SK285349B6 - Medicament for preventing and/or treating a mammary carcinoma, containing a steroidal aromatase inhibitor - Google Patents

Abstract

Use of a steroidal aromatase inhibitor for the preparation of a medicament formulated for local topical application for the prophylaxis and/or treatment of mastocarcinoma, where the medicament contains no antigestagens.

Description

Technical field

The present invention relates to a medicament for the prevention (primary and secondary prevention) and / or treatment of breast cancer.

BACKGROUND OF THE INVENTION

Breast cancer is one of the most common malignancies in women. In Germany, breast cancers account for up to 20% of all cancer cases in women; 30,000 new cases of the disease appear annually. The use of adjuvant cancer treatment currently leads to improved survival; breast cancer sereening and early surgical treatment also reduces mortality by 30%. However, due to the gradual increase in the number of new diseases, the number of deaths related to the total population remains the same or increases. Until now, it has been hardly possible to influence the number of new cases, as little is known about causal factors.

About half of all breast cancers have estrogen and / or progesterone receptors in their cytoplasm. Breast cancer of this kind requires estrogen to proliferate its cells. Estrogen acts through binding to specific intracellular (cytoplasmic) receptors of estrogen-sensitive cells into which it passes passively by diffusion from plasma. Binding alters the configuration of the receptor protein. The receptor-hormone complex controls both transcription and expression of specific genes; synthesis of growth promoting and / or inhibiting factors, thereby ultimately affecting cell growth.

Estrogen-dependent tumors are reduced after estrogen removal. The main source of estrogens in premenopausal women is the ovaries. Therefore, their surgical removal, which has been performed since 1896 in advanced breast cancer (metastasis), is called surgical hormonal therapy.

In postmenopausal women, the main source of estragone is estrone and estradiol, which results from the conversion of adrenal androgens, especially androstenedione and testosterone. This conversion to estrogens takes place in muscle and adipose tissue.

In clinical practice, both the early and advanced stages of breast cancer have been treated with tamoxifen or its derivatives (especially tamoxifen citrate) during the last twenty years. Tamoxifen occupies estrogen receptors located in the cytoplasm of tumor cells, thereby causing competitive estrogen replacement. The complex formed from tamoxifen and the estrogen receptor prevents the transcription and expression of genes that promote cell growth, which is otherwise supported by the estrogen-receptor complex.

In vitro (in vitro) experiments have shown that tamoxifen also acts to inhibit cell growth and, under certain circumstances, also has a cytostatic effect on a cell line that has no estrogen receptors. Tamoxifen inhibits protein kinase C and blocks activation of calmodulin. It increases the activity of killer cells and inhibits suppressor T lymphocytes.

Especially after long-term treatment, tamoxifen can act on tumor cells as well as estrogen in a way that is not yet known in detail and thus can promote their growth. Therefore, relatively long-term treatment with tamoxifen may lead to tumor growth under certain circumstances. In addition, it leads to a risk that increases 3 to 5 times in patients with endometrial cancer. In view of the clinical benefits of tamoxifen treatment, this risk is acceptable in breast cancer.

Systemic treatment of breast cancer with aromatase inhibitors, especially 4-hydroxyandrost-4-ene-3,17-dione (INN formestan), is known. Aromatase is a complex of the enzymatic system that catalyses the conversion of the adrenal androgens into estrone and estradiol.

Formestane is a derivative of the physiological steroid hormone androstenedione and competitively binds to other aromatase substrates. It damages the irreversible enzyme molecule during catalysis. Systemic treatment with formestane is also used as an antiestrogenic treatment for breast cancer.

SUMMARY OF THE INVENTION

The present invention is based on the preparation of the aforementioned medicament which is suitable for the treatment and in particular for the prevention of breast cancer.

This object is achieved by providing a steroid aromatase inhibitor that provides a drug intended for topical administration. The use of an anti-estrogen as an already added drug component is excluded in the present invention.

First, some terms used in connection with the present invention will be elucidated.

According to the present invention, the term steroid aromatase inhibitors as used herein are substances that inhibit the production of estrogens. They inhibit estrogen biosynthesis from androgen precursors, for example by enzymatic conversion of androstenedione to estrone or testosterone to estradiol. Since the two synthesis steps are mediated by the aromatase enzyme system (converting enzyme), aromatase inhibitors are used in the context of the present invention. Preferred inhibitors are those that bind to aromatase and irreversibly damage it. After topical administration, they penetrate the skin and concentrate in the adipose tissue.

The medicament of the invention is used topically. The medicament is administered topically to the skin, preferably the strongly lipophilic active agent is absorbed through the skin and thus locally reaches the intended site of action. The active substance is concentrated in adipose tissue around the gland ducts. In long-term treatment, the fat mass of the treated breasts is significantly reduced. This reduction reduces the amount of cells capable of producing estrogen. The lipophilicity and hydrophobicity of the active substance results in the active substance being exclusively concentrated locally in the adipose tissue and has no systemic effects. By estrogens, it is meant herein all female sex hormones that have comparable effects to estrone and estradiol.

It is known in the art that when aromatase inhibitors such as formestane are used, they are meant to be transported to the site of action via blood circulation. High serum aromatase inhibitor concentrations have the desired effect on the tumor, but also systemic side effects. In view of the severity of the disease, these side effects are acceptable in acute treatment in terms of desired success. In any case, this treatment is not contemplated in the case of preventive treatment for a previously non-existent or incomplete disease.

According to the invention, the medicament is used locally directly to or around the site of the desired action. Unlike in the past, no transport by blood circulation to the intended site of action is used. According to the invention, the resulting level of active substance in the tissue at risk (in prevention) or affected tissue (in treatment) has been achieved without significant absorption of the active substance that takes place in the bloodstream. The subject of the present invention is not only a single local administration, but a local administration in such a way that the active substance is concentrated directly in the risk tissue and / or the affected tissue and not indirectly via the bloodstream.

In the metastatic carcinomas to be treated and prevented, the medicament of the invention is administered locally to the intended site of action in an amount such that there is substantial uptake into the bloodstream and the serum levels thus generated transport the active agent into metastases. In this case, priming also takes place locally at or near the intended site of action.

This medicine is used to treat breast cancer. After primary surgical treatment, adjuvant therapy is used if necessary. This treatment can be replaced or added, and ^the hitherto conventional systemic anti-estrogen therapy.

An important advantage of the present invention is the possibility of using the medicament also for the prevention of breast cancer. A particularly important application is the so-called. secondary prevention. Patients of women who already have breast cancer have a high risk of further breast cancer on the contralateral side. This contralateral breast can be treated preventively with the medicament of the invention. The secondary preventive treatment of the diseased breast enables the local recurrence of the disease to be prevented.

In the case of so-called. For high-risk women, primary prevention can be performed. Selection criteria that apply to a high-risk group include, for example, the fact that at least one mother in the first degree of maternal affection has breast cancer unilaterally or bilaterally before her 45th year of life, or at least one woman in the first degree of maternal affinity and one other relative is suffering from breast cancer. Since the systemic side effects of the active substance due to their hydrophobicity are indeed completely eliminated by the topical administration of the present invention, the indication for primary prevention is relatively general even if the tissue has a comparatively low or moderate risk (e.g. Prechtel II histology) and III). Prevention even begins, although the common early diagnosis (palpation finding) is still negative, since the common early diagnosis is not adequate and usually only detects breast cancer when this systemic disease is barely treatable.

The medicament of the invention is preferably administered locally for relatively long periods of time (if necessary, and to the end of life). Administration is performed, for example, once or twice daily.

The active agents are selected from the group consisting of (preferably fat soluble) a steroid aromatase inhibitor. When administered locally, these fat-soluble substances penetrate into adipose tissue and locally prevent new estrogen formation from estrogen precursors.

As steroid aromatase inhibitors, for example, 4-hydroxyandrost-4-ene-3,17-dione (formestane), 6-methylenandrostra-1,4-diene-3,17-dione (exemestane), 10- (2-propynyl) are used. estr-4-ene-3,17-dione (MDL 18962) and 7-α-substituted androstenedione derivatives. (The names in brackets are internationally used names). For the terminology and structure of these substances, reference is made to the "Rote Liste" and Roempp's Chemical Encyclopedia.

The substances listed so far have only been used systemically for the treatment of breast cancer. According to the invention, however, the active agent is brought to the intended site by topical administration. When an aromatase inhibitor is used, the present invention achieves a reduction in aromatase activity in breast adipose tissue, i. j. at the site where the tumor is formed or grown.

In relatively long-term use, the adipose tissue of the breast and hence the amount of potentially hazardous tissue is reduced. Since breast cancer often occurs in the upper quadrates of breasts with increased aromatase activity, primary prevention according to the invention is particularly effective.

The aromatase inhibitors of the invention can be used either preventively or therapeutically, even in those breast cancers that have in themselves the ability to produce estrogen or autocrine / paracrine stimulation. In such tumors, lowering the plasma estrogen concentration hardly has any effect, but according to the present invention, the intratumoral aromatase concentration may be reduced, which has an effect on such tumors due to the use of permeable cell inhibitors.

Since the active ingredient administered according to the invention remains localized in the adipose tissue of the breast and exhibits the activity determined therein due to its fat solubility, the side effects caused by systemic administration are eliminated. This reduction or elimination of side effects allows a significantly wider preventive use. The medicaments according to the invention are administered by the patients themselves and therefore frequent visits to the doctor are not necessary.

The medicament formed according to the invention preferably comprises formestane.

Particularly preferred are formestane derivatives such as acetylated formestane (e.g. 4-O-acetylandrost-4-ene-3,17-dione) and the like. Acetylation of formestane significantly increases its hydrophilicity and hence penetration through the skin. Since the acetyl group is hydrolyzed under conditions prevailing in the subcutaneous area after penetration through the skin, the actual active substance formestane is re-formed in the body. Therefore, a pro-drug of the present active substance better penetrating through the skin is administered, and the inventors have found that the pro-active substances from the precursor are formed subcutaneously in the body.

As a rule, the active ingredients used according to the invention are fat-soluble and highly suitable for topical administration. As mentioned above, the concentration in breast adipose tissue prevents systemic side effects. In order to improve skin penetration, substances known to promote skin penetration, for example hyaluronidase or DMSO (dimethylsulfoxide), may be added to the medicament of the invention.

The medicament is preferably manufactured as a skin ointment, cream, gel, emulsion or lotion. A powder or oil form is also acceptable. The basics of the formulation are well known to those skilled in the cosmetics and pharmaceutical industry, so there is no need to go into more detail. Further, for example, vegetable oils and fats such as almond oil, peanut oil, olive oil, peach kernel oil, castor oil, vegetable extracts, essential oils may be used; vegetable waxes and synthetic and animal oils, fats or waxes; lecithin, lanolin alcohols, carotene, fragrances, mono- or polyhydric alcohols, urea, preservatives and coloring agents, etc. Preferably an oil-in-water or water-in-oil formulation is used.

The active substance content of the medicament (content of estrogen inhibiting agents) is in the range of 0.0001 to 20% by weight, preferably 0.6 to 10% by weight, even more preferably 1 to 5% by weight. The normal range is 0.6 to 2% by weight.

For example, when admixing agents which promote skin absorption are incorporated, their content when used as hyaluronidases is, for example, between 0.01 to 1% by weight, preferably between 0.05 to 0.2% by weight; when DMSO is used, 1 to 25% by weight, preferably 5 to 10% by weight.

The components of the invention are described later.

Description of the drawings

Example 5

The cream is prepared from the following ingredients, which are shown in Figure 1, demonstrating the cytological result of an aspirate according to international names.

adipose cells prior to use of the medicament of the invention.

INCI

Ceteareth-25 3.0 g

Figure 2 demonstrates a corresponding result after 3

PEG-4-polyglyceryl 2-stearate 2.0 g per month of daily use.

Cetearyl alcohol 4.9 g

Kerosene 10.0 g

Parrafinum perliquidum 3.0 g

DETAILED DESCRIPTION OF THE INVENTION

Sodium carbomer 400 0.14 g

Lactic acid 0.02 g

Example 1

Parrafinum perliquidum 2.0 g

They are mixed to form a cream. the following components:

Phenoxyethanol, dehydrourea acid

10 g acetic, benzoic acid 0,4 g

Titanium dioxide g

Perfume 0.08 g

Crude petrolatum g

4-Acetylandrost-4-ene-3,17-dione isopropyl palmitate

10g (acetylated formestane) 1.5 g

Peanut oil reinforced 10g

Make up to 100,0 g with water

Tween 80

5 g

Formestan g

Example 6

Make up to 50 ml with purified water

100 g

A clinical trial was performed according to the recipe of Example 1. A 25-year-old female volunteer had an over-sized breast of Example 2 and a middle degree mastopathy.

The gel is prepared from the following ingredients:

The fatty tissue aspirate was removed with a thin needle

Ethanol 90%

7.0 g (0.6 puncture needle, fixation in absolute alcohol, coloring:

Carbopol® 394 P

7,0 g

May-Gruenwald-Giemsa) (Figure 1). Larger triethanolamine was found

2.0 g of fats with eccentric embedded nucleus as polysorbate 80

5.0 g result of a large influx of estrogen.

glycerol

3,0 g

The volunteer then applied a cream according to the example of Formestan

0.75 g du 1 twice daily for 3 months. Figure 2 Demonstrated water to

100.0 g strips the fatty tissue aspirate after this use. A reduction in the volume of the adipose tissue (" shrunked here " Example 3 cells in a regular arrangement) and enlargement of the connective tissue has been found. Results for propylene glycol

25.0 g showed a 50% reduction in risk tissue and significant

isopropyl

6.0 g strengthening of connective tissue and skin.

Sorbitan monostearate 1.0 g

Polysorbate 80

2,0 g

Claims (6)

PATENT CLAIMS cetylstearyl 6,0 g stearyl 2,0 g glycerol 1.0 g Use of a steroid aromatase inhibitor for the preparation Hyaluronic acid 0.1 g of a drug adapted for topical administration for prevention Formestam 1,5g and / or treatment of breast cancer when the drug does not contain any Purified Water to 100.0 g no antigestagens. The use according to claim 1, wherein the medicament comprises for example 4 urban (4-hydroxyandrost-4-ene-3,17-dione) and / or the pharmaceutical is prepared from the following ingredients. The components are a cologically active derivative of formestane. in this example by international names. The use of claim 2, wherein the medicament comprises 4-0INCI -acetylandrost-4-ene-3,17-dione. Ceteareth-25 3,0 g Use according to any one of claims 1 to 3, wherein PEG-4-polyglyceryl 2-stearate In addition, 2.0 g of the drug contains penetration enhancers cetearyl 4.9 g skin. kerosene 10,0 g The use of claim 4, wherein the medicament comprises Parrafinum perliquidum 3,0 g DMSO. Sodium carbomer 400 0.14 g Use according to any one of claims 1 to 5, wherein Lactic acid 0.02 g of the drug is formulated as an ointment, cream, gel, emulsionParrafinum perliquidum 2.0 g zia or lotion. Phenoxyethanol, dehydro7. Use according to claim 6, wherein the active substance content is acetic, benzoic acid 0.4 g 0.0001 to 20% by weight, preferably 0.6 to 10% by weight of Perfum 0.08 g by weight and more preferably 1 to 5% by weight. Formestan 1.5 g Make up to 100,0 g with water A mixture of phenoxyethanol, dehydroacetic acid and benzoic acid shown in this formulation is available under the name Euxy ^A K702 from Schuelke & Mayr.