CS276266B6 - Prostaglandin E-based injection form? - Google Patents

Abstract

The present invention relates to an injectable dosage form for human use comprising 0.1 mg to 10.0 mg of dinoprostone in 1 ml of absolute ethanol as an active ingredient, optionally with the addition of 0.08 mg to 16.0 mg, preferably 0.4 mg. mg and 1.6 mg triethylortho-benzoate. The injection form was used as a uterotonic in all stages of pregnancy.

Description

The invention relates to a process for the preparation of an injectable dosage form based on prostaglandin E ₂ (PGE ₂ , generic name dinoprostone), at all stages of pregnancy.

especially for human use as a uterotonic in

Prostaglandins have a wide range of pharmacological properties, including the ability to stimulate organs that contain smooth muscle and modulate the organ's response to other hormonal stimuli (Advances in Prostaglandin, Thromboxane and Leukotriene Research, Vol. 14. Chemistry of the Prostaglandins and Leukotriens (Eds. JE Pike, DR Morton, Jr.), Raven Press, New York (1985), Prostaglandins in Clinical Practice (Eds. WD Watkins, MB Peterson, JR Fletcher), Raven Press, New York (1989)).

These basic properties are the reason why prostaglandins appropriately affect many aspects of physiology. Dinoprostone belongs to a group of naturally occurring substances, it induces rhythmic contractions of the uterus. Unlike the uterotonics oxytocin, it affects the activity of the uterus at any time during pregnancy.

Extensive clinical use of prostaglandin E ₂ has been hitherto an obstacle to its considerable _e n stability, especially in dilute and weakly acidic and basic solutions. In these systems, under normal conditions, PGE ₂ decomposes relatively rapidly (cleavage of the HO group from carbon 11-elimination of water) to form prostaglandin A ₂ (PGA ₂ ) and prostaglandin B ₂ (PGB ₂ ), respectively (J. lip. Res. 10, 320 (1969), J. Pharm. Pharmacol., 23, 804 (1971) However, the good stability of some PGE ₂ solutions at temperatures of -20 ° C is practically impossible from the point of view of wide therapeutic use. stabilization of dilute PGE ₂ solutions: for example, Czech Patent Certificate No. 191 244 protects tertiary butanol as a stabilizer, U.S. Pat. Nos. 3,749,800: 3,833,725: 3,826,823: 3,996,962: 4,221,793 and Euro Pat. polyethylene glycols, glycerol esters, especially triacetin, citric acid triethyl ester, etc. Significant progress has been made in stabilizing PG type E by the use of cyclic carbonate solvents - especially propylene carbonate (Us. Pat. No. 4,328,245) and stabilizers. based on dialkyl acetals of aldehydes such as acetaldehyde diethyl acetal or benzaldehyde diethyl acetal (Euro. pat. appl. No. 0 063 367).

Following this known state of the art, we have _{prepared a pharmaceutical form from PGE 2,} which is well soluble in ethanol, using pharmacopoeial quality ethanol, i.e. with a content of 95%. The stability of the dosage form due to the formation of degradation products (presence of PGA ₂ and PGB ₂ ) was unsatisfactory. In the next phase of development, ethanol of available quality in terms of water content, ie 99.6%, was used. However, even in this case, the formation of degradation products adversely affected the stability of the dosage form. Furthermore, dosage forms with the addition of triethyl orthobenzoate were prepared. Due to the fact that the minimum of excipients is more favorable from the therapeutic point of view, the development of the dosage form was continued only in ethanol solution. Verification experiments have shown that favorable results are obtained using ethanol with a content of 99.95% and appropriate modification of the technology. We have further shown that the stability of the solutions prepared in this way is further improved by the addition of 0.01 to 2.0%, preferably 0.05 to 0.2% of triethyl orthobenzoate.

The above-mentioned disadvantages are eliminated by the prostaglandin E ₂ injectable dosage form according to the invention, the essence of which consists in containing 0.1 mg to 10.0 mg of dinoprostone in 1 ml of the above-mentioned absolute ethanol, optionally with the addition of 0.08 mg to 16 mg of triethyl orthobenzoate.

The injectable dosage form according to the invention is prepared by dissolving the active ingredient dinoprostone or triethyl orthobenzoate in absolute ethanol, effectively protecting the solution from atmospheric moisture, sterilizing it by membrane filtration and filling it into ampoules under protection against atmospheric moisture.

The injectable dosage form of the invention is stable, the method of the invention has been verified by proper stability tests and has been confirmed to solve the quality and stability of the prostaglandin E1 injectable dosage form. In practice, the uterotonic effect was confirmed at all stages of pregnancy when the injectable dosage form was applied in practice.

Clinical validation confirmed the suitability of using a prostaglandin E2-based injectable formulation to terminate pregnancy in the 2nd trimester, to evacuate the uterus during a silent delivery, to induce a stillbirth, and to provoke delivery with premature amniotic fluid discharge at the time of delivery.

The stability of the prostaglandin E ₂ injectable formulation was verified by three-month stability tests at 5 ° C, 25 ° C, 35 ° C, 25 ° C / 40 ° C, 95% RH and 60 ° C. The dosage form was evaluated by an identity test, a prostaglandin E ₂ high pressure liquid chromatography test, a water content test and a sterility test. The results of stability tests were satisfactory in all parameters at temperature loads of 5 ° C and 25 ° C, at higher temperatures the content of active substance decreases. Stability tests have shown satisfactory stability of the dosage form at storage temperatures of 1 ° C to 5 ° C for at least 1 year.

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

Example 1 Dinoprostone 1.0 mg ethanol absolute ad 1.0 ml

90% by volume of absolute ethanol, with a moisture content of max. 0.05%, is measured into a vessel previously dried and further purged with dehumidified nitrogen. While intensively protecting ethanol from moisture by nitrogen saturation, dinoprostone is dissolved and made up to volume with ethanol. The solution is sterilized by filtration through a suitable membrane filter with a pore size of 0.2 .mu.m and under aseptic conditions, and is filled into ampoules under protection from atmospheric moisture.

The injections prepared in this way have an expiration date of 1 year.

stored at 1 ° C to 5 ° C, protected from the worldExample 2 dinoprostone 0.1 mg ethanol absolute ad 1.0 ml

Injections prepared in the same manner as in Example 1 and stored at 1 ° C to 5 ° C, protected from light, have an expiration date of 1 year.

Example 1 and d 3.

dinoprostone 1.0 mg triethyl orthobenzoate 1.0 mg ethanol absolute ad 1.0 ml

90% by volume of absolute ethanol, containing a maximum of 0,05% moisture, is metered into a vessel previously dried and further purged with dehumidified nitrogen. . The solution is sterilized by filtration through a suitable membrane filter □ with a pore size of 0.2 / u and under aseptic conditions, under ampoule it is filled into ampoules. '

The injections prepared in this way, hem, have an expiration date of 1 year.

stored at

Claims (1)

PATENTS. CLAIMS. Injectable dosage form based on prostaglandin E ₂ , characterized in that it contains 0.1 mg to 10.0 mg of dinoprostone in 1 ml of absolute ethanol, optionally _{with the} addition of 0.08 mg to 16.0 mg, preferably 0.4 mg to 1.6 mg triethyl orthobenzoate.