Percutaneous administration of tamoxifen

Details Percutaneous administration of tamoxifen Percutaneous administration of tamoxifen

1985-09-13

1990-04-24

Schofer, Joseph L.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

514651, A01N 3302, A61K 31135

Patent

active

049199374

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to an anti-estrogen drug which can be applied, in particular, in the treatment of certain forms of tumors, especially those of the mammary gland in their hormone-dependent forms.
At the present time, an anti-estrogen is known which can be administered orally, named tamoxifen, and consists of 1-[4-(2-N-dimethylaminoethoxy)phenyl]-1,2diphenylbut-1-(Z)-ene, which is marketed under the name "Nolvadex". However, to obtain an anti-estrogen activity at the level of the estrogen receptors, especially those of the mammary gland, it is necessary to administer per os from 10 to 30 mg per day of this compound, and this causes harmful side effects, in particular a paradoxical stimulation of the ovaries. These latter effects in large measure limit the use of tamoxifen.
It has been shown, moreover, that tamoxifen administered orally is converted during its passage through the liver to numerous metabolites, including 1-[4-(2-N-dimethylaminoethoxy)phenyl]-1-(4-hydroxy-phenyl)-2-phenylbut-1-( Z)-ene, also named 4-hydroxytamoxifen, which is the active form of the product at the molecular level. On the other hand, this 4-hydroxy derivative directly administered orally appears to be more rapidly degraded than tamoxifen and for this reason it is useless to administer it by this route. In addition, it is also known that the 4-hydroxy derivative is from twenty to one hundred times more active than tamoxifen as an anti-estrogen at the level of the estrogen receptors. However, the administration orally or parenterally, other than percutaneously, leads to a diffusion of this product throughout the organism, causing--inter alia--a detrimental paradoxical stimulation of the ovaries.
The 4-hydroxytamoxifen derivative has, indeed, been described as an anti-estrogen agent with a view to its administration orally or possibly parenterally, the administration itself being limited to injection. As mentioned above, oral administration appears to be of restricted efficacy due to the destruction of the compound itself through its passage in the liver, while injection, leading to the introduction of the said compound into the blood circulation, can induce the detrimental ovarian effects mentioned above, through a systemic effect.
The document CHEMICAL ABSTRACTS, vol. 96, No. 9, 1st Mar. 1982, page 29, abstract 62664k, COLUMBUS, OHIO (US) & Eur. J. Cancer Clin. Oncol. 1981, 17(9), 1063-5, M. SLUYSER et al., "Effect of monihydroxytamoxifen (sic) on mouse mammary tumors", describes the properties of monohydroxytamoxifen without specifying the cis or trans form, and in the context of administration as a pellet under the skin, and hence not that of percutaneous administration.
The studies of the Applicants devoted for the last 15 years to the metabolism of hormonal steriods administered percutaneously in alcoholic solution have enabled it to be demonstrated [Journal of Clinical Investigation (USA) 1970, 49 :31] that the percutaneous administration route for steroids having a short half-life permitted direct access to the target organ, whereas the oral or even intravenous administration of the same steroid favoured its metabolism in the liver at the expense of its effective concentration in the receptor tissues. The hepatic by-passes thus produced were demonstrated in the first place for testosterone [Journal of Clinical Endocrinology and Metabolism (USA) 1969, 29: 437] and then subsequently for progesterone [Journal of Clinical Endocrinology and Metabolism (USA) 1969, 29: 1590 and 1974, 38: 142 and Patent FR-A-2515041]. In the case of progesterone, it was possible to demonstrate that the administration of this steroid in alcoholic solution or in a 60% strength aqueous alcoholic gel permitted topical retention for 48 hours of the compound which had passed through the cutaneous barrier (10%). In contrast, orally, 90% of the dose administered is destroyed in the first passage through the liver.
The Applicants were hence led in their studies to try administering the 4-hydroxytamoxifen derivative percutaneously in order to av

REFERENCES:
Chem. Abstract, vol. 85, entry 14290m, Br. J. Obstet. Gynolcol. 1976, 83(3), 183-186.
Chem. Abstracts, vol. 96, entry 62664k, Eur. J. Cancer Clin. Oncol., 1981, 17(9), 1063-1065.

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