DK155144B - PROCEDURE FOR PREPARING STABLE SOLUTIONS OF A MIXTURE OF HYDROGENERED ERGOTAL CALOIDS AND HEPARIN - Google Patents

Description

in

DK 155144 B

The present invention relates to a process for preparing stable solutions of a mixture of compounds of general formula I

o R, ° "JTT}

C-NH-C

> Ao H «2 hn-y 5 wherein R represents hydrogen or alkyl of 1-4 carbon atoms, methyl, ethyl or isopropyl, R2 represents isopropyl, sec-butyl, isobutyl or benzyl, and X represents hydrogen or methoxy, or salts thereof and heparin or salts thereof, which is characterized by dissolving compounds of formula I or salts thereof and heparin or salts thereof in a mixture of water and aliphatic mono- and / or polyalcohols together with a stabilizer of the class consisting of N- acyl derivatives of aniline, as well as 15 urea and / or mono-calcium di-sodium ethylenediaminetetraacetate and optionally adjust the obtained solution to a pH of 4 - 6.

By combining compounds of formula I, especially dihydroergotamine or salts thereof, e.g. the methanesulfonate, dihydroergovaline or salts thereof, e.g. the methanesulfonate, and 6-nor-6-isopropyl-9,10-dihydro-2'p-methyl-5'a-benzylergopeptin or salts thereof, e.g. the maleate, and heparin or salts thereof, especially the sodium salt, in a pharmaceutical composition, it has not previously been possible to prepare clear solutions that were durable for a long time. The two components together have poor durability in physiologically tolerable solvents or mixtures thereof and react to form a heavy salt.

2

DK 155144 B

This salt formation can, on the one hand, be delayed for some time by using e.g. dihydroergotamine methanesulfonate in the form of a solid solution with collidone, but it cannot be completely suppressed in the long run, a fact which has led to the development of the lyophilisate as a drug form for injection. On the other hand, it is also possible to delay the reaction between the two active substances when selecting a suitable solvent mixture. This is the basis for the development of a composition in the form of a two-chamber syringe. This contains in the separate chambers a solution of compounds of formula I 10 or salts thereof, especially the dihydroergotamine methanesulfonate, respectively heparin or salts thereof, especially heparin sodium. The solutions can be mixed in the syringe and the mixture is durable for a few hours.

It has now been found that solutions of compounds of formula I and heparin can be prepared in a ratio of compounds of formula 15 I (in mg) to heparin (in IU) of 1: 500 - 70,000, preferably of 1: 2000 - 20,000, both of which may be in the form of salts, and keep them stable for a longer period of time if a stabilizing medium is used as a mixture of water and aliphatic mono- and / or polyalcohols with a stabilizer of the class consisting of 20 N-acyl derivatives of aniline, and urea and / or mono-calcium di-sodium ethylenediamine tetraacetate and optionally then adjust the solution to a pH of 4 - 6.

In the stabilizing medium, water with a proportion of 45-72% is used in the aliphatic mono- and / or polyalcohols in a proportion 25 of 28-55% (all calculated on the final volume of the solvent mixture), with alcohols and polyalcohols are used ethanol, propylene glycol, polyethylene glycol (average molecular weight 400), diethylene glycol and glycerol. Combinations of ethanol and triethylene glycol (weight ratio 1: 6 - 10, especially 8) and glycerol and propylene glycol 30 (weight ratio 1: 8 - 12, especially 10) are preferred. Preferred as stabilizers of the class consisting of N-acyl derivatives of aniline are 2- (diethylamino) -N- (2,6-dimethylphenyl) acetate, 2- (butylamino) -N- (2-chloro-6-methylphenyl) acetamide and 2 - (2-diethylamino-acetamido) -m-toluenic acid methyl ester or salts thereof, e.g. the hydrochloride.

35 These substances should be present at a concentration of 1 - 2%, calculated as 3

DK 155144 B

the total weight of the finished preparation. Urea or mono-calcium di-sodium di-ethylenediamine tetraacetate should be present in the mixture in an amount of 2 - 5 mg, calculated on a proportion of 5000 I.E. heparin.

The process of the invention is preferably carried out in the manner that, in the presence of the stabilizer and under protective gas, especially CC> 2, a solution of compounds of formula I or salts thereof, especially dihydroergotamine or salts thereof, in particular the methanesulfonate (mesilate) ) in the alcohol mixture, e.g. in the mixture of glycerol and propylene glycol, then to this solution, also under 10 protective gas, in particular CC₂, is added an aqueous solution of a heparin salt, especially of the sodium salt, and urea and / or mono-calcium di-sodium. -ethylenediamine tetraacetate (commercially under the name "Calcium Titriplex").

The adjustment of the pH of 4-6 in the thus obtained stabilized medium is conveniently made by the addition of organic acids, especially methanesulfonic acid.

Preservatives may be added to the solutions obtained, e.g. chlorocresol or trichloro-tert.butanol in an amount of 0.2 - 1%, calculated on the sut preparation. The obtained solutions are conveniently tapped after sterile filtration under aseptic conditions, preferably under inert gas, in ampoules or disposable syringes. In this form, the stable solutions of compounds of formula I or salts thereof, e.g. the methanesulfonates, maleates or tartrates, and heparin or salts thereof, e.g. the sodium, potassium or calcium salt, long lasting, i.e. for 2 - 5 years. The administration of the thus obtained stable solutions is done by subcutaneous injection, e.g. as described in West German Publication No. 25 54 533.

The invention is further illustrated by the following examples: 4

DK 155144 B

Example 1.

Preparation of a Heparin-Dihydroergotamine Solution for Injection and Containing 5000 I.E. heparin and 0.5 mg dihydroergotamine per ml.

5 a) Preparation of the dihydroergotamine solution.

In a 50 liter stirrer, 18.4 kg of propylene glycol and 1.84 kg of anhydrous glycerol are poured and the mixture is stirred for 10 minutes under CC atmosphere. With further stirring and CC 30 minutes 0.0286 kg of dihydroergotamine mesilate and 0.426 kg * 10 lidocaine hydrochloride to the mixture and dissolve therein.

b) Preparation of hepa ri nless solution.

In a 30 liter stirrer, 18.4 kg of water (for injection use) is poured and stirred for 10 minutes under CC 2 atmosphere. With further stirring and under CC 2 atmosphere, is added over approx. 30 minutes 15 1,898 kg of heparin sodium (corresponding to 285.7 million I.E.) and 0.114 kg of "Calcium Titriplex" (the calcium salt of ethylenediamine tetraacetic acid) and dissolve therein.

(c) Mixing the solutions prepared under (a) and (b).

The solution prepared according to b) is added under CC 2 atmosphere to the solution prepared according to a). Then, the container in which solution b) was prepared is rinsed with 1 kg of water (for injection) and this water is also added to the solution prepared according to a). The combined solutions are stirred for 10 minutes under CC 2 atmosphere (the pH of the combined solutions should be about 5.7 here) and then, with the addition of water (for injection), make up to a final weight of 42,810 kg (equivalent to 40 liters of liquid).

DK 155144 B

D) Filtration.

d.l) Pre-filtration: The pre-filtration is carried out through a membrane filter (0.2 µm - "Ultipor nm Pali").

d.2) Sterile filtration: The solution prepared and pre-filtered according to c) is filtered directly on the bottling machine with CC ^ via a sterilized membrane filtration apparatus (0.2 µm "Ultipor nm Pali") under a pressure of 1.7 bar.

The sterile filtered solution is drained under aseptic conditions into 1 ml ampoules (fill volume 0.8 ml).

Example 2.

Preparation of a heparin-dihydroergotamine solution for injection containing 2500 LE. heparin and 0.5 mg dihydroergotamine per ml.

a) Preparation of the dihydroergotamine solution.

The solution is prepared using the procedure described in Example 1 a) with 15.3 kg of propylene glycol, 1.53 kg of glycerol, 0.03 kg of dihydroergotamine mesilate and 0.32 kg of lidocaine hydrochloride.

b) Preparation of the hepa ri solution.

The solution is prepared using the procedure described in Example 1 b) with 0.997 kg of heparin sodium (corresponding to 150 milliliters I.E.) and 0.12 kg of Calcium Titriplex et al.

c) The solutions prepared according to (a) and (b) are combined, the total solution is stirred for 10 minutes under (X 2 atmosphere (the pH should be about 5.7) and filled with water for injection to a final weight of 32.04 kg.

Claims (8)

A process for preparing stable solutions of a mixture of compounds of general formula I; o «1 fHkrj II U.o. J c — NH-yr x ΓηΊ O. Wherein R represents hydrogen or alkyl of 1-4 carbon atoms, 15 R | represents methyl, ethyl or isopropyl, R 2 is isopropyl, sec-butyl, isobutyl or benzyl, and X represents hydrogen or methoxy, or salts thereof and heparin or salts thereof, characterized by dissolving compounds of formula 20 I or salts thereof and heparin or salts thereof in a mixture of water and aliphatic mono- and / or polyalcohols together with a class stabilizer consisting of N-acyl derivatives of aniline, and in DK 155144 B urea and / or mono-calcium di-sodium. ethylene diamine tetraacetate and optionally sets the solution obtained to a pH of 4 - 6. Process for the preparation of a stable solution according to claim 1, characterized in that one dissolves dihydroergotamine as a compound of formula I or a pharmaceutically tolerable salt thereof and heparin or a pharmaceutically tolerable salt thereof in a mixture of water, aliphatic monohydric acid. and / or polyalcohols, 2- (diethylamino) -N- (2,6-dimethylphenyl) acetamide or 2- (butylamino) -N- (2-chloro-6-methylphenyl) acetamide or 2- (2-diethylamino) acetamide acetamido) -m-toluenoic acid methyl ester or its salts and urea and / or mono-calcium di-sodium ethylenediamine tetraacetate and optionally adjust the solution obtained to a pH of 4-6. Process for the preparation of a stable solution according to claim 1, characterized in that dihydroergovaline and 6-nor-6-isopropyl-9,10-dihydro-2'-3-methyl-5 are used as compounds of formula I 15 α-benzyl ergopeptin or its salts. Process for the preparation of stable solutions according to any one of claims 1 to 3, characterized in that the solution contains compounds of formula I (in mg) and heparin (in IU) in a ratio of 1: 500 - 70,000. Process for the preparation of stable solutions according to any of claims 1-3, characterized in that compounds of the formula I (in mg) and heparin (in IU) are present in a ratio of 0 , 5: 2,500 or 5,000. 5 The solution is filtered directly on the bottling machine with CC ^ via a sterilized 0.2 m membrane filter ("Ultipor um Pali") under a pressure of 1.7 bar. The sterile-filtered solution is drained under aseptic conditions into 1 ml ampoules. Process for preparing stable solutions according to any one of claims 1-3, characterized in that water is present in the stabilizing medium in a proportion of 45-72% and that mono- and / or polyal -The alcohols occur in a proportion of 28 - 55%. DK 155144 B Process for the preparation of stable solutions according to any one of claims Ί - 3, characterized in that the stabilizer is present in a concentration of 1 - 2%, based on the total quantity of the finished solution. Process for the preparation of stable solutions according to any one of claims 1-7, characterized in that as compounds of formula I, dihydroergotamine in the form of methanesulfonate, dihydroergovaline in the form of methanesulfonate and 6-nor-6-isopropyl is used. 9,10-dihydro-2 '(5-methyl-5'o-benzyl-ergopeptin in the form of maleate.