SK25299A3 - Transdermal therapeutical approach involving a combination of active substances containing oestriol - Google Patents

Abstract

Disclosed is a transdermal therapeutical approach involving oestriol as an active substance, characterized in that oestriol is combined with one or more active substances.

Description

The invention relates to a transdermal therapeutic system with estriol comprising a combination of active ingredients.

Estrogens are steroid hormones that are derived from the tetracyclic Cis steroid estran. Estrogen, estradiol and estriol are distinguished between natural estrogens, with estrone and estriol being most important physiologically.

Estriol is one of the final metabolic products of estradiol metabolism. It has a number of pharmacological and biological peculiarities that differ from other estrogens.

Already before adsorption, it is almost completely bonded. Only 1 - 2% of estriol used is in the bloodstream as free estriol. The ratio of free estriol to connectable is 1: 500.

At an oral dose of 2 mg, no proliferative effect on the endometrium appears, since it remains very briefly associated with the cell nucleus receptors. The estrogenic effect is only manifested if the estrogenic substance remains in the nucleus for a long time. This can be achieved when estriol is administered several times a day.

Another peculiarity of estriol is that it is effective when administered for several months.

The vaginal application has the advantage that the estriol non-connectivity to serum is 10 to 20 times higher than at an oral dose at which intestinal metabolism is possible. After dose

0.5 mg of estriol for vaginal administration can be expected to have a high serum level of 100-150 pg / ml after only two hours. In contrast, an oral dose of 10 mg is required to achieve the same effect.

The foregoing findings conclude that estriol is a transdermal therapeutic system (TTS), a galenical system of choice. These systems can ensure that estriol is used for a certain period of time, e.g. seven days, continuously transmitted to the body.

To date, the active substance estriol has been attributed to a lack of therapeutic action in substitution therapy (HRT). This is particularly true when estriol is used to prevent osteoporosis. The official opinion of the German Society of Endocrinology emphasizes the ineffectiveness of estriol as a prophylaxis for osteoporosis (cf. German Medical Newspaper - Medical Reports, 85, 1322-1325, 1988).

The fact that estriol does not act on bones has also been published in relevant medical books (Freimut A. Leidenberger, Clinical Endocrinology for Female Doctors, Springer Publishing House 1992, p. 356).

The ineffectiveness of estriol alone in the treatment of osteoporosis is also pointed out in the Product Information Sheet for preparations that include estriol as an active ingredient (eg Jenapharm Drugs: Assortment and Census, July 1, 1991, p. 67).

In contrast, estriol is the only one for use in the treatment of osteoporosis in the form of a transdermal therapeutic system in PCT application WO 93/18774. Estragol from tarragons is found to be suitable for continuous hormone replacement therapy and in particular for the treatment of climacteric osteoporosis. Indeed, on continuous administration, effective therapy or prevention is achieved on the one hand, while on the other hand, there is usually no obvious estrogenic carcerogenic effect and even anticarcerogenic effect can even be expected.

SUMMARY OF THE INVENTION

Starting from the present state of medical primary object of the invention consists in that said substantially improved transdermal therapeutic system of estriol containing a combination of active ingredients, and having no risk of side effects, in particular for ¹ 'ii using estriol, a high therapeutic activity and acceptance to prevent osteoporosis, arteriosclerosis, and / or cardiac insufficiency in old age.

Surprisingly, it has been found that transdermally administered estriol is supported by transdermally administered bisphosphonates, beta-ablocators and Ca-antagonists and that transdermally applied estriol in combination with beta-blockers and Ca-antagonists is used in the treatment of arteriosclerosis or in the treatment of heart failure . In combination with bisphosphonates, it is also suitable for transdermal application in the treatment of osteoporosis.

In other uses, it has been found that dransdermal administration of bisphosphonates in combination with estriol is preferable to estriol alone in the treatment of osteoporosis. A dosage form is preferred which releases 8 to 16 mg of estriol and 3 to 7 mg of bisphosphonates per TTS over 24 hours.

For this purpose, all transdermal therapeutic systems with estriol containing combinations of active ingredients which guarantee the continuous release of active ingredients for at least 24 hours are intended according to the invention. The preparation of such a system with corresponding individual substances is known to the person skilled in the art and is also described accordingly.

Claims (5)

Transdermal therapeutic system with an active ingredient of estriol, characterized in that it comprises a combination of estriol with one or more other active ingredients of the class of beta-blockers, Ca-antagonists or bisphosphonates. Transdermal therapeutic system according to claim 1, characterized in that it contains amlodiopine, carvedilol, pimobendon, timolol, mepindolol, verapamil, nifredipine and / or nimodipine in combination with estriol. Transdermal therapeutic system for the treatment of osteoporosis, characterized in that a bisphosphonate is contained in combination with estriol. Transdermal therapeutic system according to claim 3, characterized by the release of an estriol group of 8-16 mg or 3-7 mg of bisphosphonate per day. Transdermal therapeutic system for the treatment of cardiac insufficiency in old age or arteriosclerosis, characterized by a combination of the active ingredients of estriol with the active ingredients of the beta-blocker and / or Ca-antagonist class according to claim 1 or 2.