Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Patent
1996-05-21
1999-01-12
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
424448, A61F 1300, A61K 970
Patent
active
058583947
DESCRIPTION:
BRIEF SUMMARY
The invention relates to an agent for transdermal administration, characterized in that it contains gestodene esters with 1 to 20 carbon atoms in the ester radical optionally in combination with one or more estrogen(s).
These gestodene esters are characterized by the general formula ##STR1## in which R means an acyl radical with 1 to 20 carbon atoms.
The invention preferably relates to agents for transdermal administration with gestodene esters with 2 to 12 carbon atoms in the acyl radical and especially agents which contain gestodene alkanoates with 2 to 8 carbon atoms in the alkanoyl radical. As suitable gestodene esters that were unknown up until now, gestodene propionate, gestodene valerate, and especially gestodene capronate can be especially emphasized, which also are object of this invention, and their production is described at a later point.
As is generally known, gestodene itself is a substance with unusually high gestagenic effectiveness (B. Dusterberg, Steroids 43, 1984, 43 ff), which is used in combination with estrogenically effective substances for the production of contraceptive agents (Femovan.RTM.) that are to be administered orally. It is known that gestodene itself can be administered transdermally (EP-A 0370220). Further, it is known that the esters of gestodene also exert a strong gestagenic action in the case of oral administration (U.S. Pat. No. 4,081,537).
It has now been found, surprisingly enough, that gestodene esters can be used optionally in combination with one or more estrogens often better for the production of an agent for transdermal administration of active ingredients than combination preparations that contain gestodene itself.
By the esterification of the 17.beta.-position hydroxyl group of the gestodene, the physicochemical properties of this substance are targeted and bioreversibly altered toward pro-drug formation.
If the skin penetration of gestodene is compared with that of its esters, the latter are generally distinguished by considerably higher transdermal flows. This is especially true in the processing of esters in matrix-transdermal systems, such as, for example, those of the acrylate type (as are described at a later point in Example 2).
The unusually high transdermal flows are due especially to the surprisingly advantageous solubilities that have been found for the above-mentioned esters of the gestodene in conventional skin contact adhesives and mixtures of them with cosolvents of respective penetration enhancers. Based on these properties, highly loaded and stable matrix transdermal systems with molecularly dispersely distributed gestodene-pro-drugs can now be produced for the first time. Even active ingredient loads that on a molecular basis are higher by a factor of 10 than the comparable ones achievable for gestodene result in stable systems. This is a decisive advantage compared to the gestodene-containing systems, which are previously known from EP-A 0370220, since the difference in concentration between transdermal systems and skin is decisively responsible for the levels of the transdermal flows that can be achieved.
Thus, with the aid of the agent according to the invention, it is possible to achieve high uniform flows of gestodene esters with comparatively small transdermal systems.
It was already mentioned that in addition to gestodene esters, the agent according to the invention can also contain one or more estrogens. Suitable estrogens are, for example, estradiol, estriol, ethinylestradiol, mestranol, 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol (WO 88/01275), the 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,16.alpha.,17.beta.-trio l (WO 91/08219) and their esters (EP-A 163596), such as estradiol dipropionate, estradiol dihexanoate and estradiol didecanoate. In addition to 1 or 2 gestodene esters, these combination preparations according to the invention contain preferably 1 to 3, and especially 1 to 2 estrogen(s).
For the production of pharmaceutical preparations, the active ingredient or the active ingredient mixtur
REFERENCES:
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patent: 5376377 (1994-12-01), Gale
Nelder et al., "Selection and Use of Crystallization Inhibitors . . . ", The Computer Journal, 7 (1965), S. 308-313.
Lipp et al., "Rational Design of Prodrugs . . . ", Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 22 (1995), Controlled Release Society, Inc.
R. Lipp, "X-Ray Structure Determination of Crystals . . . ", Pharmaceutical Research, Oct. 1994 (Supplement), vol. 11, No. 10, S-213.
R. Guy et al., "Percutaneous Penetration Enhancement . . . ", Library of Congress Cataloging-in-Publication Data, 1992.
Esperling Peter
Gunther Clemens
Laurent Henry
Lipp Ralph
Riedl Jutta
Howard Sharon
Page Thurman K.
Schering Aktiengesellschaft
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