CS277352B6 - Prostaglandin Ei in Forxic Injection - Google Patents

Abstract

The solution relates to an injectable dosage form for human use, which contains 0.01 to 10 mg of prostaglandin Ei in 1 ml of a pharmaceutically acceptable alcohol miscible with water, optionally with the addition of 0.01 to 10% by weight of stabilizers. In clinical practice, the vasodilating effect is mainly used.

Description

The invention relates to prostaglandin E1 in an injectable dosage form for use in human medicine.

Prostaglandins, called tissue hormones, are highly active biological substances that affect most of the body's basal functions. They stimulate the smooth muscle of the gastrointestinal and reproductive system (use as a uterotonic, abortive, induction of labor), relax and contract the smooth muscle of the respiratory system (bronchodilators), significantly affect the cardiovascular system, inhibit fatty acid lipolysis, stimulate gastric juices and in Prostaglandin, Thromboxane and Leukotriene Research, Vol. 14, Chemistry of the Prostaglandins and Leuokotriens (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).

In addition to prostaglandin E _{2, the} use of prostaglandin E 1 is of particular importance in clinical practice. Vasodilation, inhibition of platelet aggregation and stimulation of intestinal and uterine smooth muscle are among the most important effects of prostaglandin E 2. It is indicated for palliative therapy to temporarily maintain patency of the arterial duct before surgery can be performed. The effect on cavernous rafts can be advantageously used in the treatment of erectile dysfunction. The vasodilatory effect can be used in the treatment of all forms of ischemic disease of the lower limbs (see citations above and below) International Conference on Prostaglandins and Related Compounds (Proceedings) Florence (Italy), May 28-June 1, 1990. Fandizone GL, Milan , Italy, 1990. The widespread clinical use of prostaglandin E1 has so far been hampered by its low stability, especially in dilute solutions, especially in the presence of acidic or basic reagents, in which prostaglandin Eg decomposes relatively rapidly under normal conditions (cleavage of the HO group). from carbon 11 - elimination of water) to form prostaglandin A 1 or prostaglandin B 2 (J. Lip. Res. 10, 320 (1969), J. Pharm. Pharmacol. 23, 804 (1971), Prostaglandins 31, 923 (1986)). , J. Pharm.Sci., 62, 576 (1973) However, the relatively good stability of some solutions of prostaglandin Ej at temperatures of -20 ° C is practically impossible from the point of view of wide therapeutic use. of prostaglandin Ε _χ in dilute solutions. E.g. CS AO 191 244 protects the target as a stabilizer, butanol, U.S. Pat. files 3,749,800: 3,833,725. 3,996,962: 4,221,793 and Euro. Pat. Appl. Anhydrous low molecular weight alcohols, polyethylene glycols, glycerol esters, especially triacetin (see also J. Pharm. Sci. 68, 114 (1979)), hydroxylated fatty acid derivatives (U.S. Pat. No. 4,431,833), esters of higher fatty acids. acids with glycerol (Euro. Pat. Appl. 0 183 237 A 2). Significant progress in stabilizing prostaglandin Ej has been made by the use of cyclic carbonate-based solvents, in particular propylene carbonate (U.S. Pat. No. 4,328,245) and dialkyl acetal-based stabilizers such as acetaldehyde-diethyl acetal or benzaldehydeCS 277352 B6

-diethyl acetal (Euro. Pat. Appl. 0 063 367 A 2). Following the prior art, it has now been shown according to the invention that a stable injectable dosage form can be prepared from prostaglandin E in pharmaceutically acceptable alcohols which are miscible with water and optionally with the addition of stabilizers.

The invention relates to prostaglandin E1 in an injectable dosage form containing in 1 ml of a solution of 0.01 to 10 mg of prostaglandin E1 in a pharmaceutically acceptable water-miscible alcohol, optionally with the addition of 0.01 to 10% by weight, of a stabilizer.

According to the invention, the injection solutions are prepared as follows.

The active ingredient prostaglandin E _1r or a stabilizer is dissolved in a pharmaceutically acceptable water-miscible alcohol. The solution is sterilized by membrane filtration and filled into ampoules or vials under aseptic conditions. Pharmaceutically acceptable and water-miscible alcohols are to be understood as meaning ethanol, 2-propanol, 1,2-propanediol, glycerol or mixtures thereof, it being preferred that the water content of the injection solution does not exceed 5% by weight, particularly preferably 0.05% by weight. By adding the prostaglandin stabilizer Ej. based on 1,3-dioxolane derivatives or carboxylic acid orthoesters favorably affects the stability of injectable solutions, the stabilizing effect being greater when anhydrous alcohol is used. Preferably, 2,4-dimethyl-1,3-dioxolane, 2,4,5-trimethyl-1,3-dioxolane, 2-phenyl-4-methyl-1,3-dioxolane is used as the 1,3-dioxolane derivative. or 2-phenyl-4-hydroxymethyl-1,3-dioxolane, which are both well miscible with the pharmaceutically acceptable alcohol and water. Of the carboxylic acid orthoesters, triethyl orthoacetate is preferably used. The stabilizing effect of these compounds is not only in that they remove water from alcoholic solutions of prostaglandin E 2, but they show a strong stabilizing effect on prostaglandin E 2 alone.

The advantages of the injectable dosage form according to the invention are easy and simple preparation, cheap and available solvents and additives (stabilizers), high stability and biological activity of prostaglandin £ 2.

The process according to the invention is demonstrated by means of examples of specific embodiments, which are merely illustrative and in no way limit the scope of the subject matter of the invention.

Example 1 Prostaglandin £ 2 0.010 mg ethanol absolute ad 1,000 ml

In a pre-dried vessel, alprostadil (prostaglandin E2) is dissolved in 90% by volume of absolute ethanol, with a moisture content of max. 0.05%, under intensive protection against moisture, and the volume is made up to volume with ethanol. The solution is filtered under aseptic conditions

CS 277352 B6;

Membrane filter with a pore size of 0.2 .mu.l. Filling into ampoules or vials is performed under protection against atmospheric humidity under aseptic conditions.

The injections thus prepared, stored at 1 to 5 ° C, protected from light, have an expiration date of 1 year.

Example 2 prostaglandin E2,4 dimethyl-1,3-dioxolane ethanol 95%

0.500 mg

5,000 mg to 1,000 ml

Dispense 90% by volume of ethanol with a maximum moisture content of 5% into the vessel, dissolve 2,4-dimethyl-1,3-dioxolane, then prostaglandin and make up to volume with ethanol. The solution is filtered under aseptic conditions with a suitable membrane filter with a pore size of 0.2 .mu.l. It is filled into ampoules or vials under aseptic conditions.

The injections thus prepared, stored at 1 to 5 ° C, protected from light, have an expiration date of 1 year.

Claims (5)

First Prostaglandin E ^ in injectable dosage form, characterized in that it contains from 0.01 to 10 mg of prostaglandin E ₁ in 1 mL of a pharmaceutically acceptable alcohol miscible with water, optionally with the addition of 0.01 to 10% by weight of stabilizers. 2. Prostaglandin E1 in injectable dosage form, characterized in that it contains 0.1 to 5 mg of prostaglandin E1 in 1 ml of solution for injection. 3. Prostaglandin E1 in injectable dosage form, characterized in that the pharmaceutically acceptable alcohol is ethanol, 2-propanol, 1,2-propanediol, glycerol or mixtures thereof containing less than 5% by weight, water preferably below 0.05% mass 4. Prostaglandin Ε _χ in injectable dosage form, characterized in that it contains, as stabilizer, a 1,3-dioxolane derivative, preferably 2,4-dimethyl-1,3-dioxolane or 2-phenyl-4-methyl-1,3-dioxolane preferably in an amount of 0.1 to 5% by weight. 5. Prostaglandin Ε · ^ in injectable dosage form, characterized in that it contains triethyl orthoacetate based on carboxylic acid orthoesters as a stabilizer.