CS277085B6 - Luteolytically active prostaglandin analogue dosage form - Google Patents

Abstract

The solution relates to an injectable dosage form for veterinary use, which contains as an active substance 100 to 300 pg of the optically active d-isomer of 16 - 3 - chloro - phenoxy- - 9a, 11a, 15-trihydroxy-17,18,19,20-tetranor-5 - cis — 13 - trans prostadienoic acid (generic name cloprostenol), in a citrate buffer with a pH of 5.5 to 6.5 in the presence of 2 to 4 mg of a preservative based on alkyl esters of 4-hydroxybenzoic acid and water for injection to a total volume of 2 ml. The injectable dosage form is used in the synchronization of estrus in 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 luteolytically active optically active d-cloprostenol of the general formula Ia, which is used in veterinary medicine, in particular in oestrus synchronization.

.farm animals, induction of farrowing in sows and treatment of a number of pathological conditions of the genital organs in cattle. From the series of injectable dosage forms used so far, the preparation Estrumate by ICI / GB pat.spis has found wide application in veterinary medicine. 1 350 971, MS. Authorial Certificates No. 204595 and No. 204594 / and Oestrophane ^R Spofa containing as active ingredient a mixture of d, 1-isomers of cloprostenol. Recently, it has been proven by intensive research / Biologization and chemicalization of animal production, Veterinarian XXIV / XXX, / 3 /, 217/1988 / and XXV / XXXI / 4 /, 293/1989 /, Cs. Pat. Are you sleeping. 26 59 47 / that only the optically active d-isomer of cloprostenol of formula Ia has a high specific luteolytic effect, while its active 1-isomer of formula 1b acts as its antagonist, i.e. it has a luteotropic effect. It is thus clear that in order to achieve the desired effect - synchronization of oestrus in heifers and cows - it is necessary to apply a relatively / several times / higher single dose of a preparation containing a mixture of d, 1-isomers of cloprostenol of formula I. This fact, although the active substance is relatively fast in the body degraded, results in an adverse effect on the animal / cow, heifer and in weaker pieces sweating and trembling / and in addition, during the first milking in the milk is present residues in concentrations of about 0.1 μg / ml. Another disadvantage of the injectable dosage form according to GB 1 386 146, Ger. Offen 2 223 365, GB1350 971 / containing a mixture of d, 1-isomers of prostaglandin analogues F _{2 and} if _a and as additional buffering components phosphate buffer without preservative is that they show limited stability.

Substantial improvement is achieved by using an injectable dosage form containing as active ingredient only the optically active d-isomer of formula Ia in a citrate buffer medium and in the presence of a preservative of the chloroalkylphenol type. The preservative p-chloro-m-cresol used in this case irritates the mucous membranes and the skin and can act as a sensitizer (see J. Marhol in the book: Review of Industrial Toxicology, Organic Substances, Volume 1, p. 528, Avicenum Prague 1986, N.I. Sax in the book: Dangerous Properties of Industrial Materials, 5th edition, p. 490, Van Nostrand Reinhold Co., New York 1979 /, is therefore disadvantageous from the point of view of occupational safety in the preparation of injectable solutions and the use of higher doses in injectable dosage form. These known facts are followed in a positive sense by the injectable dosage form according to the invention, which substantially reduces or eliminates the above-mentioned drawbacks.

An injectable dosage form according to the invention, which consists in dissolving in water for injection a preservative based on alkyl esters of 4-hydroxybenzoic acid and sodium hydroxide and citric acid. The pH is adjusted as needed with sodium hydroxide solution or citric acid solution. After dissolving the active substance d-cloprostenol, the solution is sterilized by membrane filtration and filled into ampoules or vials.

The injectable dosage form of the invention is stable, the method of the invention has been successfully verified by proper stability tests and has been confirmed to solve the quality and stability problem of cloprostenol-based injectable dosage form. The effect of controlling the ovarian function of livestock has been confirmed in practice when administering the injectable dosage form. The method according to the invention is simple and the quality of the obtained injections allows the production and possible export.

The following exemplary embodiments of the injectable dosage form of the invention merely illustrate, but do not limit.

Example 1 d-cloprostenol 7.5 g citric acid 995.0 g sodium hydroxide 500.0 g 4-hydroxybenzoic acid methyl ester 180.0 g 4-hydroxybenzoic acid propyl ester 20.0 g water for injection ad 100.0 l

A conversing agent based on alkyl esters of 4-hydroxybenzoic acid is dissolved in about 90 l of water for injection at a higher temperature, preferably 90 ° C + 5 °, then the solution is cooled, preferably to 20 ° C, + 5 ° C, the hydroxide is dissolved. sodium and citric acid. The pH is adjusted with a sodium hydroxide solution or a citric acid solution in the range of pH 5.5 to 6.5, preferably 5.9 to 6.1. Make up to the required volume with water for injections, ie 100 1. A part of this solution (buffer) is taken and the active substance is dissolved in the remaining volume of buffer and made up to the required volume with buffer. The solution is sterilized by filtration through a membrane filter with a pore size of 0,2 μ and aseptically filled into ampoules or vials. ‘

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

Example 2 d-cloprostenol 5.0 g citric acid 955.0 g sodium hydroxide 500.0 g 4-hydroxybenzoic acid methyl ester 100.0 g water for injection ad 100.0 l

Injections prepared in the same way as Layout 1 and stored at a temperature of 10 to 25 cm have a shelf life of at least 2 years.

Example 3 d-cloprostenol 5.0 g citric acid 955.0 g sodium hydroxide 500.0 g 4-hydroxybenzoic acid methyl ester 200.0 g water for injection ad 100.0 l

Injections prepared in the same way as Layout 1 and stored at a temperature of 10 to 25 cm have a shelf life of at least 2 years.

Example 4 d-cloprostenol. 15.0 g citric acid 955.0 g sodium hydroxide 500.0 g 4-hydroxybenzoic acid methyl ester 100.0 g water for injections ad 100.0 1

Injections prepared in the same way as 1 and stored at a temperature of 10 or 25 have a shelf life of at least 2 years.

as indicated in ° C, protected from light as indicated in ° C, protected from light as indicated in ° C, protected from light i «*

CS 277085 B6 4

Example 5 d-cloprostenol 15.0 g citric acid 955.0 g sodium hydroxide 500.0 g 4-hydroxybenzoic acid methyl ester 200.0 g water for injection ad 100.0 l

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 a luteolytically active prostanglandin analogue, characterized in that it contains 100 to 300 μg of the optically active d-isomer of 16- / 3-chlorophenoxy-9a, 11α, 15-trihydroxy-17,18,19,20-tetranor. -5-cis-13-trans prostadienoic acid (generic name cloprostenol) of formula Ia 0H 1a in citrate buffer pH 5.5 to 6.5 in the presence of 2 to 4 mg of a preservative based on alkyl esters of 4-hydroxybenzoic acid and water for injection in a total volume of 2 ml. Injectable dosage form according to Claim 1, characterized in that it contains 125 to 175 μg of the optically active d-isomer of cloprostenol of the formula Ia in 2 ml of solution for injection. Injectable dosage form according to Claim 1, characterized in that it contains 2 to 4 mg of methyl or propyl 4-hydroxybenzoate, in the case of a mixture thereof, in 2 ml of an injectable aqueous solution.