the a~ount di~char~ed by breathing, the amounts o fe~us and u~$ne diacharged, and the amount stored ln the body was de~ined a~ the percutaneous absorption amoUnt in body. ~he above te8t results are shown ~n ~able 1-3.

Table 1-3 _ _ Pexcutaneous abaorp-tion amount ln body Example 1-3 28.8 Comparat~ve Example 1-4 4.g Comparatlve Example 1-5 4.6 (aftex 48 hours) ~l) Dexamethasone 0.025 ( a ) Propylene glycol 8.0 (3~ Glycerine 5,0 t4~ Flu$d paraffin l.0 (S) Diisopropyl adipate 3,0 (6~ ~auriC acid die~hanolamide 0.6 (7~ N,N-dlmethyl-N-lauxyl-N- 0.3 carboxymethylammonium betaine (8) Glycerine monofatty acid ester 1.5 ~9) Pxegerva~ive q.s.
(lO) Clay minexal ~benton$~e) 6.0 ~ Purified water balance 3~ ~Pxeparation Method~
To t5) were added (l), (4), ~8) and (9) and the~e - ~ . . . ~

, . .. .. . .

components were dissolved and mixed by heating to 70C.
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 addition and mixing of the components (2) and (3). This was called composition (B), While composition (B) was stirred at a temperature maintained at 70C, 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) under stirring, and cooled to obtain a cream.
ComParative Example 2-1: Cream (1) Dexamethasone 0.025%
(2) Propylene glycol 8.0 (3) Glycerine 5.0 (4) Fluid paraffin 1.0 (S) 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~
1 25 According to Example 2-1.
¦ Text Example 2-1 For the creams prepared in Example 2-1 and Compara-tive Example 2-1, the vasoconstrictive action was compared as in Test Example 1-1.
The results are shown in Table 2-1.

' X
,, ,. . ,~ .

- 21 - 13268~-~able 2-1 Average score Ba~eater 4 hours _ Example 2~1 1. 5 Comparative Sxample 2-1 1. 0 System of Example 2-1 from which dexamethasone is remove~ O
System of ComparAtive Example 2-1 from which dexamethasone ~g removed ., ~ . . _ As apparent from Table 2-1, it can be ~oen that the cream o~ Example 2-1 had an excellent vaso~onstr~ctive action.
Exam~le 2-2~ Gel ~1) Indomethacin 1.0 ~2) 3thyl alcohol 50.0 ~3) Carboxy vinyl polymer 1.2 (4~ POE 1.5 hardenoa ca6~er oil (S) ~auryldlmethyl~mlne oxide C.6 16) P.O.E. ~15 mole) oleyl amine 0.8 ~7) N,N-dimethyl-N-lauryl-N- 1.0 sulfomethylammonium betaine ~8) Lauric acid diethanolamide 0.35 ~9) Diisopropanolamine 0,35 (10) Purified water balance LPrepara~ion Method~
A~er (5), ~6), ~7) and ~8) we~e dissolved in (10~, ~3) was well di~persed in the ~olution. The d~sper~ion w~R added to a solution of (1) and ~4) added and dis-solved in ~2), followed by thorough mixing. Further, tothi~ mixture was ~dded (9~ and the mixture stlrred and ~nlx-d to obtain a gel.

, !
..

` - 22 - 1 32 6820 Com~a~ative Exam~le 2-2 ~1) Indomethacin 1.0 (2~ Ethyl alcohol 50.~
(3) Carboxy vinyl polymer 1.2 ~4) PO~ hardened caster oil 1.5 (51 Diisopropanolamine 0.35 ~10) Pur$fiod wster balance tPrep~ratlon Meth~d~
According to Example 2-2.
Compa~ative ExamPle 2-3 Commer~lally available ointment contain~ng 1%
indomethaoin ~gel~ e external agent).
Tes~ Exam~l~ 2-2 ~ or th- a~ove gol-like bases, the pharmacological effect8 were examlned and oo~paxed as in Test Example 1-2 acaording to the carageenin edema inhibition t-~t.
The above test re~ults are ~hown in Table 2-2.

. T~ble 2-2 .
Carageonin foot edema $nhibition (~) .
Ex~mplQ 2-2 50.8 Camparative Example 2-2 11.2 Comparative Example 2-3 8.5 As apparent f~om the table, it can be seen that the gel base of Example had an excellent carageenin edema inhl~itlon action.
ExamPle 2~3 tl) ~ C~ Hydroquinone 1.0 ~2) Cooonut fatty acid diethanolamid~ 0.8 (3~ ~odecyld~methylamine o~ide 0,5 .
- . ~ - .

..

.

, - 23 - ~3268~o ~4) Purified water balance ~Preparation ~ethodj Aftcr (2~ and (3) were dissolved in (4), (1) was added, and the mix~ure stirred and dissolved to provide a sample.
comPar;tive ~xampl, 2-4 ~1) t 4C3 Hy~roquinone 1. O~
(2) Pur~fle~ water balance ~P~ep~ration Mothod]
Acoording to Example 2-3.
- ComPa~;tlye Example 2-4 I ~ 1, r c 1 ~ydro~uinone1.0~
(2) Uroa 5 0 ~3) Purlfl-d wator balance ~Pr-parAtion Method]
According to Example 2-3.
T-~t ExamPl- 2- 3 For ~he samplos obtained above, the percu~aneous absorp~ion ~mounto were determ~n-d as in Test Example 1-3.
~ h- above test result4 are shown in Table 2-3.

Table 2-3 . .
¦ Peroutaneous ! ab30rpt~on amount , Example 2-3 26.8%
, Comparative Example 2-4 4.9 Comparative ~xample 2-S 4.6 ~after 48 hours) :`
Example 3-1: Cream (1) Dexametha~one 0.025%
~2) Propy~ene glycol 9.0 s ~ : .

r- ~ `24 ~ 1 32 682 0 (3) Glycerine 5,0 (4) Fluid paraffin 1,0 ~5~ Diisopropyl adipate 3.0 ~6) Sodium myristylsulfate 2.5 (7) Sorbitan monooleate l,o ~ ly~Rrine monofatty acid e~ter 1. 5 tg) PrQservative q.s.
(10) ~lay mineral tbentonite) 6.0 (11) Purlf~ed water balance Preparation Method To (5~ wo~ added (1), ~4), ~8) and ~l and these component~ were dl~solvfld and mixed by heat$ng to 70~C.
~hls wa~ callQd composition tA), ~he components (6~
and l7) w~re added to a part of (11) to be dissolv~d therein, ollowed ~urther by an addition and mixing o components ~2~ ~nd ~3). Thi~ was aalled composi-tion ~E~. While composition ~B) was stirred at a temperature maintainod at 70C, composition ~A) was gradually added to efect prellminary emulsl~ication, zo follow-d by mulsi~ication by A ho~omixer.
The resultant emul~lon wa~ addod to a disper~ion having added and ~i~persod ~10) ln the rema~nder of (11) undex 8tlrrlng, and cooled to obtain a ox~am.
ComParatlv~ Example 3~ Cream (1~ Doxamethasone 0.025 ~2) Propylene glycol 8.0 ~3) Glycerine 5,0 ~4) Fluid paraf~in 1.0 ~5) Dii80propyl adipate 3.0 ~6) Glycerine monofatty acld ester 1.5 ~7) Preservative q.s.
~8) Clay mineral tbentonite) 6.0 ~9) Puri~i~d water balance c~reParAtion Method~
According ~o Example 3-1.
~e4t ~xample 3-1 Fo~ the cr~ams prepared in Example 3-1 and Compara-.

- 25 _ ~ 32 682 0 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 Base 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 35cPreparation Method~
After (5), (6), (7), (8) and (9) were dissolved in (11), (3) was dispersed in the solution. The dispersion ,j 1 3268~0 was added to a solution of ~1) and (4) added and ~is-solved in t2), followed by thorough mixing. Fuxthex, ~o this mixture was added (1~ and the mixture was stlrred and mixed to obtain ~ gel.
ComPaxatlve Example 3-2 (1) Indomethac~n 1.0 ~2) ~thyl alcohol 50.0 (3) Carboxy vinyl polymer 1.2 (4) Polyoxyethylene l,S
~40 mole addi~ion) hardened caster oil (5) Di~opropa~olamine 0,35 (6~ Purified water balance ~Preparat~on Method~
Accordin~ to Example 3-2.
Comparative ~xam~le 3-2 Commercially available oint~ent contain~n~ 1 indomethacin (gel~like external agent).
Test Exam~le 3-2 . For ~he above gel base~, the pharmacologi~al ~o effecte were xamined and oomparod a~ ln Test Example 1-2 according to the Carageenin edema inhlbition test.
The above t~8t ~es~lts are ~hown ln ~able 3-2.

Table 3-2 :j -. , ~ . . ~, ;~ Ca~ageenin 3 foot edem~
inhibition ~) E~ample 3-2 48.3 Comparat~ve Example 3-2 11.2 Comparative Example 3-3 8.5 ;,. . .
, As apparent from the table, it can be seen tha~ the gel base of Example 3-2 had an excellent carageenin .. . .

.

.:;

, . . : ~ . .: -- 27 ~ 1 32 68 ~

edema inhibition act~on.
Example 3-3 (1) L14C~ Hydroquinona 1.0 (2) Sodium N-lauroyl glutamate 1. ?
~3) Polyoxyethylene 1.6 ~15 mole addition) etearyl ether ~4) Purl1ed water balance ~Preparat~on MethodJ
A~tex ~) and ~3) were dissolved in (4), ~1) wa~
added and th~ mixture st~rred and dlg~ol~e~ to provlde a sampl~. -Comuaxative Example 3-4 (1) ~ C~ Hydroquinone 1,0~
t~) Puri~ied water bala~e Preparation Method Accordin~ to Example 3-3.
Comparative Example 3-5 4C~ Hyd~o~uinone 1.0~ :
~2) Urea S.0 ~3) Purifled water balanae PreparAtion Method Ao~ordlng ~o Example 3-3.
TeBt Example 3-3 For th- samples obt~lned above, ~he percutaneoU6 absorption amount6 were determined as ln Test Example 1-3.
The above test re~ults are snOwn in Ta~le 3-3.

- .- , ~. i ~ ~ 3268~

Tab le 3 - 3 Percu'caneous absorption amo~nt Example 3-3 21.8 comparative Example 3-4 4.9 Co~pa~ative Example 3-5 4.6 , ~ (after 48 hou~ B ) ':
~xample 4-ls ~resm ~1) Dexamethason~ 0.025 ~,, (2) Propylene glycol ~.0 ,i ~3) Glycerine 5.0 ~4) Fluld paraffin 1.0 (5) Diisop~opyl adlpate 3,0 ~6) Fatty acid alkanolamlde 1.8 7) Sorbit~n monooleat~
(8) Glycerine monofatty acid ester 1.5 i ~9) P~eservatlve q.~.
~,i (10) Clay mineral (bentonite) 6.0 e` ~11) Purif~ed water balance 25[Preparation Method~
To (5) were added ~13, t4), (8) and ~9) and these componen~s were dissolved and mixed by heating to 70C, This was called composition ~A). The componen~s (6) and (7) were added to a part o4 ~11) to be dl~aiolved therein, followed further by an addition and mi~in~ of componentR (2) and (3). This was called composi-tion ~B). While compo~i~ion (B) was stirred at a , ~emperature maintaine~ at 70C, composition ~A) was .~. gradually added to e~fect prel~minary emulslfication, ~t 35 followed by emul~ification by a homomixer.
.~ The resultant emulsion wa~ added to a d~spersion having added and dispersed (10) in the remainder of (11) . .
., .

- 29 _ ~ 326~20 under stirring, and cooled to obtain a cream.
Com~arative Example 4-1: Cream ~1) D0xamethasone 0.025 ~2) Propylene glycol 8,0 ~3) Glycerine 5,0 (4) Fluid paraff1n 1~0 (5) DLisopropyl adipato 3,0 ~6) Glycerine monofatty ac~d ester 1.5 ~7~ Preservative q. 5.
~8) Clay mineral (bentonite) 6.0 ~9) Purified water balance ~Preparation Method~
Accordlng to Example 4-~.
~t Ex~P~
For the creams prepared in ~xample 4-1 and Compara-t~ve Example 4-1, the vasoconstrictive action was compaxed as in Tes~ Example 1-1, The results are 8hown in ~able 4-1.

T~ble 4-1 . .
a Average ~core a-- after 4 hours ~xample 4-1 1.5 Comparative ~xample 4-1 1.0 Sys~em ~f ~xample 4-1 0 from which dexamethasone ig ~emoved System of Comparatlve 0 ~xampl~ 4-1 from which dexamethasone i5 removed As appa~ent rom the table, it can ~e seen that the cre~m of ~xample 4-1 had an exaellent vasocon~trictlve act$on.
Exam~le 4-2: Gel ~ .
' - 30 ~ 1 32 6820 (1~ Indomethacin 1.0 ~2) Ethyl alcohol 50.0 (1) Carboxy vinyl polymer 1.2 (4) Polyoxyethylene 1.5 (40 mole addition) harden~d caQter oil (5) Laur~o acid dlethanolamide 1.5 ~6) Lau~yl~imethylamine ox~de 1,0 t7) Lauryl ~eta~ne 0.5 (8) POE 80r~itan mono~tearate 1.14 ~9) Sucrose fatty scid ester 0.2 ~10) Dilsopropanolamine 0.35 (11) Purified water bal~nce LPreparation Metho~
A~ter tS), ~), t7~, ~8) and ~9) were dis~olved in lS ~11), (3) wa~ d~spersed in the solution. The dispe~ion was added to a ~olution o (1) and (4) added and dis-301ve~ in ~2), followed by thorough mixih~. Fuxther, ~o thls mixtu~e was aaded (10) and the mixtuxe was stix~ed and mixed to ob~aln a gel, Com~axatlve ExamPle 4-2 ~1) Indomothacln 1.0 ~2) Ethyl al~ohol 50.0 (3) Carboxy ~lnyl polymer 1.2 ~4) Poly~xyethylene 1. 5 (40 mole addltion) hardened caster oil t5) ~ opropanolamine 0,35 ~6) Purified watex balance ~Preparation Method~
Accordin~ to Example 4-2.
Com~arative ~xample 4~3 Commercially available ointment containing 1 indomethacin ~gel-like ex~ernal agent).
~est ~xam~le 4-2 For the abo~e gel bases, ~he pharmaeological ef~ects were exam~ned and compared as ln Test Example 1-2 according to the carageenin edema inh~bition te-t.

. , .. - , .- . . .

- 31 _ ~ 32 6820 The above test results a~e shown in Table 4-2, Table 4-2 .
Carageenin foot edema $nhlbition ~) .
-ExampIe 4-2 ~49.1%
Comp~ratlve Example 4-2 ll.2 ComparaSivo Sxample 4-3 8.5 ,~ .
As appar-nt ~rom the table, it can be understood that the gal ba~- o~ ExAmple 4-Z had an excellent caragoenin edema ~nhlbltion action.
I Examcl~ 4-3 I ~l) Hydroquinon- l,04 ~2) ~i~tearyldimethyl ammonlum 0.5 ohlorid-~3) Triglycerlne monolaurate 1.5 . ~4) Purl~iot w~t~r balAnce ~Preparatlon M-thot~
Afte~ ~2) and ~3) were dissolved ln ~4), ~1) wa~
added and the mixture ~tirred and alssolved to provide a ~ample.
Compara,tive ~xamPlo 4-4 4C~ Hydroguinone 1.0%
~2) Pu~i~ie~ water balance ~, 30 {prepAration M~thod~
Accoxdlng to Example 4-3.
omPaxattve ExamDle 4-S
4C~ Nydroquinone 1.0%
(2) Urea - 5,0 ~3~ Pur~ fied water balance ~Preparation M~thod~
Ac~oxdlng ~o Ex~mple 4-3.

~.

. :, . : , , ., , ~ :
. . . ~ . , . -. ~ . . .

1 3~6820 Te s t Exampl e 4 - 3 ~or the samples obtained above, the percutaneous absorption amounts were determlned as in Test Example 1-3.
The above test re~ults are shown in Table 4~3.

Table 4-3 Percutaneous ab~orption amount Example 4-3 23 . 7 Comparatlve Example 4-4 4.9 ComparAtiVe Example 4-5 4.6 -~a~ter 48 hours) ~xAmpleo 5-1 ~ 5-5 e~Yg~ LY-3~
A drug permeabili~y test was conducted fo~ amlne oxide, which ~s the prod~ct o the pre~ent invention.
Pha~m~ceut~c~l ~ampl-s compri~ing tho ~ollowing composition were p~epared.
~1) Hydroquinone 1,0 (2) ~es~ substance 0.1 (3) ~thanol 20.0 (4) Purified ~ater balance Preparatlon Method After ~ nd ~2) were dissolved in ~31, ~4) was added and mixed to provide a sample.
Test Sub~tance ~e~ts were condu~ted or the following test substances .
~A~ ~m~ne oxide in~oluble or slightly soluble in water Example 5-1: Dimethylstea~ylamine oxlde . - ~ , ..... ~ ~ . ............ .
~. : . . .

Example 5-2: Dimethylbehenylamine oxide Example 5-3: Dihydroxyethylstearylamine oxide (B) Water-soluble amine oxide Example 5-4: Dimethyllaurylamine oxide Example 5-5: Dimethylmilistylamine oxide Comparative_Example 5-1 (1) Hydroquinone l.O~
(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 ;~ area of 2 cm2 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 32C 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 quantitated by high performance liquid chromatography. The results are represented in drug permeability (%). The results are shown in Table 5-1.
~.
i,........................................................................ . .
~' ~;' , .' ~' . -Table 5-1 Drug Test substance perme- Effect ability Example 5-1 Dimethylstearylamine oxide 44.0 Excellent Example 5-2 Dimethylbehenylamine oxide 28.6 Excellent Example 5-3 Dihydroxyethylstearylamine 30.5 Excellent oxide Example 5-4 Dimethyllaurylamine oxide 9.4 Fair (Comparative example) Example 5-5 Dimethylmilistylamine oxide 11.8 Fair (Comparative example) Comparative - 2.1 Example 5-1 , 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.

~o. Drug Percutaneous Absor~tion Test Exam~le 5-6 (1) [14C]Hydroquinone 1.0%
¦ (2) Dimethylstearylamine oxide 0.1 (3) Ethanol 20.0 (4) Purified water balance ~ [Preparation Method]
After (I) and (2) were dissolved in (3), (4) was added and mixed ' to provide a sample.

~' C

, . : . : . .

- 34a -ComParatiVe Example 5-2 (.1) tl4C]Hydroquinone 1. 096 (2) Ethanol 20.0 (3) Purified water balance [Preparation Method]
According to Example 5-6 ~ .
'.`
~ ,, - ~

_ 35 _1 32 6 Comparative Example 5-3 (1) Ll4c~ 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 abisorption 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%
I 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 5.0 ! (4) Fluid paraffin 1.0 (5) Diisopropyl adipate 3.0 :

;,,, .. , - . . .. ~. , ~ .
:~. . . .
$;"

" - 36 - l 326820 (6) Dimethylstearylamine oxide 5.0 (7) Glycerine monofatty acid ester 1.5 ~8) Preservative q.s.

(9) Clay mineral tbentonite) 6.0 (lO~ Puri~ied water balance ~Prepara~ion M~thod~
To (6~ were added (l~, (4), (S~, (7~ and ~8) and these components were dis~olved and mixed by heating to 70C. This was called composition (A)~ The compo~
nents (2) and (3) were ~dded ~o a part of ~lOl. This was called compo~tion ~B~. While oomposi~ion ~B) was stirred at a temperature maintained at 70~, compo~i-tion ~A) wa~ gradually added to ef~e¢t prelim~nary emulsification, ~ollcwed by emulsifi~at~on by a homomixer. Tho re~ultant emuls~on was added to a di~per~ion having added and dispersed ~9) in the remain-der of ~10) under stirring, and cooled to obtain a cr~a~, Compara~iv- Example 5-4: Cream exam~thaaone 0.025 ~2~ Propylone glycol 8.0 ~3) Glycerine 5.0 ~4) Fluid paraf~ln l.0 ~5~ Dli~opropyl adipate 3.0 (6) Glycerine mono~atty acid ester 1.5 ~7) Pre~ervati~e q.s.
(8~ Clay mineral (bentonite) 6.0 ~9) Puxif1ed water balance [Preparation Method]
According to Example 5-7.
Tsst Example 5-3 For the creamC prepared ln Example and Comparative Example, tho vasoaonstriative action was compared as in : Te~ Example 1-1.
~he results are shown in Table 5-3.

. . ............ .. .
...
. .

~ 37 ~ 1 32 6 8 2 0 Table 5-3 Average score Base after 4 hours _ Example 5-7 1.8 Comparative Example 5-4 0.9 System of Example 5-7 0 rom which dexamethasone is removed System of Comparative 0 Example 5-4 from which dexamethasone is removed ,15 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 ~i (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.
~; 30 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 ,...
,;
r,: ~

~. ~ :. , . : . . ' , " .' ', ~ ~ . ' . - :

(S) Diisopropanolamlne 0.35 (6) Purified water balance [Preparatlon Method~
According to Exa~ple 5-8.
S Comparative Exam~le 5-6 Commerc$ally avallable ointment containing 1%
indomethaoln (~el-l~ke external agent).
Te!t Exam~l- 5-4 For the above gel base~, the pharmacological ef~ect3 were ex~mined an~ compare~ a~ in Test Example 1-2 according to the car~geenin edema inhibition t~st.
The abov- t-st re~ults are ~hown in Tabl~ 5-4.

Table 5-4 .
Cara~eenin foot edema inhibltion ~) ~xampl- 5-8 56.1 Comparativo Exampl- 5-5 12.0 Compar~tive Example S-6 10.8 A~ apparent ~rom the table, it can be seen that the gel ~a~e of Example 5-8 had an excellent carageenin edema inhibition action.
Test Example 6-1 ~he effect o~ the promotion of a pe~outaneous absorption of ~rugs with the test substances shown in ~abl~ 6-1 w~re evaluated ~ ln Test Ex~mple 5-1.

:

. . . .
, . -~ ~ ~ ~g r ~ ~

d~
o O O ~ o o rl l ~0 ~0 oP d~ ~ ~P OP OP OP
~D ~ U~
ooo~ooc~o ., , ,, ~ , .

In the table, nu~erical values (~) in the column of test substance and drug show the ooncen~rations in aqueou~ solu~ion.
As apparent from the results in the above table, it S can be understood that the test substances (percut~neous absorp~on promotin~ agent) of Examples 6-1 - 6-5 accordin~ to the present inventlon have a rema~ka~le effect of promoting an oxcellent Qkln permeability of dxugs.

-.~ . , ....,

Claims (24)

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 in a molar ratio of 20 : 1 to 1 : 20.

2. A dermatological preparation, comprising a drug component and a percutaneous absorption promoting agent according to claim 1.

3. 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 in a molar ratio of 20 : 1 to 1 : 20.

4. A dermatological preparation, comprising a drug component and a percutaneous absorption promoting agent according to claim 3.

5. 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 in a molar ratio of 20 : 1 to 1 : 20.

6. A dermatological preparation, comprising a drug component and a percutaneous absorption promoting agent according to claim 5.

7. A percutaneous absorption promoting agent for a drug component, comprising 0.0001 to 10% by weight, in the dermatologic preparation, of an amine oxide, which is insoluble or slightly soluble in water, as the active ingredient.

8. A dermatological preparation, comprising a drug component and a percutaneous absorption promoting agent according to claim 7.

9. A dermatological preparation, comprising a drug component selected from prednisolone, dexamethasone, indomethacin, flufenamic acid, mefenamic acid, chlorpheniramine, diphenhydramine, promethazine, sulfa monomethoxine, sulfamethizole, penicillin, cephalosporin, chloramphenicol, streptomycin, naphtiomate, clotrimazole, cyclophosphamide, busulfan, actinomycin, morphine, codeine, nalorphine, pentazocine, aspirin, acetanilide, aminopyrine, prostaglandins, barbital, thiopental, chlorpromazine, reserpine, chlordiazepoxide, chlorzoxazone, levodopa, digitoxin, digoxin, procainamine hydrochloride, dipyridamole, amyl nitrite, diazoxide, minoxydil, guanethidine nitrate, para-aminobenzoate ester, hydroquinone, arbutin, kojic acid, Vitamin C esters, para-hydroxycinnamate, 8-methoxypsoralene, Vitamine A, Vitamin E, Vitamin C, coenzyme Q10 (Vitamin Q), cepharanthin, swertiamrin, oxendolone, insulin, estradiol and methyltestosterone and a percutaneous absorption promoting agent according to claim 1.

10. The use of a composition comprising at least one anionic surfactant and at least one surfactant having a nitrogen atom in the molecule other than anionic surfactants for the manufacture of a dematological preparation containing a drug component and having improved percutaneous absorption.

11. The use of a composition comprising at least one anionic surfactant and at least one surfactant having a nitrogen atom in the molecule other than anionic surfactants in a dematological preparation containing a drug component and having improved percutaneous absorption.

12. A dermatological preparation, comprising a drug component selected from prednisolone, dexamethasone, indomethacin, flufenamic acid, mefenamic acid, chlorpheniramine, diphenhydramine, promethazine, sulfa monomethoxine, sulfamethizole, penicillin, cephalosporin, chloramphenicol, streptomycin, naphthiomate, clotrimazone, cyclophosphamide, busulfan, actinomycin, morphine, codeine, nalorphine, pentazocine, aspirin, acetanilide, aminopyrine, prostaglandins, barbital, thiopental, chlorpromazine, reserpine, chlordiazepoxide, chlorzoxazone, levodopa, digitoxin, digoxin, procainamide, hydrochloride, dipyridamole, amyl nitrite, diazoxide, minoxydil, guanethidine nitrate, para-aminobenzoate ester, hydroquinone, arbutin, kojic acid, Vitamin C esters, para-hydroxycinnamate, 8-methoxypsoralene, Vitamin A, Vitamin E, Vitamin C, coenzyme Q10 (Vitamin Q), cepharanthin, swertiamarin, oxendolone, insulin estradiol and methyltestosterone and a percutaneous absorption promoting agent according to claim 3.

13. The use of a composition comprising at least one anionic surfactant and at least one nonionic surfactant not having a nitrogen atom in the molecule for the manufacture of a dermatological preparation containing a drug component and having improved percutaneous absorption.

14. The use of a composition comprising at least one anionic surfactant and at least one nonionic surfactant not having a nitrogen atom in the molecule in a dermatological preparation containing a drug component and having improved percutaneous absorption.

15. A dermatological preparation, comprising a drug component selected from prednisolone, dexamethasone, indomethacin, flufenamic acid, mefenamic acid, chlorpheniramine, diphenhydramine, promethazine, sulfa monomethoxine, sulfamethizole, penicillin, cephalosporin, chloramphenicol, streptomycin, naphthiomate, clotrimazole, cyclophosphamide, busulfan, actinomycin, morphine, codeine, nalorphine, pentazocine, aspirin, acetanilide, aminopyrine, prostaglandins, barbital, thiopental, chlorpromazine, reserpine, chlordiazepoxide, chlorzoxazone, levodopa, digitoxin, digoxin, procainamide, hydrochloride, dipyridamole, amyl nitrite, diazoxide, minoxydil, guanethidine nitrate, para-aminobenzoate ester, hydroquinone, arbutin, kojic acid, Vitamin C esters, para-hydroxycinnamate, 8-methoxypsoralene, Vitamin A, Vitamin E, Vitamin C, coenzyme Q10 (Vitamin Q), cepharanthin, swertiamarin, oxendolone, insulin estradiol and methyltestosterone and a percutaneous absorption promoting agent according to claim 5.

16. The use of a composition comprising at least one surfactant selected from amphoteric surfactants and semi-polar surfactants and at least one nonionic surfactant having a nitrogen atom in the molecule for the manufacture of a dermatological preparation containing a drug component and having improved percutaneous absorption.

17. The use of a composition comprising at least one surfactant selected from amphoteric surfactants and semi-polar surfactants and at least one nonionic surfactant having a nitrogen atom in the molecule in a dermatological preparation containing a drug component and having improved percutaneous absorption.

18. The use of a composition comprising at least one surfactant selected from nonionic surfactants, amphoteric surfactants, semi-polar surfactants and cationic surfactants having a nitrogen atom in the molecule and at least one nonionic surfactant not having a nitrogen atom in the molecule in a molar rating of 20:1 to 1:20 for the manufacture of a dermatological preparation containing a drug component and having improved percutaneous absorption.

19. The use of a composition comprising at least one surfactant selected from nonionic surfactants, amphoteric surfactants, semi-polar surfactants and cationic surfactants having a nitrogen atom in the molecule and at least one nonionic surfactant not having a nitrogen atom in the molecule in a molar rating of 20:1 to 1:20 in a dermatological preparation containing a drug component and having improved percutaneous absorption.

20. The use as claimed in claim 18 or 19, characterized in that the drug component is selected from prednisolone, dexamethasone, indomethacin, flufenamic acid, mefenamic acid, chlorpheniramine, diphenhydramine, promethazine, sulfa monomethoxine, sulfamethizole, penicillin, cephalosporin, chloramphenicol, streptomycin, naphthiomate, clotrimazole, cyclophosphamide, busulfan, actinomycin, morphine, codeine, nalorphine, pentazocine, aspirin, acetanilide, aminopyrine, prostaglandins, barbital, thiopental, chlorpromazine, reserpine, chlordiazepoxide, chlorzoxazone, levodopa, digitoxin, digoxin, procainamide, hydrochloride, dipyridamole, amyl nitrite, diazoxide, minoxydil, guanethidine nitrate, para-aminobenzoate ester, hydroquinone, arbutin, kojic acid, Vitamin C esters, para-hydroxycinnamate, 8-methoxypsoralene, Vitamin A, Vitamin E, Vitamin C, coenzyme Q10 (Vitamin Q), cepharanthin, swertiamarin, oxendolone, insulin estradiol and methyltestosterone.

21. A percutaneous absorption promoting agent for a drug component, comprising a water-insoluble or only slightly water-soluble amine oxide as the active ingredient.

22. A dermatological preparation, comprising a drug component selected from prednisolone, dexamethasone, indomethacin, flufenamic acid, mefenamic acid, chlorpheniramine, diphenhydramine, promethazine, sulfa monomethoxine, sulfamethizole, penicillin, cephalosporin, chloramphenicol, streptomycin, naphthiomate, clotrimazone, cyclophosphamide, busulfan, actinomycin, morphine, codeine, nalorphine, pentazocine, aspirin, acetanilide, aminopyrine, prostaglandins, barbital, thiopental, chlorpromazine,.
reserpine, chlordiazepoxide, chlorzoxazone, levodopa, digitoxin, digoxin, procainamide, hydrochloride, dipyridamole, amyl nitrite, diazoxide, minoxydil, guanethidine nitrate, para-aminobenzoate ester, hydroquinone, arbutin, kojic acid, Vitamin C esters, para-hydroxycinnamate, 8-methoxypsoralene, Vitamin A, Vitamin E, Vitamin C, coenzyme Q10 (Vitamin Q), cepharanthin, swertiamarin, oxendolone, insulin estradiol and methyltestosterone and a percutaneous absorption promoting agent according to claim 21.

23. The use of a water-insoluble or only slightly water-soluble amine oxide for the manufacture of a dermatological preparation containing a drug component and having percutaneous absorption.

24. The use of a water-insoluble or only slightly water-soluble amine oxide in a dermatological preparation containing a drug component and having percutaneous absorption.