NO790059L - PROCEDURE FOR THE PRODUCTION OF PROSTAGLAND-CONTAINING THERAPEUTIC PREPARATIONS - Google Patents

Description

Process for the production of prostaglandin-containing therapeutic preparations.

The present invention relates to a method for the production of prostaglandin-containing therapeutic preparations, characterized in that prostaglandins are mixed with the hydrogenated starch hydrolyzate and/or non-ionic esters obtained by reacting a triglyceride with a polyalkylene glycol.

Advantageously, it contains hydrogenated starch hydrolyzate

4 to 15% D-sorbitol and at least 85% hydrogenated oligo- and polysaccharides.

Advantageously, esters obtained by reaction between nut kernel oil, almond oil, ground nut oil, olive oil and/or palm oil with polyethylene glycol are used.

Advantageously used as prostaglandin 1a / 15R-dihydroxy-

16, 16-dimethyl-9-keto-2,3-transmethylene-prosta-5-cis-13-trans-dienoic acid or 15-deutero-llxx, 15R-dihydroxy-16, 16-dimethyl-9-keto-2, 3-(-)-trans-methylene-prosta-5-cis-13-trans-dienoic acid.

The preparations are obtained by mixing the prostaglandins with the hydrogenated starch hydrolyzate specified under a) and/or the non-ionic esters specified under b).

The hydrogenated starch hydrolyzate used described under a) is prepared in a manner known per se, e.g. as described in British Patents 1,169,538 and 1,062,283.

A manufacturing method consists in e.g. glucose syrup, corn, potato starch, rice or wheat starch is subjected to an acid and/or enzymatic hydrolysis and the hydrolysis product is reduced at elevated temperature and high pressure in the presence of a nickel catalyst, whereby all free reducing end groups are reduced. The hydrogenated hydrolyzate thus obtained can be a viscous liquid at room temperature, but is preferably a solid powder. The carbohydrate portion is from 2 to 15% D-sorbitol and at least 85% hydrogenated oligo- and polysaccharides. A preferred hydrolyzate is "lycasin" or "polysorb" manufactured by Roquette Freres S.A. Lille, France, especially as "lycasin" 80-55 or "polysorb" 80-83.

The weight ratio between prostaglandins and hydrolyzate is suitably from 1 to 20 to 1 to 500, preferably 1 to 100. The prostaglandins are here in the form of a water-soluble salt, e.g. the trihydroxymethylaminomethane salt. The composition is prepared by dissolving the hydrogenated hydrolyzate in a small amount of distilled water, e.g. 0.5 ml for 20 to 50 mg of hydrolyzate and a solution of the prostaglandin salt in water is added (e.g. 1 mg for 0.5 ml of water) at temperatures between 5 and 50°C, the mixture is adjusted to a pH of 5, 5 to 6 and then freeze-dried. The preparation can be brought in the form of unit doses for enteral administration, e.g. tablets or hard gelatin capsules.

On the other hand, the preparation can also be in powder form.

The non-ionic esters described under b) can be prepared on

in and of itself known way, e.g. as described in US patent 3,288,824. The esters can consist of a mixture obtained by transesterification of two molar parts of triglycerides, e.g. from nut kernel oil, almond oil, ground nut oil, olive oil and/or palm oil, with a molar proportion of polyethylene glycol with a molecular weight of from 200 to 800. These esters are offered on the market under the trade names "Labrafil" (Fiedler, Lexikon der Hilfsstoffe, page 320, 1971 ) and offered by establishment Gattefosse, Boulogne sur Seine, France.

The preferred ester is "Labrafil M 1944CS" (a glyceridoleate-polyoxyethylene mixture). The preferred weight ratio of prostaglandins to nonionic esters is from 1 to 50 to 1 to 500, preferably from 1 to 80 to 1 to 150 and especially

1 to 100. Appropriately, a natural oil is also present, e.g. castor oil, which may contain 80% ricinoleic acid triglyceride and has a specific gravity of 0.954 to 0.964. The weight ratio of ester to natural oil is from 1 to 5 to 1 to 15, suitably from 1 to 10. A solubilizer such as methyl lactate with a specific gravity of about 1.042 may be present, especially when the prostaglandins are in the free acid form. The preferred weight ratio of ethyl lactate to esters is about 1 to 1 and if the above oil is present, the preferred ratio of ester to ethyl lactate to natural oil is about 1 to 1 to 1. The nonionic esters (e.g. 1 mg), the prostaglandins (e.g. 0.2 to 20 mg) and optionally also the natural oil and/or the ethyl lactate can be mixed together at temperatures from - 10 to +50°C and brought in the form of unit doses for enteral or parenteral administration, e.g. in a capsule or preferably, when ethyl lactate is present, as an injection solution or drop solution in an ampoule. If a mixture consisting of a hydrogenated starch hydrolyzate according to a) and a non-ionic ester according to b) is used for stabilization, the weight ratio between a) and b) must be 50-90 to 50-10. The component b) can be partially replaced by ethyl lactate, but the proportion of ethyl lactate must not amount to more than 20% of b). Here too, the weight ratio of the prostaglandins to be stabilized to the mixture of a) and b) should be from 1 to 20, to 1 to 500, preferably 1 to 100.

Prostaglandins are used in the invention in particular

compounds with formula

where A means groups with formulas and B stands for groups with formulas

in which X stands for hydroxy, alkoxy with 1-10 carbon atoms, lysergyloxy, lysergylamino or dihydrolysergylamino, and C stands for a prostaglandin end group.

Y stands for hydrogen, deuterium or alkyl, or the formula in which B, Y and C have the above meaning and and D together either stand for 0 or B is preferably B1 or B4. X is preferably hydroxy or alkoxy. If X stands for alkoxy, this group preferably has 1-4 carbon atoms, in particular X means methoxy or ethoxy. If Y stands for alkyl, the alkyl group preferably has 1-4 carbon atoms.

C is a prostaglandin end group from natural or synthetic prostaglandins. In particular, C can mean a hydrocarbon group that contains up to 16 carbon atoms and, beyond this, optionally also contains cyclic and/or unsaturated groups and/or a heteroatom such as oxygen. Prostaglandin end groups that can be used in the invention include

a) alkyl groups with 1-16 carbon atoms, especially groups with the formula

wherein and R^ independently of each other stand for hydrogen or alkyl with 1-4 carbon atoms,

b) Groups with formula

in which R^ and R_ have the above meaning, Z stands for -CH2~ or -O-, and R^ stands for hydrogen, fluorine, chlorine or trifluoromethyl-,

c) alkenyl groups with 3-10 carbon atoms, or

d) cycloalkyl groups with 3-10 carbon atoms, which are either unsubstituted or can be substituted with alkyl groups

with no more than 6 carbon atoms.

C is preferably Ca), as indicated above. R^ and/or R^,

to the extent that they stand for alkyl, 1 or 2 carbon atoms and in particular they stand for methyl. If one of the substituents R^

and R2 stands for alkyl and the second of these substituents means hydrogen, then the carbon atom located in the 16-position can have R or S configuration.

Compounds of formula I in which A stands for A4 and A7 are preferred. The particularly preferred compounds are 11a > 15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid and 15-deutero-11a,15R -dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid.

The prostaglandin-containing preparation can be examined with regard to storage stability so that the amount of the remaining prostaglandin and the amount of the cleavage products (e.g. prostaglandin A in the case of prostaglandin E) are determined after a storage time of 1 - 6 months at a storage temperature of 50° C. The quantity of the remaining intact prostaglandins can be determined in a manner known per se, e.g. by means of high-pressure liquid chromatography.

In addition to this, the preparations can be tested for their pharmacological effect, e.g. as a uterotonic in the rat uterus after administration of 1 to 100 µg/kg, the onset of a uterine stimulating effect being determined at 30 minute intervals.

The prostaglandin-containing preparations have the same pharmacodynamic effect as the prostaglandins contained therein and the amount of the preparation is chosen so that the amount of prostaglandin actually contained therein is supplied. Usually the daily dose is 0.1

to 20 mg of prostaglandins which are appropriately administered 2 to 4 times daily in a dose of 0.02 to 10 mg.

In the following examples, all temperature indications are given in °C.

EXAMPLE 1:

100 mg of lycasin 05/60 powder is dissolved at 20°C in 0.5 ml of distilled water and the resulting solution is added at the same temperature to a solution of 1.305 mg of lia,15R-dihydroxy-16,16-dimethyl-9-keto-2 ,3-(-)-trans-methyleneprosta-5cis,13-trans-dienoic acid-trishydroxy-methylaminomethane (equivalent to 1 ml of prostaglandin) in 0.5 ml of water. The resulting solution is stirred, adjusted to pH 6 using 0.1N hydrochloric acid and then freeze-dried. This lyophilisate is processed into tablets or capsules.

EXAMPLE 2:

10 mg of 1α /15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid are mixed at 25°C with

a) 1 ml labrafil M 1944 CS or

b) 1 ml of a mixture of labrafil M 1944 CS and castor oil

(weight ratio 1 to 10) or

c) a mixture of labrafil M 1944 CS, castor oil and ethyl lactate (weight ratio 1 to 1 to 1) or d) 1 ml of a mixture of labrafil M 1944 CS and ethyl lactate (weight ratio 1 to 1).

The solution obtained is filled in the case of a) and b) into a hard or soft gelatin capsule or in the case of c) or d) into an ampoule.

Claims (4)

1. Process for the production of prostaglandin-containing therapeutic preparations, characterized in that prostaglandin is mixed with hydrogenated starch hydrolyzate and/or non-ionic esters, which are obtained by reacting a triglyceride with a polyalkylene glycol. 2. Method as stated in claim 1, characterized in that hydrogenated starch hydrolyzate containing 4 to 15% D-sorbitol and at least 85% hydrogenated oligo- and polysaccharides is used. 3. Procedure which. specified in claim 1, characterized in that the esters are obtained by reacting nut kernel oil, almond oil, ground nut oil, olive oil and/or palm oil with polyethylene glycol. 4. Method as stated in claim 1, characterized in that the prostaglandins used are lla-15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5-cis- 13-trans-dienoic acid or 15-deutero-lla, 15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis-13-trans-dienoic acid.