Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-07-08
1993-09-21
Schenkman, Leonard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514249, 514357, 514406, 514427, 514548, 514947, A61K 3144, A61K 31225
Patent
active
052469492
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a preparation for endermism containing a dopamine derivative. More particularly, it relates to a preparation for endermism containing dopamine derivative which shows a high skin permeability and a low skin irritativeness.
BACKGROUND OF THE INVENTION
Dopamine, which is represented by formula (II): ##STR2## wherein R.sup.3 is a hydrogen atom; and dobutamine, which is represented by the above formula (II) wherein R.sup.3 is a group, ##STR3## have been used for the treatment of, for example, hypotension, cardiac circulatory insufficiency and cardinogenic shock. However, since each of these compounds has a free catechol group and is scarcely absorbed when administered orally or percutaneously, the administration of them is restricted to the continuous intravenous way.
Recently, ibopamine represented by formula (III): ##STR4## has been developed as a drug which exerts a dopamine-like effect and can be orally administered (cf. U.S. Pat. Nos. 4,218,470 and 4,302,471). However this compound is still unsatisfactory in sustained effect and it is reported that the half-life of this compound in plasma is 1.54 hour [cf. E. Lodola et al; Arzneim.-Forsch./Drug Res., 36(1), 345-348 (1986)]. It is further reported that the effect of ibopamine on improvement of the circulation, when evaluated by the cardiac coefficient, sustains 3 to 6 hours [cf. SOL I. Rajifer et al.; Circulation, 73, 740-748 (1986)].
Recently, further attempts have been made to develop a preparation capable of gradually releasing a drug in the blood for a prolonged period of time so as to improve the persistence of the effect of the drug. For example, U.S. Pat. No. 4,581,225 discloses a sustained release nasal preparation which comprises a catechol amine (for example, dobutamine), an emulsifier, a dispersant and an agent rendering the drug slowly released such as oleic acid, linolic acid or an ester thereof. Further, Okumura et al. have studied on the application of dopamine hydrochloride to the skin and reported that the use of a 5% aqueous solution of glyceryl monocaprylate can elevate the percutaneous penetration rate of dopamine hydrochloride to a level 34 times as high as that achieved by using dopamine hydrochloride alone [cf. Chem. Pharm Bull., 37(5), 1375-1378 (1989)]. In the practical clinical application, however, it is preferable to establish a higher skin permeability. There is an additional problem, furthermore, that dopamine hydrochloride is highly irritative to the skin and causes skin damage if it can be percutaneously absorbed. Therefore, this compound is unsuitable for practical application.
Other known dopamine derivatives, which might exert the dopamine- like effects, include those synthesized by introducing variuos substituents into the catechol and/or amino group [cf. C. Casagrande et al.; Arzneim.-Forsch./Drug Res., 36(2), 291-303 (1986)].
SUMMARY OF THE INVENTION
An object of the present invention is to provide a preparation for endermism, having the dopamine-like effects, which is expected to be prolonged for a long period of time, a high skin permeability and a low skin irritativeness. As a result of extensive studies, the present inventors have found that the use of lactic acid esters, fatty acid monoglycerides or higher alcohols in combination with a dopamine derivative represented by the following formula (I) remarkably promotes the percutaneous absorption of said compound; and that the use of an unsaturated fatty acid monohydric alcohol ester remarkably reduces the skin irritativeness of said compound.
Accordingly, the present invention provides a preparation for endermism which comprises the following ingredients (A) and (B):
(A) a diacylated dopamine derivative represented by formula (I): ##STR5## wherein R.sup.1 represents an alkyl group having 3 to 7 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted phenyl group or a substituted or unsubstituted nitrogen-containing heterocyclic group; and R.sup.2 represents a hydrogen atom or
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Fujimori Hiroyuki
Ishino Yoshio
Kasai Masayoshi
Kobayashi Toyohiko
Konita Noriko
Sansho Co., Ltd.
Schenkman Leonard
Takasago International Corp.
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