SK283022B6 - Compositions comprising Cetrorelix acetate for the treatment of female infertility and gonadal protection - Google Patents

Abstract

Disclosed is a use of cetrorelix acetate for production of a medicament for treatment of female infertility and gonadal protection.

Description

Technical field

The invention relates to a medicament for the treatment of female infertility and for the protection of the gonads.

BACKGROUND OF THE INVENTION

A known method for treating female infertility is to stimulate the maturation of follicles by administering human menopausal gonadotropin (HMG) and to trigger ovulation by administering human chorionic gonadotropin (HCG). To ovulation, i. j. rupture of ovarian follicles (corpus luteum) occurs 32 hours later. The released egg cells are thus available at a relatively accurate time interval for extracorporeal fertilization.

A disadvantage of this method of treating female infertility is the use of appropriate exogenous antagonists instead of human factors stimulating the development of ovarian follicles and then triggering ovulation, in that up to 10 follicles mature during the stimulation phase. This increased follicular maturation activity results in peak hormone levels of luteinizing hormone (LH). These peak levels of luteinizing hormone triggering ovulation cause disturbances in the ovulation process, with the result that it is not possible to accurately estimate the timing of ovulation. These ovulation disorders occur in 25% of all cases realized. This is disadvantageous since the cycle that exhibits such impaired ovulation is lost to retrieve egg cells, and the further attempt may be repeated about a month later. Another disadvantage of this known stimulatory treatment is the long treatment time required to achieve satisfactory suppression of endogenous luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol. In addition, with the use of antagonists, in 1-2% of cases, a hyperstimulation syndrome occurs in which the follicle cells hypertrophy. The risk of hyperstimulation is particularly high in polycystic ovaries. The hyperstimulatory syndrome is a serious side effect of said treatment of female sterility and in some cases may also lead to the death of the patient.

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that the use of an antagonist which is a sterile lyophilisate of cetrorelix acetate (cetrorelix is an acid amide end group decapeptide: acetyl-3- (2-naphthyl) -D-alanyl-4-chlorophenyl-D-alanyl- 3- (3-pyridyl) -D-allynyl-L-seryl-T-tyryl-N'carbamoyl-D-omityl-L-leucyl-L-arginyl-L-propyl-D-alaninamide) the general disadvantages of using antagonists in the treatment of female infertility. To achieve complete suppression of the endogenous hormone system, only 5 days are sufficient when centrorelix acetate is used. There is no hyperstimulation syndrome when centrorelix acetate is used. In addition, HMG can be saved in the second phase of therapy, the ovulation triggering phase. This is a significant economic factor in in vitro fertilization. For example, in-vitro fertilization is used in the presence of fallopian tube anomalies. In this therapy, it is necessary to regulate the menstrual cycle precisely and, if possible, to precisely determine the ovulation time. Until now, this has been achieved only to a limited extent, given that pre-ovulatory increases in LH levels occurred frequently and early in stimulation. However, suppressing such an early increase in LH is critical to the success of the treatment so that the time of fertilization can be accurately determined. This will also reduce both the physical and psychological burden on patients and utilize optimal clinical logistics. In order to achieve this goal with greater reliability, endogenous hormone production (LH-FSH, estradiol) should be suppressed as far as possible in order to simultaneously stimulate follicular maturation by adding exogenous gonadotropins (HMG / HCG) and regulate hormonal status at any time. . Then, when a sufficiently high number of follicles (4-6) have substantially the same degree of maturation, ovulation is triggered by injecting an HCG bolus.

Another field of application of the sterile lyophilisate cetrorelix acetate is its use for protecting the gonads, especially the male glands. Male patients are pretreated with cetrorelix acetate lyophilisate to support their gonadal function and thus reduce the sensitivity of the gonadal tissue to subsequent radiation therapy or chemotherapy.

The present invention provides the use of cetrorelix acetate lyophilisate for the manufacture of a medicament for the treatment of female infertility and for the protection of the gonads.

The sterile cetrorelix acetate lyophilisate is prepared by dissolving cetrorelix in aqueous acetic acid, then diluting the solution with water for injection and filtering the solution so obtained, filling the vials and lyophilizing. Preferably, cetrorelix acetate is used as the starting product. A 30% by weight aqueous acetic acid solution is preferably used to dissolve the cetrorelix. Preferably, a structuring retention agent is added to the solution during sterilization filtration. Preferably, mannitol, glucide, sorbitol, D-sorbitol, dulcite, allite, idite, urea or sodium chloride are used as the structural retention agent.

Cetrorelix acetate is administered subcutaneously at a dose of 0.1 to 20 mg.

The preparation of sterile cetrorelix acetate lyophilisate using a structuring retention agent (Example 1) will be described below.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

About 1.5 L of water for injection is introduced into one glass container. 210 g of water for injection and 91.17 g of acetic acid are introduced into another glass vessel. The calculated amount of cetrorelix acetate (1.62-1.695 g, depending on the cetrorelix content in the batch used) was dissolved in the 30% acetic acid thus obtained with stirring. The solution thus obtained is transferred to a glass container containing 1.5 liters of water for injection. 82.2 g of mannitol are added. After dissolution, the solution is made up to 3039 g with water for injection. The solution obtained has a pH value of 2.5 to 3.0, a density of 1.009 to 1.017 g / cm 3 at 20 ° C and a refractive index of 1.227 to 1.340 at 440 nm and 20 ° C during the process. Sterilization filtration of the solution is performed by filtration through a 0.2 µm membrane filter under aseptic conditions. Separate 100 ml of the front fraction as an unusable front. The filter is sterilized by pressure steam. The filtrate obtained is dispensed under aseptic conditions into colorless bottles (DIN 2R) of hydrolytic class I and, after lyophilization, they are equipped with sterile freeze-dried plugs. The contents of the vials are 2.0 ml = 2.026 g. Lyophilization of the frozen vial contents was carried out at a temperature of -40 ° C to 20 ° C. The sterilization apparatus is then filled with nitrogen, the vials are sealed with stoppers under a nitrogen atmosphere and fitted with a flanged cap.

Chronic toxicity of cetrorelix acetate lyophilisate

Toxicological studies in rats and dogs (0.02, 0.1 and 0.5 mg / kg s.c.) performed over 26 weeks yielded analogous results that are comparable to those already known during the 4- and 13-week study. In particular, no significant changes in hematological and biochemical parameters were observed. In addition to the histopathological findings described in the 13-week rat study, adrenal and bone findings were found in the 26-week study. Reticular zone atrophy, increased incidence of pigment deposition in the adrenal cortex, and reduced vacuolization of the adrenal cortex were observed. At medium and high doses, limited bone spongiosis can be observed in experimental animals. With the exception of vacuolization in the adrenal cortex, all histopathological findings observed return to baseline after an 18-month recovery period. For the same dose range, 26-week dosing results were obtained in dogs that were comparable to those obtained at 13-week dosing. The most sensitive organs (target organs) were the male and female genital systems, the pituitary gland and injection sites. All changes were perfectly reversible after a 49-month recovery period. This also applies to the functional stage of the tests, which could have been screened by evaluating spermatagrams. Changes in injection sites tended to be reversible. Examination of histological samples and evaluation of spermatograms after a 49-week recovery period showed that there was no atrophy of the target organs due to administration of said lyophilisate.

Teratogenicity and mutagenicity of cetrorelix acetate lyophilisate

The teratogenic risk was tested in rats (HD 0.0464 mg / kg for 10 days) and rabbits (HD 0.0215 mg / kg for 13 days). In gene and chromatosome mutation tests, it was found that cetrorelix acetate lyophilisate had no mutagenic potential.

Claims (2)

PATENT CLAIMS Use of cetrorelix acetate lyophilisate for the manufacture of a medicament for the treatment of female infertility. Use of cetrorelix acetate lyophilisate for the manufacture of a medicament for the protection of the gonads.