HK1018215A - Combined pharmaceutical preparation containing lhrh-analogous substances and antiestrogens for treating gynaecological disorders - Google Patents

Description

Pharmaceutical combination of LHRH-analogues and anti-oestrogens for the treatment of gynaecological disorders

The invention relates to a combined pharmaceutical preparation consisting of LHRH analogues and antiestrogens with tissue-selective estrogenic action, and its use for the treatment of gynaecological disorders, in particular endometriosis and uterine fibroids.

Gynecological disorders and diseases reduce the quality of life of women to a large extent and often lead to intolerable pain and infertility. The most common disease (5% to 10%) in women of childbearing age is endometriosis. Intense pain and reduced fertility and even infertility can therefore occur during the menstruation period. Uterine fibroids are a benign tumor in the musculature of the uterus and have a high incidence (10% to 25% of women around the age of 30). Uterine fibroids can cause very abnormal menstrual bleeding (menorrhagia), painful menstrual bleeding (dysmenorrhea) and intermenstrual bleeding (metrorrhagia and menorrhagia), and depending on the location, can also lead to infertility. In addition to dysmenorrhea due to endometriosis and uterine fibroids, there are dysmenorrhea caused by functional disorders (via hormonal disorders and autonomic nerve disorders).

Among the described conditions, gonadotrophins (estrogens, progestogens) and growth factors (cytokines also belong to this class) which are regulated by the hypothalamic-pituitary system play a decisive role. Hormones such as LHRH-analogues are commonly used to treat these diseases and disorders (Lemay, A. et al, fertility and infertility (Fertil. Steril.), stage 41, page 863-871 (1984)). However, such drugs have side effects in some women. It is known that treatment with LHRH-potentiators may cause side effects such as hypoestrogenism (risk of osteoporosis) (Dawood, M.Y., et al, fertility and infertility (Fertil. Steril.), stage 52, pages 21-25 (1989)), and treatment with danazol may cause androgenic symptoms (Dwowski, W.P., et al, J.Obstet. Gynecol.), stage 130, pages 41-48 (1978)).

So far, no drug long-term treatment method effective on the hysteromyoma is created. The current drug treatment has obvious side effects. The use of LHRH-potentiators for more than 6 months leads to a low estrogenic status in women (Matta, W.H., et al, journal of british medicine (Br.Med.J.), 294, 1523. sup. 1525 (1987)), and thus to a decrease in bone density and an increased risk of osteoporosis (Dawood, M.Y., et al, journal of International gynaecological sciences (int.J.Gynecol.Obstet.), 40, 29-42 (1993)). Other side effects associated with estrogen lowering (Hot-red symptoms) are likewise described in the Dawood literature.

To avoid these side effects, it is known to use LHRH-analogues and estrogens, the so-called increase-return-mode of treatment or HRT-mode of treatment, studies for the treatment of gynaecological disorders. However, no estrogen dose has been successfully found to date which completely avoids the decrease in bone density under LHRH-potentiator-treatment (Howell, R. et al, fertility and infertility (Fertil. Steril.), stage 64, page 474-481 (1995)) without causing stimulation of endometriosis and endometrium, leading to endometrial hyperplasia and associated endometrial cancer.

The object of the present invention is therefore to produce a pharmaceutical combination for the treatment of gynecological diseases, in particular endometriosis and uterine fibroids, which avoids the disadvantages of the prior hormonal therapy and the reduction in bone mass density.

The object is achieved by a pharmaceutical combination which comprises two active substances, wherein the first active substance is an LHRH-analogue or a mixture of LHRH-analogues and the second active substance is an antiestrogen with a tissue-selective estrogenic effect.

LHRH-analogues are LHRH-potentiators or-antagonists.

In the present invention, all LHRH-potentiators and-antagonists can be used. Preferred LHRH-analogues are selected from the group of compounds: leuprorelin, Cetrorelix, ampeptide (Antide), Buserelin, Ramorelix, Zoladex, 2- (4-acetyl-aminophenyl) -4, 7-dihydro-7- (2-methoxybenzyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno- [2,3-b ] -pyridine-5-carboxylic acid ethyl ester, and 5-benzoyl (Benzyol) -7- (2, 6-difluorobenzyl) -4, 7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-propionylaminophenyl) 4-oxothieno [2,3-b ] -pyridine.

The active substances are generally present in separate administration forms or, in the case of orally bioavailable LHRH antagonists, in a combined administration form.

LHRH-analogues which are preferably used are known, from the patent specifications US4,005,063 (leuprorelin), EP-B10299402 (Cetrorelix), GB 1523623 (Buserelin), EP-A0451791 (Ramorelix), WO-A89/01944 (ampeptide), WO-A92/20711(Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys (mor) -D-Ala-NH-D₂) US4,100,274(Zoladex) and WO-A95/284052- (4-acetylaminophenyl) -4, 7-dihydro-7- (2-methoxybenzyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno- [2,3-b]-pyridine-5-carboxylic acid ethyl ester.

They are prepared and packaged in a manner known per se, and may be used as desired for the application in oral or nasal form, as long-acting preparations for injection or topical or intravaginal application. LHRH-analogues can be administered in a single dose or in a long-acting form according to the invention.

Each dosage unit contains a different dosage of the active agent, depending on the form of administration. For example, the LHRH-analogue is generally administered orally in an amount of 2. mu.g to 20mg per kg body weight. The administration can be in solid form or liquid form. The LHRH-like substance is administered by intravenous injection, subcutaneous administration, intramuscular administration, intranasal administration or intravaginal administration in a dosage of 0.02 μ g to 2.5mg per kg body weight. For parenteral administration, preferably isotonic physiological saline or glucose solution is used, which is optionally adjusted to a pH of 5-9, preferably to the pH of the blood, with a buffer.

Leuprorelin is preferably administered orally at a dose of 2-200 μ g/kg body weight (daily dose); each tablet preferably contains 0.1-5.0mg leuprolide. The dosage for parenteral administration is preferably 0.02-1.0. mu.g/kg body weight.

The use of Cetrorelix is preferably in the form of a physiological saline solution containing 0.1-2.5mg/kg body weight of active substance. Slow release dosage forms of ceftorelix are also described in DE 4342092.

Buserelin is preferably applied in the following doses of 0.02-1. mu.g/kg body weight (intravenous), 0.02-2. mu.g/kg body weight (subcutaneous), 0.02-10. mu.g/kg body weight (intramuscular), 0.1-50. mu.g/kg body weight (intranasal) and 10-200. mu.g/kg body weight (oral).

As with Cetrorelix, slow release dosage forms may also be used. When used as an implant, it contains 1-6mg of Cetrorelix.

Zoladex is preferably used in oral doses of 50. mu.g to 20mg/kg body weight and in parenteral doses of 0.2 to 100. mu.g/kg body weight or in slow release dosage forms (WO-A93/24150).

The ampeptide is administered in the same manner as Cetrorelix at a dose of 0.1-2.5mg/kg body weight.

The administration of Ramorelix is preferably in the form of liposomes.

Long-acting dosage forms (microsomes, implants) of peptides are furthermore described in EP 0505966 and EP 0315875.

The second active ingredient of the combined preparation of the invention is an antiestrogen with tissue-selective estrogenic action.

The antiestrogens are particularly useful in the treatment of tumors.

Antiestrogens with tissue-selective estrogenic action are to be understood in the present invention as so-called SERM's (selective estrogen-receptor modulators), the tissues and organs of which selectively act as partially synergistic (partalagoniostisthe) estrogens.

All antiestrogens with tissue-selective estrogenic action can be used according to the invention. Preferably selected from the following group of compounds: raloxifen, Droloxifen, Centchroman or derivatives thereof. Especially preferred are the Raloxifen-type antiestrogens.

The antiestrogens listed above are known. For example, Raloxifen is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl ] benzo [ b ] thiophene. The combination of Raloxifen and derivatives with parathyroid hormone serves to increase bone mass (EP 0635270).

The active substance content of the antiestrogen applied by the invention is 0.1 mu g-10mg/kg body weight according to different daily dosage of administration forms. The antiestrogens can be administered intravenously, subcutaneously, intramuscularly, orally, intranasally or intravaginally. It may also be a slow release formulation. The daily dosage delivered is also within the above ranges.

Administration of the LHRH-analogue and the antiestrogen to the patient may be simultaneous and/or sequential in time. There may be various treatment modes: simultaneous application of LHRH-analogues and tissue-selective antiestrogens during the same period of time. It may be administered daily, every 3 days, weekly or monthly over a period of 1-6 months. Of course, long-term use is also possible. The long acting dosage form is preferably used with monthly administration. 2. First an LHRH-analogue and a tissue-selective antiestrogen are applied simultaneously over a certain period of time. The same applies as for the duration and frequency of administration, as described in method 1, followed by continued treatment with antiestrogens alone.

The same applies to the length of time and frequency of administration of the medicament as described in method 1. 3. The treatment with LHRH-analogues is carried out for a certain period of time and then ended. Followed by the application of tissue-selective antiestrogens. The length of time and frequency of administration of each component can be selected as described in method 1.

It has been determined that: treatment with the combination preparation of the invention surprisingly inhibits the hitherto observed decrease in bone density caused by LHRH-analogues without re-stimulating endometriosis whose growth has been inhibited as well as the growth of normal endometrium.

The pharmaceutical combination according to the invention is particularly suitable for the long-term treatment of endometriosis and uterine fibroids and other steroid (sex) -hormone-related diseases, since on the one hand the side effects normally occurring with LHRH analogs (potentiators and antagonists) can be avoided and on the other hand the lost bone mass can be reconstructed (for example with tissue-selective antiestrogens after the end of LHRH analog treatment). At the same time, the growth inhibition of endometriosis can be ensured without stimulating endometrium.

Method 1 is particularly preferably suitable for long-term treatment.

The preparation method of the pharmaceutical combination preparation of the present invention is, for example: the LHRH-analogues and the antiestrogens with tissue-selective estrogenic action are formulated separately from each other with the usual pharmaceutical carrier substances, adjuvants and/or additives, where the administration forms of the individual active ingredients do not necessarily have to be identical. For example, it is entirely possible to administer one active substance orally and the other subcutaneously or intranasally in a combined preparation.

In the case of oral bioavailability of LHRH-analogues, the two active substances may also be formulated together in an oral dosage form. It may likewise be a separate oral dosage form.

The invention also includes a packaging unit (Verpackungseinheit) which, in the case of peptide LHRH-analogues, comprises at least three components. It contains two spatially separately packaged active substances, one of which is an LHRH-analogue or a mixture of LHRH-analogues and the other of which is an antiestrogen with tissue-selective estrogenic action. The third component is instructions for the simultaneous and/or sequential administration of the administration forms.

Another subject of the invention is the use of LHRH-analogues or mixtures of LHRH-analogues and anti-oestrogens with tissue-selective oestrogenic action for the treatment of gynaecological disorders, in particular endometriosis and uterine fibroids.

The present invention is further illustrated by the following examples, but the contents are not limited thereto. Examples example 1 effect on endometriosis in experimentally generated rats when LHRH and Raloxifen were administered 1.1 comparison of the active substances administered separately and simultaneously (combined preparation) with the active substances:

the endometrial fragments were implanted in different parts of the abdominal cavity of 60 animals, respectively.

The development of endometriosis (cystic endometriotic foci) was examined after 4 weeks.

The animals were then treated with the LHRH-antagonist ampeptide (0.5 mg/animal, administered subcutaneously once every 3 days) and Raloxifen (3 mg/animal, administered orally once daily), either alone or in combination for 4 weeks. Finally, the size of the endometriotic foci before treatment was compared to that after 4 weeks of treatment.

The combined use of LHRH-antagonist plus Raloxifen results in complete degeneration of endometriosis without significant osteopenia. While there was no estrogenic response of the uterus (no stimulation of the endometrium).

In comparison, treatment with LHRH-antagonists alone, while also allowing complete regression of endometriotic foci, also resulted in a decrease in endogenous estrogen levels, comparable to hysterectomy. There is a significant decrease in bone density and an increase in osteoclast activity.

The endometriosis is partially degenerated by administration of Raloxifen alone. 1.2 Simultaneous and chronologic administration of LHRH-antagonist ampeptide and Raloxifen

60 animals were dosed simultaneously with the LHRH-antagonist ampeptide and Raloxifen for the first 2 weeks, followed by Raloxifen alone for 2 weeks. The dosage is selected according to 1.1.

The results, as well as the simultaneous administration of the active substances, showed a complete regression of the endometriotic foci without a significant reduction of bone mass. While there is no estrogenic response in the uterus. 1.3 chronologically administering combinations

The 60 animals were dosed with LHRH-antagonist ampeptide for 2 weeks. Administration of LHRH was followed by administration of Raloxifen for 2 weeks.

This sequential treatment likewise leads to 100% degeneration of endometriotic foci without a decrease in bone density. Example 2

In a manner similar to that of example 1, 40 pairs were preparedAnimals are treated with LHRH-antagonist Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys (mor) -D-Ala-NH₂And Droloxifen.

The same results as in example 1 were obtained.

Claims (15)

1. Pharmaceutical combination comprising two active substances, one of which is an LHRH-analogue or a mixture of LHRH-analogues and the other is an antiestrogen with tissue-selective estrogenic effect.

2. Combination according to claim 1, characterized in that: LHRH-analogues are LHRH-synergists or LHRH-antagonists.

3. According to claim 1 or 2Combined preparation characterized by: LHRH-analogues are selected from the group of compounds: leuprorelin, Cetrorelix, Buserelin, ampeptide, Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys (mor) -D-Ala-NH₂Ramorelix, Zoladex, or derivatives thereof.

4. A combined preparation according to any one of claims 1 to 3, characterised in that: LHRH-analogues or mixtures of LHRH-analogues have oral bioavailability.

5. Combined preparation according to any one of claims 1 to 4, characterized in that: LHRH-analogues are non-peptide LHRH-synergists or LHRH-antagonists.

6. Combined preparation according to any one of claims 1 to 5, characterized in that: the antiestrogen is selected from the group of compounds: raloxifen, Droloxifen, Centchroman or derivatives thereof.

7. Combined preparation according to any one of claims 1 to 6, characterized in that: the antiestrogen is Raloxifen type.

8. Combination according to any one of claims 1 to 7, characterized in that: the two active substances are present in separate administration forms.

9. Combination according to any one of claims 1 to 7, characterized in that: both active substances are present in a common administration form.

10. The preparation method of the drug combination preparation is characterized in that: LHRH-analogues or mixtures of LHRH-analogues and tissue-selectively acting antiestrogens are formulated together or separately from one another with customary pharmaceutical carrier substances, adjuvants and/or additives.

11. The method of claim 10, wherein: LHRH-analogues or mixtures of LHRH-analogues and anti-oestrogens with tissue-selective oestrogenic action are formulated separately from each other.

12. The method of claim 10, wherein: LHRH-analogues or mixtures of LHRH-analogues are co-formulated with anti-oestrogens with tissue-selective oestrogenic action.

Use of LHRH-analogues or mixtures of LHRH-analogues and anti-oestrogens with tissue-selective oestrogenic action for the treatment of gynaecological disorders, in particular endometriosis and uterine fibroids.

14. Use according to claim 13, characterized in that: the administration of the LHRH-analogue and the antiestrogen is carried out simultaneously and/or sequentially in time.

15. A packaging unit containing two spatially separately packaged active substances, wherein one of the active substances is an LHRH-analogue or a mixture of LHRH-analogues and the other active substance is an antiestrogen with tissue-selective estrogenic action, and instructions for simultaneous and/or chronological administration of the dosage form as a third component.