HK1022849A - Compositions comprising cetrorelix acetate for the treatment of female infertility and gonadal protection - Google Patents

Description

Cetrorelix is a decapeptide with a terminal acid amide group used as an acetate salt.

The active substance is intended to be administered subcutaneously at a dose of 0.1 to 20 mg. The aqueous solutions of the decapeptide are unstable, autoclave in the final container is not possible. The decapeptide tends to decompose under arsenic sterilization.

However, the amount of active substance in the solution to be lyophilized is so low that at low concentrations of active substance only a loose fluid is produced on the glass wall of the ampoule after drying the solution free of active substance, which is carried out with the stream of water vapour used for sterilization from the vial. It is therefore necessary to use a scaffolding forming a stable cake. At high concentrations this active substance can be omitted. The following excipients are suitable as excipients: hexite, especially mannitol, glucite, sorbitol, such as D-sorbitol, dulcitol, allyl, sorbitol (for example, D-L-sorbitol), or sorbitol (for example, D- and L-sorific acid), the active substances of which are intended to be used as optical agents (for example, D- and L-sorific acid), which can be used in all solutions, but not in all the above mentioned ones, such as D- and D-for example, D- and L-sorific acid, and sulfitic acid, which can be used in all the solutions, for example, D- and D- and D-for example, and Dulcitol, and L-sorific acid, which are not used in all the solutions mentioned above.

In addition to hexit, other common pharmaceutical excipients can be added, such as amino acids such as alanine, glycine, lysine, phenylalanine, aspartic acid, glutamic acid, leucine, lactose, polyvinylpyrrolidone, glucose, fructose, albumin and equivalent strengthening agents. Urinary and sodium chloride can be used as scaffolding agents. The total amount of such substances in the solution used for freeze drying is, for example, 0-16.9 parts by weight, e.g. 0.1-7 parts by weight, which is more than 1 part by weight. Lyoprophelix contains up to 16.9 parts by weight of total strengthening agents. Lyoprophelix may contain up to 8.9 parts by weight, which is more than 1 part by weight. If the amount of such excipients is greater than or equal to 0.5 parts by weight, then Lyoprophelix may contain up to 0.1 parts by weight of total strengthening agents.

During the development of the lyophilisate, however, it was discovered that the active substance behaved very differently and unpredictably during processing.

For example, from the literature, Powell, M. F.: Pharmaceutical Research, 1258-1263 (8) 1991; Dathe, M.: Int. J. Peptide Protein Res. 344-349 (36)1990; Szejtli, J.: Pharmaceutical Technology International 16-22, 1991 it is known that oligopeptides, especially those with a terminal acid amide function, tend to yellow. This is evident in the rate of filtration during sterile filtration, often even organoleptically, the increased viscosity of such solutions.

Table 1 lists the different results of the first 11 approaches.

The active substance levels vary between 100% and 36%. Tabelle 1:

Cetrorelix-Acetat
Charge	Dosierung	Wirkstoffgehalt %
1	100 µg	100
2	500 µg	100
3	500 µg	90
4	500 µg	36
5	500 µg	100
6	500 µg	85
7	1 mg	80
8	1 mg	100
9	2mg	100
10	2mg	80
11	2mg	100

To avoid this yellowing, the following additives have been used experimentally in the literature:

Organic solvents such as acetonitrile, n-butanol, tertiary butanol, ethanol, isopropanol, octanol and benzyl alcohol are suitable, and salts and buffer solutions such as acetate buffer, citrate buffer, sodium chloride, sodium phosphate, sodium EDTA, sodium bicarbonate, phosphate buffer, guanidine acetate, urea can be used. Other applications include polymers such as gelatine, polyethylene glycol 600, hydroxyethyl starch, polyvinylpyrrolidone, polyvinyl alcohol. Addition of amino acids such as alanine, glycine, lysine, phenylalanine, aspartic acid, glutamic acid and leucine have also been described. Carbohydrates and cyclodextrins such as glucose, lactose, mannitol, sucrose, alpha-, beta-, and gamma-cyclo-dextrins, hydroxypropyl-alpha- and beta-cyclo-dextrins, hydroxyethyl-cyclo-dextrins and methyl-cyclo-dextrins have also been used and tested as filtering aids to prevent the formation of yellow.

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Lyophilisate is used in the treatment of female infertility. One treatment method so far consists of stimulating follicular maturation by human menopausal gonadotropin and then triggering ovulation by administration of human chorion gonadotropin. The resulting ovulation occurred 32 hours later. The resulting eggs are available for extracorporeal fertilization. A disadvantage of this agonist therapy is that up to 10 follicles mature during the stimulation phase. This increased follicular maturation leads to hormone peaks in LH. These peaks result in an early stage of follicular maturation and ovulation at an unforeseen time. This ovulation disorder occurs in about 25% of the treated cases and is a disadvantage because the cycle that shows such an ovulation disorder is lost for the production of eggs and must be repeated for the entire treatment about 1 month later.

Another disadvantage of conventional stimulation therapy is the long duration of 4 weeks of treatment that is necessary to achieve satisfactory suppression. Agonists continue to show hyperstimulation syndrome, in which the follicle cells hypertrophy in 1-2% of cases. The risk of hyperstimulation is particularly high in polycystic ovaries.

The antagonist Cetrorelix has been shown to have the following benefits in this particular treatment:

Example 1 Fertilization disorders:

In addition, in the second phase of therapy, the ovulation initiation phase, HMG can be saved. This is a significant cost advantage of this in vitro fertilization treatment. In vitro fertilization is used, for example, in the presence of a tubal abnormality. For this therapy, it is necessary to monitor the cycle and to determine the time of ovulation as precisely as possible. This has so far been achieved only to a limited extent, as stimulation with HMG/ GHC at the same time has often reduced or prevented the production of LHG-LHG. However, it is possible to achieve the optimal level of hormonal activity by injecting this hormone (HGH) into the body and to reduce the production of estrogen (HGH) and to achieve the optimal level of hormonal excretion (HGH) by injecting it into the body.

The use of an antagonist makes treatment much more successful and safe for the patients.

Example 2 Gonadal protection:

Another application of the Cetrorelix lyophilisate according to the present invention is in the protection of gonads in male patients. The male patients are treated with Cetrorelix lyophilisate as a prophylactic and the activity of the gonads is supported. This makes other harmful noxious agents, such as radiation therapy or cytostatic therapy, have no or only a limited ability to act on the sensitive gonadal tissue.

Example 3 Manufacturing process:

Approximately 1.5 litres of water for injections are introduced into a suitable glass container. 210 g of water for injections are introduced into another glass container and 91.17 g of acetic acid are added. The calculated amount of Cetrorelixa acetate (1.62 - 1.695 g, depending on the batch) is dissolved in the 30% acetic acid produced by stirring. The solution is transferred to the glass container with 1.5 litres of water for injections, 82.2 g of mannitol is added, dissolved and filled with water for injections to 3039 g. Other

Inprozeßkontrollen:
pH-Wert	2,5 - 3,0
Dichte
Brechungsindex	1,227 - 1,340 bei 440 nm und 20 °C

The solution is sterilised by filtration via a suitable membrane filter (pore diameter 0,2 μm) under aseptic conditions. 100 ml of the pre-filter is to be discarded. The filters are to be sterilised with pressurised water vapour. Cetrorelix freeze-dry solution is to be stored protected from recontamination. The solution is to be dosed immediately in DIN 2R colourless, hydrolytic class I vials under aseptic conditions and fitted with sterile freeze-dry caps. The recommended filling amount is 2.0 ml = 2.026 g.

The 2 ml vials were rinsed on a vial washer and dried and sterilised with hot air. The cleaned freeze-drying plugs were autoclaved. The pre-sealed vials were transferred to a freeze-drying system and frozen at a plate temperature of -40 °C. The drying process was carried out by raising the plate temperature from -40 °C to +20 °C. The system was then wiped with sterile nitrogen, the vials were sealed in the system and the plugs were sealed with a lid.

The vials are inspected visually for closure and external defects and any defective vials are sorted and destroyed.

Cetrorelix lyophilisate 1 mg is a white solid freeze-drying cake in a colourless 2 ml vial closed with a grey freeze-drying stopper and a yellow flip-off cap.

Claims (5)

1. Composition containing cetrolelic acetate in the form of a sterile lyophilisate and any excipients for use as agents in conjunction with the treatment of female infertility.
2. Composition containing cetrolexacetate in the form of a sterile lyophilisate and, if necessary, excipients to protect the gonads against germ cell-damaging noxious agents such as radiation and chemotherapy with cyto-statics.
3. Use of cetrolelic acetate as a sterile lyophilisate in combination with the treatment of female infertility.
4. Use of cetreolix acetate as a sterile lyophilisate in combination with the treatment of female infertility as claimed by controlling the timing of ovulation by cetreolix administration during ovarian stimulation treatment by avoiding a pre-ovulatory LH surge and then inducing ovulation by exogenous gonadotropin administration after follicle maturation.
5. Use of cetrorelixa acetate as a sterile lyophilisate to protect gonads against germ cell-damaging noxious agents such as radiation and chemotherapy.