Topical administration of toremifene and its metabolites

Details Topical administration of toremifene and its metabolites Topical administration of toremifene and its metabolites

1994-10-31

1997-02-25

Phelan, D. Gabrielle

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

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

424449, 514648, 514937, 514944, 514969, A61F 1300

Patent

active

056057008

DESCRIPTION:

BRIEF SUMMARY
This invention relates to topical preparations containing as active ingredient toremifene or one of its metabolites N-demethyltoremifene (4-chloro-1,2-diphenyl-[4-[2-(N-methylamino)ethoxy-]phenyl]-1-butene) or 4-hydroxytoremifene (4-chloro-1-(4-hydroxyphenyl)-2-phenyl-1-[4-[2-(N, N-dimethylamino)ethoyoxy]phenyl]-1-butene) or their pharmaceutically acceptable non-toxic salts. The use of such topical preparations e.g. for the treatment of cancers localized in the skin or on a short distance from the skin such as metastatic lesions of breast cancer is also within the scope of the invention. Moreover, the use of these topical preparations for the adjuvant therapy of breast cancer as well as their use for the reversal of multidrug resistance of cancer cells to cytotoxic drugs are also within the scope of the invention. Topical administration of toremifene or its metabolites are of particular interest in the treatment of melanoma, lymphoma, Kaposi's sarcoma and fungoides mycosis.
Tamoxifen and toremifene are triphenylethylene antiestrogens used in the treatment of estrogen receptor positive breast cancer. These drugs are the most frequently prescribed as endocrine agent for the treatment of breast cancer. Tamoxifen and toremifene inhibit estrogen-induced growth by competitive antagonism of tumor estrogen receptors (ER's). Antiestrogen therapy is effective in prolonging a disease-free state and overall survival of women following primary surgery. Antiestrogen therapy delays recurrence and prolongs survival in patients with primary breast cancer undergoing adjuvant therapy after mastectomy. About two-thirds of patients with estrogen receptor (ER) positive metastatic breast cancer will have a temporary remission on tamoxifen. Although tamoxifen is considered a relatively benign drug, recent evidence suggests that women receiving tamoxifen as adjuvant therapy may have increased risk of developing endometrial neoplasms (Fornander T et al, Lancet 1989, 21:117-120). Histopathology identifies these tumors as infiltrating endometrial tumors unrelated to breast tumor metastasis. The factors contributing to this increased risk are not well understood. However, a variety of studies have linked endometrial cancer to agents with estrogen activity (Smith Dc et al, N England J Med 1975; 293: 1164-67).
The development of multidrug resistance (MDR) is one of the major mechanisms by which cancer becomes refractory to chemotherapeutic agents, especially anthracyclines and the vinca alkaloids. Classical MDR is associated with the overexpression of a mdr-1 gene that codes for a plasma membrane P-glycoprotein (p170). The expression of the MDR-1 gene is believed to be associated with a decreased cellular accumulation of drug due to an active dependent efflux mechanism.
Although many agents including verapamil, the trifluoperizines, and cyclosporins have been shown to reverse multidrug resistance in vitro, most agents do not achieve high enough in vivo concentrations to reverse without substantial toxicity to the patient. This is particularly true for verapamil which is associated with significant cardiotoxicity.
The non-steroidal triphenylethylene antiestrogens have demonstrated in vitro chemosensitizing activity apparently unrelated to their antiestrogenic effects. Toremifene and its metabolites N-demethyltoremifene and 4-hydroxytoremifene are examples of new triphenylethylenes that have chemosensitizing activity in MDR-positive cells at concentrations that are achieved in humans without significant toxicity. Toremifene appears to be unique in that concentrations that reverse resistance in vitro (5 .mu.M) can be achieved in vivo following oral therapy without substantial toxicity (Wiebe VJ et al, Cancer Chemother Pharmacol, 1990, 25: 247-251). Plasma concentrations of toremifene and N-demethyl-toremifene following large oral doses are on the order of 10 .mu.M. However, plasma concentrations may not reflect the effective anti-MDR activity at the tumor level. Although the systemic toxicity of high-dose toremifene (400 mg/day) is general

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patent: 4996225 (1991-02-01), Toivola et al.
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"Cyclodextrins in the Pharmaceutical Field", O. Bekers et al., Drug Development and Industrial Pharmacy, 17(11), pp. 1503-1549 (1991).

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