DD141260A5 - METHOD FOR PRODUCING A STABILIZED PROSTAGLANDINE-CONTAINING COMPOSITION - Google Patents

Description

Application s field of the invention

The invention relates to a process for the preparation of a stabilized therapeutic composition containing as active ingredients prostaglandins, in particular prostaglandins of the D, E or I type.

The compositions prepared according to the invention are used as medicaments.

Characteristic of the known technical solutions

It is known from JP-OS J5-0105815 that stabilization of prostaglandins of the Ε-type by means of vegetable oils, for example, sesame oil and / or esters, e.g. Ethyl lactate can be achieved.

Aim of the invention. , '

The aim of the invention is to provide more stable therapeutic compositions containing as active ingredients prostaglandins, in particular of the D, E or I ~ type, with better storage stability.

Explanation of the essence of the invention

The invention has for its object to find stabilizers for prostaglandins with improved stabilizing properties.

According to the invention, a therapeutic composition is prepared in which the prostaglandins present by

a) a hydrogenated starch hydrolyzate and / or

b) stabilizing nicotinic acid esters obtained by reacting a triglyceride with a polyalkylene glycol.

These compositions are obtained by mixing the prostaglandins with the hydrogenated starch hydrolyzate indicated under a) and / or the non-ionic esters indicated under b),

The hydrogenated starch hydrolyzate used according to the invention described under a) is prepared in a manner known per se, e.g. as in the GB-PS Urn. 1 169-538 and 1062283.

One method of preparation consists of, for example, subjecting glucose syrup, corn starch, potato starch, rice starch or wheat starch to acid and / or enzymatic hydrolysis and reducing the hydrolysis product at elevated temperature and pressure in the presence of a nickel catalyst, reducing all free reducing end groups , The hydrogenated hydrolyzate thus obtained may be a viscous liquid at room temperature, but is preferably a solid powder. The carbohydrate compartment is from 4 to 15 % D-sorbitol and at least 85 % hydrogenated oligo- and polysaccharides. A preferred hydrolyzate is Lycasin or Polysorb®, which is offered by Roojiette Fre "res S" A _e Lille, France, in particular Lycasin 80-55 or 80-83 Polysorb® "

The weight ratio of the prostaglandins to the hydrolyzate is suitably from 1 to 20 to 1 to 500, preferably 1 to 100. The prostaglandins are hereby

in the form of a water-soluble salt, for example the trihydroxymetbylaminomethane salt. The composition is prepared by dissolving the hydrated hydrolyzate in a small amount of distilled water, for example 0.5 ml for 20 to 50 mg of hydrolyzate, and a solution of the prostaglandin salt in water (for example 1 mg for 0.5 ml of water). 'is added at temperatures between 5 and 50 ⁰ C, adjusting the mixture to a pH of 5.5 to 6, and freeze-dried thereafter. the composition can then be brought into unit dosage form for enteral administration, for example tablets or hard gelatin capsules. on the other hand, the Composition also be powdery.

The nicnt-ionic esters described under b) can be prepared in a known manner, for example so as in the US-PS Hr _# 3288824 loading

210 ΑΊ7

is written. The esters may consist of a mixture obtained by transesterification of two parts by mole of triglycerides, for example of nut kernel oil, almond oil, ground nut oil, olive oil and / or palm oil, with one mole fraction of polyethylene glycol having a molecular weight of 200 to 800. These esters are marketed under the trade name LABRAFIL (Fiedler, Lexikon der Hilfsstoffe, page 320, 1971) and are offered by the Gattefosse establishment, Boulogne sur Seine, France.

The preferred ester is LABRAFIL M 19 44 CS (a glyceridoleate polyoxyethylene blend). 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 most preferably 1 to 100, conveniently also a natural OeI, for example castor oil, which may contain 80% ricinoleic acid triglyceride and a specific gravity of 0.954 to 0.064, present. The weight ratio of the ester to the natural oil should be from 1 to 1 to 15, suitably from 1 to 10. A solubilizer such as ethyllactate with a spec. Weight of about 1.042 may be present, especially if the prostaglandins are in free acid form. The preferred weight ratio of ethyl lactate to the esters is about 1 to 1, and if the above-mentioned OeI is present, the preferred ratio of esters to ethyl lactate and natural OeI is about 1 to 1 to 1. The nonionic esters (at -

210 477

- s-

For example, 1 rag), the prostaglandins (for example, 0.2 to 20 mg) and optionally also the natural OeIe and / or ethyllactate can be mixed together at temperatures of -10 to + 50 ° C and in unit doses for enteral or parenteral administration / for example in a Capsule or, preferably, if ethyl lactate is present, as an injection solution or dripping solution in an ampoule.

If a mixture consisting of a hydrogenated starch hydrolyzate according to a) and a nonionic ester according to b) is used for stabilization, then the weight ratio of a) to b) should be 50-10 to 50-10. Component b) may be partially replaced by ethyl lactate, but the proportion of ethyl lactate should not account for more than 20% of b). Here again, the weight ratio of the prostaglandins to be stabilized to the mixture of a) and b) should be from 1 to 1 to 500, preferably 1 to 100.

As prostaglandins are used according to the invention in particular compounds of the formula

where A is a group of the formulas

210 477

O "

al

A2

A3

A4

A 5

means, and B for groups of the formulas

COX

bl

B2

or

or

COX

B3

COX

wherein X is hydroxy, alkoxy of 1-10 carbon atoms, lysergyloxy, lysergylaraino or dihydrolysergylamino, and C is a prostaglandin end group.

Y stands for hydrogen, deuterium or alkyl.

or the formula

210 477

II

In which B, Y and C have the above meaning and D ^ and D together either for = o or

OH ^N H

or <or < stand.

B is preferably Bl or B4. X is preferably hydroxy and alkoxy. If X is alkoxy, it preferably has 1-4 carbon atoms, in particular

X is methoxy or ethoxy. If Y is alkyl, then the alkyl group preferably has 1-4 carbon atoms.

  C is a prostaglandin end group of natural or synthetic prostaglandins In particular, C may be a hydrocarbon group having up to 16 carbon atoms and optionally also containing cyclic and / or unsaturated groups and / or a heteroatom such as oxygen Prostaglandin end groups useful in accordance with the invention include ν

a) alkyl groups having 1-16 carbon atoms, in particular groups of the formula

R

C 1

wherein R .. and

independently of one another are hydrogen or alkyl having 1-4 carbon atoms,

b) Groups of the formula

C 2

wherein R ₁ and R _{0 have the} above meaning, Z is -CH- or -O-, and R_ is Wi trifluoromethyl,

or -0 ~, and R_ is hydrogen, fluorine, chlorine or

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

a) cycloalkyl groups having 3-10 carbon atoms, which may either be unsubstituted or substituted by alkyl groups having at most 6 carbon atoms.

C is preferably Ca) as indicated above. R, and / or R "have, if they are alkyl, 1 or 2 carbon atoms, in particular they are methyl. If one of the substituents R ₁ and R _{0 is} alkyl and the other of these substituents is hydrogen, the carbon atom in position 16 may have the R or S configuration.

Preference is given to compounds of the formula I in which A is A4 and A7. The particular preferred connections

These are the 11-, 15-dihydro-16,16-dimetbyl-9-keto-2,3- (-) - trans-nietbylene-prosta-5α-si-13-trans-dienoic acid and the 15-deutero-HgC, I ^ Rd-ibyäroxy-i6,16-dime-t-butyl-9-keto-2,3 - (-) - trans-methylene-prosta-5cis, i3trans-dienoic acid.

The prostaglandin-containing composition can be tested for storage stability by determining the amount of remaining prostaglandin and the amount of decomposition products (for example, prostaglandin A in the case of prostaglandin E) after a storage period of 1 to 6 months at a storage temperature of 50 ^° C. , The amount of remaining intact prostaglandin can be determined in a manner known per se, for example by means of high-pressure liquid chromatography.

Moreover, the composition can be assayed for its pharmacodynamic action, for example, as uterotonicum in rat uterus after administration of 1 to 100 / g / kg, with the occurrence of an uterine stimulating effect being determined every 30 minutes.

The prostaglandin-containing compositions have the same pharmacodynamic effect as prostaglandins contained therein, and the amount of the composition should be selected to administer the amount of prostaglandin actually contained therein. In general, the daily dose should be from 0.1 to 20 mg of prostaglandins, conveniently administered 2 to 4 times a day in doses of 0.02 to 10 mg,

embodiment

The invention will be explained in more detail below on some embodiments.

In the following examples, the temperatures are given in degrees Celsius.

210 477

- ΛΟ -

100 mg Lycasin 05/60 powder are dissolved at 20 ° in 0.5 ml of distilled water and the resulting solution at the same temperature with a solution of 1.305 mg lla, 15R ~ dihydroxy-16,16-dimethyl-9-keto ~ 2 , 3- (~) -trans-methylenprosta-5cis, 13trans-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 a 0.1N hydrochloric acid and then freeze-dried. This lyophilisate is made into tablets or capsules.

10 mg of llcc, 15R-dihydroxy-16,16-diirethyl-9-keto-2,3- (-) trans-methylene-prostac-5-cis, 13-trien ~ dienoic acid are carried at 25 °

a) 1 ml Labrafil M 1944 CS or

b) 1 ml of a mixture of Labrafil M 194 4 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 ία) 1 ml of a mixture of Labrafil M 194 4 CS and ethyl lactate (weight ratio 1 to 1)

mixed. 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)

2ί0 477 Claim for invention 1, A process for the preparation of a stabilized therapeutic composition containing as active ingredient a prostaglandin, characterized in that. the prostaglandin is mixed with a hydrogenated starch hydrolyzate and / or nonionic esters obtained by reacting a triglyceride with a polyalkylene glycol, 2. The method according to item 1, characterized in that one uses a hydrogenated starch hydrolyzate containing 4-15 % D-sorbitol and at least 85 % hydrogenated oligo- and polysaccharides, 3. The method according to item 1, characterized in that one uses non-ionic esters, which are obtained by reacting nut oil, almond oil, ground nut oil, olive oil and / or palm oil with Polyathylenglykol. 4, Method according to points 1 to 3, characterized in that as prostaglandin Ho. .., 15R-dihydroxyi6, i6-dimethyl-9-keto-2,3 - (-) ~ trans ~ methylene-prosta-5 -cis ~ 13, ~ trans ~ dienic acid used.