MXPA00009126A - Medicament for preventing and/or treating a mammary carcinoma, containing a steroidal aromatase inhibitor - Google Patents

Abstract

The invention relates to the use of a steroidal aromatase inhibitor for producing a medicament formulated for topical use, for preventing and/or treating a mammary carcinoma. The inventive medicament provides a way of avoiding the side effects associated with systematic use. It is therefore possible to carry out a primary preventative treatment or else a secondary preventative treatment after the appearance of a mammary carcinoma.

Description

DRUG FOR THE PROPHYLAXIS AND / OR THE TREATMENT OF CANCER OF MAMA, WHICH CONTAINS A STEROIDAL AROMATASE INHIBITOR DESCRIPTION OF THE INVENTION The invention relates to a medicament for prophylaxis (primary or secondary prophylaxis) and / or treatment of breast cancer. Breast cancer is the most frequent malignant cancer disease in women. In Germany, breast cancer constitutes approximately 20% of all cancer cases in women; The incidence to date is approximately 30,000 new cases of disease per year. The adjuvant therapy against cancer currently used leads to an increase in the survival rate; an analysis of breast cancer and early surgical treatment also reduce mortality by 30%. However, since the number of new cases of disease continually increases, the death rate measured over the total population remains the same or increases. Until now, it has rarely been possible to alter the number of new cases, because little is known about the triggers. In about half of all breast cancers, estrogen or progesterone receptors have been found, or both in the cytoplasm. Breast cancers of this type need estrogen for the proliferation of their cells. Estrogens act by binding to specific intracellular (cytoplasmic) receptors of estrogen-sensitive cells, within which they are passively introduced by diffusion from the plasma. The binding changes the configuration of the receptor protein. The receptor-hormone complex controls both the transcription and expression of specific genes as well as the synthesis of factors that promote growth or inhibit growth which ultimately causes it to have an effect on cell growth. Through the removal of estrogen, a regression of estrogen-dependent tumors can be performed. In premenopausal women, the ovaries are the main source of estrogen. Its surgical removal so far has been carried out since 1896 with advanced stage breast cancer (formation of metastases) and what is called surgical hormone therapy. In postmenopausal women, the conversion of adrenal androgens, especially androstenedione and testosterone, to estrone and estradiol is the main source of estrogen. The conversion of estrogen takes place in muscle and fat tissue. In clinical practice, for more than twenty years, both the early and advanced stages of breast cancer have been treated with tamoxifen or its derivatives (particularly tamoxifen citrate). Tamoxifen occupies the estrogen receptors located in the cytoplasm of cancer cells and therefore causes a competitive displacement of estrogen. The complex that is formed from tamoxifen and the estrogen receptors prevents the transcription and expression of genes that promote cell growth, which is otherwise caused by a complex formed from estrogen and the receptor. In in vitro experiments, it has been shown that tamoxifen also has a growth inhibitory effect, and under some circumstances, even cytostatic on cell lines which do not have estrogen receptors. Tamoxifen inhibits protein kinase C and blocks the activation of calmodulin. IncDecreases killer cell activity (killer) and inhibits suppressor T lymphocytes. In particular, after a relatively prolonged treatment, tamoxifen can act on cancer cells as well as on estrogens in a manner which is not known in greater detail and promotes its growth. Treatment with relatively long lasting tamoxifen therefore leads, under certain circumstances, to tumor growth. It also leads to risk which increases by a factor of 3 to 5 of suffering cancer in the endometrium. In view of the clinical benefits of tamoxifen therapy, this risk is accepted in patients with breast cancer.

The systemic treatment of breast cancer with aromatase inhibitors, in particular 4-hydroxyandrost-4-ene-3,17-dione (INN formestane) is additionally known. Aromatase is a complex enzyme system that catalyzes the conversion of adrenal androgens to estrone and estradione. Formestane is a derivative of the physiological steroid hormone androstenedione and binds competitively to other aromatase substances. During the catalysis, irreversibly damages the enzyme molecule. Systemic treatment with formestane is also used as an antiestrogenic therapy against breast cancer. The invention is based on the objective of creating a medicament of the type mentioned at the beginning, which is suitable for treatment, and in particular also for the prophylaxis of breast cancer. The invention achieves this objective by formulating a spheroidal aromatase inhibitor to provide a medicament designed for topical application. The use of antigestagens as an additional constituent of the medicament is excluded in the context of the invention. First, some terms used in the context of the invention will be explained. According to the invention, spheroidal aromatase inhibitors are used as substances that inhibit the formation of estrogens. These inhibit the estrogen biosynthesis from androgenic precursors, for example the enzymatic conversion of androstenedione to estrone or from testosterone to estradiol. Since the two synthetic steps mentioned are mediated by the aromatase enzyme system (converting enzyme), aromatase inhibitors are used in the context of the invention. Preferred inhibitors are those which bind aromatase and irreversibly damage it. After topical application, they penetrate through the skin and concentrate on the fatty tissue. The medicament according to the invention is designed for topical application. The drug is applied locally to the skin, preferably a strongly lipophilic active compound is transdermally absorbed and therefore locally reaches the desired site of action. The active compound is concentrated in the periductal fatty tissue. In a long-term treatment, the fat of the treated breast is markedly reduced. This reduction decreases the amount of estrogen-forming cells that have estrogen-forming ability. The lipophilicity and hydrophobicity of the active compound has the result that the active compound is concentrated exclusively locally in the fatty tissue and may exhibit a non-systemic action. It is understood that estrogen means all female sex hormones that have an action comparable, for example, with that of estrone or estradiol.

In the use of aromatase inhibitors known from the prior art, such as formestane, it is intended to transport this to the site of action via blood circulation. High serum concentrations of aromatase inhibitor are sought which, in addition to the desired action in the tumor, can lead to systemic side effects. In view of the severity of the disease, such side effects are accepted in acute therapy in view of the desired success. However, this does not come into consideration in the case of a prevention treatment against a disease that is still non-existent or clearly detected. However, according to the invention, it is intended to apply the medicament topically immediately on or in the vicinity of the proposed site of action. ke the prior art, no transport is sought by means of blood circulation to the proposed site of action. According to the invention, the result obtained is an adequate concentration of the local active compound of the tissue at risk (in prophylaxis) or in the diseased tissue (in therapy) without a remarkable absorption of the active compound in the blood circulation taking place . The basis of the invention therefore is not only the topical application per se, but the local topical application in such a way that the active compound is immediately concentrated in the tissue at risk or in the diseased tissue, and not indirectly via the circulation blood If a treatment or prophylaxis of metastatic carcinomas against these is also to be carried out, the medicament according to the invention can be applied topically to the proposed site of action in such an amount that it is absorbed in a remarkable way in the blood circulation and that In addition, an accumulation of serum concentration is carried out which also transports the active compound for metastasis. In this use also, local absorption is carried out in or within the vicinity of the proposed site of action, primarily. The medication can be used for the treatment of breast cancer. After primary surgical care and, if appropriate, appropriate adjuvant therapy, this treatment can replace or supplement the usual systemic antiestrogenic therapy until now. An important advantage of the invention is the possibility of also using the medicament for prophylaxis of breast cancer. A particularly advantageous possibility of use is what is called secondary prophylaxis. In female patients in whom breast cancer is already present, there is a particularly high risk of an additional carcinoma in the contralateral breast. The contralateral breast can be treated prophylactically with the medicament according to the invention. A secondary prophylactic treatment of the diseased breast to avoid local recurrences is equally possible.

In the case of so-called high-risk women, primary prophylaxis can be carried out. The selection criteria which can be used for such a high-risk group are, for example, the facts that at least one first-degree relative of the female gender on the mother's side is or has suffered from breast cancer in one of the sides before 45 years of age or bilaterally, or where on the mother's side, at least one relative of the female gender, once removed and a female first-degree relative and an additional female relative are or have suffered from breast cancer. Since the local application according to the invention virtually avoids the possible collateral systemic effects of the active compound when considering its hydrophobicity, the indication of primary prophylaxis can be performed relatively generously already in the presence of tissue having a comparatively low risk on average (for example, Prechtel II or III histological finding). Prophylaxis can be initiated even if the conventional early diagnosis (palpation finding) is still negative, since this usually early diagnosis is inadequate and as a rule only detects a breast cancer when a systemic disease is already present, which is rarely yet It is curable. The medicament according to the invention preferably is applied locally or topically over a relatively long period of time (if needed, during the rest of life) and the application is carried out, for example, once or twice a day. The active substances are selected from the group consisting of spheroidal aromatase inhibitors (preferably liposoluble). Before local application, fat-soluble substances penetrate the fatty tissue and locally prevent the de novo formation of estrogens from the estrogen precursors. For example, spheroidal aromatase inhibitors such as 4-hydroxyandrost-4-ene-3, 17-dione (formestane), 6-methylenandrosta-l, 4-diene-3, 17-dione may be used. (exmestane), 10- (2-propynyl) -estr-4-ene-3, 17-dione (MDL 18962) and 7-a-substituted androstenedione derivatives. The names that are mentioned in parentheses are the INN (international non-patented names). For the terminology and structure of the substances mentioned, reference is also made to the chemical encyclopedia Rote Liste and Rómpp. Until now, the mentioned substances have only been used for systemic therapy of breast cancer. Nevertheless, according to the invention, the active compound is placed at the desired application site by local application. When aromatase inhibitors are used, the invention obtains a reduction of the aromatase activity in the fat tissue of the breast, ie, exactly in the position in which the tumor can be formed or can grow. When used relatively long term, the fat of the breast and therefore the amount of possible tissue at risk is reduced. Since breast cancers are often formed in the upper breast quadrants of increased aromatase activity, a particularly effective prophylaxis is possible in that place according to the invention. The use according to the invention of aromatase inhibitors can be carried out prophylactically or therapeutically even against those breast tumors which themselves are capable of producing estrogen or autocrine / paracrine stimulation. A decrease in plasma estrogen concentration rarely has an effect on such tumors, but the reduction of the intratumoral aromatase concentration obtained according to the invention can affect such tumors when considering the use of cell-permeable inhibitors. . Since the active compounds administered according to the invention remain localized in fatty tissue of the breast and show their proposed action in that place when considering their lipid solubility, their side effects induced by systemic application are eliminated. This reduction or exclusion of side effects allows a significantly broader prophylactic use. The medicine according to the invention can be applied by the patients themselves and frequencies are no longer necessary to the doctor for this purpose. A medicament formulated according to the invention preferably contains formestane. Similarly, formestane derivatives, such as, for example, acetylated formmestane (for example 4-0-acetylanthrost-4-ene-3, 17-dione), can be used. The acetylation of the formestane increases its hydrophobicity and therefore its penetration into the skin significantly. Since the acetyl group is hydrolyzed under the conditions prevailing in the subcutaneous region after the spleen through the skin, the active compound formmestane is formed again in situ. When such acetylated formestane is used, a precursor of the actual active compound penetrates better through the skin and is therefore applied, and the inventors have recognized that the actual active compound is formed in situ subcutaneously from this precursor. As a rule, the active compounds used according to the invention are liposoluble and highly suitable for topical application. As already described above, the concentration in the fatty tissue of the breasts avoids the systemic side effects. To improve penetration into the skin, substances known in the prior art which promote this, according to the invention, for example hyaluronidates or DMSO (dimethyl sulfoxide) can be added to the medicament. The medicament is preferably formulated as an ointment, cream, gel, emulsion or lotion. Formulation as a powder or oil is also feasible. The formulation phases are familiar to those skilled in the art of the cosmetic and pharmaceutical industry and do not need to be explained in more detail here. For example, vegetable oils and fats such as almond oil, peanut oil, olive oil, peach seed oil, castor oil, plant extracts, heteral oils may be used.; also vegetable waxes and synthetic or animal oils, fats or waxes; lecithin, lanolin alcohols, carotene, fragrances, mono or polyhydric alcohols, urea, preservatives and dyes, etc. The formulation is preferred as an oil in water or water in oil emulsion. The content of active compound of the medicament (the content of substances that inhibit the formation of estrogen) can be between 0.0001 and 20% by weight, preferably 0. 6 and 10% by weight, additionally preferably between 1 and 5% by weight. A typical range is from 0.6 to 2% by weight. If the substances are mixed to promote absorption by penetration into the skin, their content can be, when hyaluronidases are used, for example, between 0.01 and 1% by weight, preferably 0.05 and 0.2% by weight; when DMSO is used between 1 and 25% by weight, preferably 5 and 10% by weight. The embodiments of the invention are described below. In the drawing: Figure 1 shows a cytological result of a fat cell aspirate before the use of the drug, according to the invention, Figure 2 shows the corresponding result after daily use during the course of 3 months.

Example 1 The following constituents are mixed to generate a cream: Urea 10 g Titanium oxide 15 g Raw petroleum jelly 20 g Isopropyl palmitate 10 g Hardened peanut oil 10 g Tween 80 5 g Formestane. 1 g constituted with purified water up to 100 g Example 2 A gel is prepared from the following constituents: Ethanol 90% 7.0 g Carbopol® 934 P 7.0 g Triethanolamine 2 g Polysorbate 80 5.0 g Glycerol 3.0 g Formestane 0.75 g purified water up to 100 g Example 3 A cream is prepared from the following constituents: Propylene glycol 25.0 g Isopropyl myristate 6.0 g Sorbitan monostearate 1.0 g Polysorbate 80 2.0 g Cetyl stearyl alcohol 6.0 g Stearyl alcohol 2.0 g Glycerol monostearate 1.0 g Hyaluronic acid 0.1 g Formestane 1.5 g purified water up to 100 g Example 4 A cream is prepared from the following constituents. The constituents are indicated in this example by their INCI names.

INCI Ceteareth-25 3.0 g 2-stearate of PEG-4-polyglyceryl 2.0 g Cetearyl alcohol 4.9 g Petrolatum 10.0 g Perliquid paraffin 3.0 g Sodium carbomer 400 0.14 g Lactic acid 0.02 g Paraffin paraffin 2.0 g Phenoxyethanol, dehydroacetic acid, benzoic acid 0.4 g Perfume 0.08 g formestane 1.5 g constituted with water up to 100 mg The mixture of phenoxyethanol, dehydroacetic acid and benzoic acid mentioned earlier in the formulation can be obtained from Schülke and Mayr under the name EuxylMR K702.

Example 5 A cream is prepared from the following constituents, which are indicated by their INCI names.

INCI Ceteareth-25 3.0 g 2-stearate of PEG-4-polyglyceryl 2.0 g Cetearyl alcohol 4.9 g Petrolatum 10.0 g Perliquid paraffin 3.0 g Sodium carbonate 400 0.14 g Lactic acid 0.02 g Paraffin paraffin 2.0 g Phenoxyethanol, dehydroacetic acid, Benzoic acid 0.4 g Perfume 0.08 g 4-acetilandrost-4-ene-3, 17 -dione (acetylated formestane) 1.5 g constituted with water up to 100 mg Example 6 A clinical test of the recipe is carried out according to Example 1. The effects of excessively developed breasts and mid-grade mastopathy are present in subjects of 25 years of age. A suction is extracted with a fine needle from the fatty tissue (0.6 mm perforation with water, fixation in absolute ethanol, staining: May-Grünwald-Giemsa) (figure 1). Distended fat cells and eccentric cell nuclei are detected as a result of a high flow of estrogen. The subject is then applied the cream according to Example 1 twice a day for a period of 3 months. Figure 2 shows a fat tissue aspirate after this use. A reduction in the volume of fatty tissue ("wrinkled" fat cells in a regular array) and an increase in connective tissue due to the aromatase inhibition is detected. The results show a reduction of the tissue at risk, by approximately 50% and a different feature of the connective tissue and skin.

Claims (7)

1. Use of a spheroidal aromatase inhibitor for the preparation of a medicament formulated for local topical application for the prophylaxis and / or treatment of breast cancer, wherein the medicament does not contain antigestagens.

2. Use as described in claim 1, characterized in that the medicament contains formestane (4-hydroxyandrost-4-ene-3, 17-dione) and / or a pharmacologically active formestane derivative.

3. Use as described in claim 2, characterized in that the medicament contains 4-O-acetilandrost-4-ene-3, 17-dione.

4. Use as described in one of claims 1 to 3, characterized in that the medicament additionally contains substances to promote penetration into the skin.

5. Use as described in claim 4, characterized in that the medicament contains DMSO.

6. Use as described in one of claims 1 to 5, characterized in that the medicament is formulated as an ointment, cream, gel, emulsion or lotion.

7. Use as described in claim 6, characterized in that the content of active compound is

0. 0001-20% by weight, preferably 0.6-10% by weight, still more preferably 1-5% by weight.