CS276790B6 - Injectable dosage form based on the luteolytically active prostaglandin analogue F2 alpha - Google Patents

Abstract

The solution relates to an injectable dosage form for veterinary use, which contains as an active substance 100 to 300 Aig of the optically active d-isomer of 16-3-chlorophenoxy-9Λ, 11 dS , 15-trihydroxy-17,18,19,20-tetranor-5- -cis-13-trans prostadienoic acid (generic name cloprostenol), y acetate buffer with a pH value of 5.5 to 6.5 and 0.5 to 2.5 mg of alkylchlorophenol and water for injection to a total volume of 2 ml. The injectable dosage form is used in the synchronization of farm animals, induction of parturition in sows and treatment of a number of pathological conditions of the genital organs in cattle.

Description

The invention relates to an injectable dosage form of a luteolytically active prostaglandin analogue

F_ . „ containing as active substance the optically active d-isomer 16-/3-chlorophenoxy/Z ail and *

-9 £ , 11 X, 15-trihydroxy-17,18,19,2D-tetranor-5-cis-13-trans-prostadioic acid (generic name cloprostenol) of formula la, which

It is used in veterinary medicine, especially in synchronizing estrus in livestock, inducing parturition in sows, and in treating a number of pathological conditions of the genital organs in cattle.

Of the many injectable dosage forms used so far, the preparation Estrumate by ICI (G. 8. pat. file 1 350 971, A0 204 595, A0 204 594) and Oestrophane R Spofa containing a mixture of d,l-isomers of cloprostenol as the active substance have found wide application in veterinary medicine. Recently, intensive research has shown (Biologization and Chemization of Animal Production, Veterinaria: XXIV/III, (3), 217 (1988) and XXV/XXXI (4), 293 (1989), Cs. pat. file 26 59 47) that only the optically active d-isomer of cloprostenol of formula la has a high specific luteolytic effect, while its optically active 1-isomer of formula Ib acts as its antagonist, i.e. exhibits a luteotropic effect. It is therefore obvious that to achieve the desired effect of estrus synchronization in heifers and cows, it is necessary to apply a relatively (several times) higher single dose of a preparation containing a mixture of d,l-isomers of cloprostenol of formula I. This fact, although the active substance is relatively quickly degraded in the organism, has the following consequences: an adverse effect on the animal (the cow, heifer and weaker animals sometimes experience sweating and trembling); and, moreover, the first milking in milk residues are present in concentrations of about 0.1 µg/ml. Another disadvantage of the injectable dosage form according to patent documents GB 1 386 146, Ger. Offen 2 223 365, GB 1 ³⁵⁰ 971) containing a mixture of d,l-isomers of prostaglandin analogues Fj _and ^f _and as an additional buffering component phosphate buffer without preservative is that they show limited stability.

A significant improvement is achieved by an injectable dosage form containing as active substance only the optically active d-isomer (formula la) in a citrate buffer environment and in the presence of a preservative of the chloroalkylphenol type.

These known facts are positively followed by the injectable dosage form according to the invention, which substantially limits (reduces) or eliminates the above-mentioned shortcomings.

Injectable dosage form according to the invention, the essence of which is that sodium acetate and acetic acid are dissolved in water for injection. The pH value is adjusted with sodium acetate solution or acetic acid as needed. After dissolving the active ingredient d-cloprostenol, the solution is sterilized by membrane filtration and filled into ampoules or vials.

The injectable dosage form according to the invention is stable, the method according to the invention has been successfully verified by proper stability tests and has been confirmed to solve the problem of quality and stability of the injectable dosage form based on cloprostenol. When applying the injectable dosage form in practice, the effect in controlling the ovarian functions of farm animals has been confirmed. The method according to the invention is simple and the quality of the injections obtained allows for production and possible export.

The following examples of embodiments of the injectable form according to the invention only illustrate, but do not limit it.

EN 276 790 B6

7.5 grams

60.05 grams

558.95g

100.0 g ad 100.0 1

Example 1 d-cloprostenol acetic acid sodium acetate 2-chloro-5-methylphenol water for injections

In about 90 l of water for injections, 2-chloro-5-methyl-phenol, sodium acetate and acetic acid are dissolved. The pH is adjusted with sodium acetate solution or acetic acid, in the pH range of 5.5 to 6.5, preferably 5.9 to 6.1. The desired volume, i.e. 100 l, is made up with water for injections. A part of this solution (buffer) is taken and the active substance is dissolved in the remaining volume of the buffer and the desired volume is made up with buffer. The solution is sterilized by filtration through a membrane filter with a pore size of 0.2 μ and filled into ampoules or vials under aseptic conditions.

Injections prepared in this way, stored at a temperature of 10 to 25 °C and protected from light, have a shelf life of at least 2 years.

Example 2 d-cloprostenol 5.0 g acetic acid 60.05 g sodium acetate 1,558.95 g 2-chloro-5-methyl-phenol 125.0 g water for injection ad 100.0 1 Injections prepared in the same manner as in Example 1 and stored at room temperature stored at 10 to 25 °C, protected from light, have a shelf life of at least 2 years.

Example 3 d-cloprostenol 5.0g acetic acid 60.05 grams sodium acetate 1,558.95 grams 2-chloro-5-methyl-phenol 25.0g water for injection ad 100.0 1

Injections prepared in the same manner as in Example 1 and stored at a temperature of 10 to 25 °C, protected from light, have a shelf life of at least 2 years.

Example 4 d-cloprostenol 15.0 grams acetic acid 60.05 grams sodium acetate 1,558.95 grams 2-chloro-5-methyl-phenol 125.0g water for injection ad 100.0 1

Injections prepared in the same manner as in Example 1 and stored at 10 to 25°C, protected from light, have a shelf life of at least 2 years.

Example 5 d-cloprostenol 15.0 grams acetic acid 60.05 grams sodium acetate 1,558.95 grams 2-chloro-5-methyl-phenol 25.0g water for injection ad 100.0 1

Injections prepared in the same manner as in Example 1 and stored at 10 to 25°C, protected from light, have a shelf life of at least 2 years.

Claims (3)

PATENT CLAIMS An injectable dosage form based on the luteolytically active prostaglandin analog F 1, 2 and 11, characterized in that it contains 100 to 300 μg of the optically active d-isomer of 16- (3-chlorophenoxy) -9cC, cheekium, 15-trihydroxy -17,18,19,20-tetranor-5-cis-13-transprostadienoic acid (generic name cloprostenol) of formula Ia. OH 1a in acetate buffer at pH 5.5 to 6.5 and 0.50 to 2.50 mg of alkyl chlorophenol and water for injection to a total volume of 2 ml. 2. An injectable dosage form according to claim 1, characterized in that it contains 125 to 175 [mu] g of the optically active d-isomer of cloprostenol of the formula I in 2 ml of solution for injection. 3. The injectable dosage form according to item 1, characterized in that it contains 2-chloro-5-methylphenol as an preservative in an amount of 0.5 to 2.5 mg in 2 ml of solution for injection.