FI72045B - FOERFARANDE FOER FRAMSTAELLNING AV EN STABIL LOESNING AV DIHYDROERGOTAMINMETANSULFONAT OCH SODRIUMHEPARINAT - Google Patents

Description

1 72045

Process for the preparation of a stable solution of dihydroergotamine methanesulphonate and sodium heparinate

The invention relates to a process for preparing a stable solution of dihydroergotamine methane-5-sulfonate and sodium heparinate, which solution contains dihydroergotamine (in mg) and heparin (in IU) in a ratio of 1: 500 to 70,000.

By using a combination of dihydroergotamine or its salts, such as methanesulfonate, and heparin or its salts, especially the sodium salt, in a pharmaceutical preparation, it has not hitherto been possible to prepare clear and long-lasting solutions. Both components are poorly stable to each other in physiologically acceptable solvents or mixtures thereof and react to form a poorly soluble salt.

This salt formation, on the other hand, can be slowed by using, for example, dihydroergotamine methanesulfonate as a solid solution with collidone, but over time it cannot be completely prevented, a finding that has led to the development of a lyophilizate as a drug for injection. On the other hand, it is also possible to slow down the reaction of both active ingredients by selecting a suitable solvent mixture. The development of the preparation as a double-chamber injection is based on this feature. It contains, for example, a solution of dihydroergotamine-25 methanesulfonate and a solution of heparin or its salts, in particular heparin sodium. The solutions can be mixed by injection and the mixture is stable for a few hours.

It has now been found that stable solutions of dihydroergotamine methanesulfonate and sodium heparinate containing dihydroergotamine (in mg) and heparin (in IU) in a ratio of 1: 500 to 70,000, preferably 1: 2,000 to 20,000, can be prepared according to the invention. by a method characterized in that dihydroergotamine methanesulfonate is dissolved in propylene glycol and glycerol in the presence of 2- (diethyl-35-amino) -N- (2,6-dimethylphenyl) acetamide and the solution is combined with an aqueous solution of sodium heparinate in the presence of is set to about 5.7.

According to the invention, aliphatic mono- and / or polyalcohols in a proportion of 28-55% (depending on the final volume of the solvent mixture in each case) are used in combination with water in a proportion of 45-72%, in which case ethanol, propylene glycol, for example polyethylene glycol (average-10 average molecular weight 400), diethylene glycol and Gly-serine. Combinations of ethanol and triethylene glycol (weight ratio 1: 6 to 1:10, preferably 1: 8) and glycerin and propylene glycol (weight ratio 1: 8 to 1:12, preferably 1:10) are then preferred. As stabilizers from the 15-group of N-acyl derivatives of aniline, 2- (diethylamino) -N- (2,6-dimethylphenyl) acetate, 2- (butylamino) -N- (2-chloro-6-methylphenyl) acetamide and 2 - (2-Diethylamino-acetamido) -m-toluic acid methyl ester or their salts, for example the hydrochlorides. These substances should be present in a concentration of 1-2%, taking into account the total amount of finished preparation. The urine or monocalcium disodium methylenediamine tetraacetate should be present in the mixture in a proportion of 2 to 5 mg, based on the amount of heparin of 5,000 IU.

The process is preferably carried out by first preparing a solution of dihydroergotamine methanesulfonate (mesilate) in an alcohol mixture, for example a mixture of glycerol and propylene glycol, in the presence of a stabilizer, using a shielding gas, in particular CC4 shielding gas, and finally adding a shielding gas, in particular CC , an aqueous solution of a heparin salt, especially a sodium salt, and a calcium salt of ethylenediaminetetraacetic acid (trade name "Calcium-titriplex").

The pH of the stabilized substance thus obtained is adjusted to 4-6 expediently by the addition of organic acids, in particular methanesulfonic acid.

3 72045

Additional preservatives, for example chlorocresol or trichlorotert-butanol, may be added to the resulting solutions in a proportion of 0.2-1%, taking into account the final composition. The resulting solutions are conveniently filled after sterile filtration under aseptic conditions, preferably under an inert gas atmosphere, into ampoules or disposable syringes. In this form, the stable solutions prepared according to the invention are stable for a longer period of time, i. For 2-5 years. The stable solutions thus obtained are administered by subcutaneous injection as described in DE 2,554,533.

Example 1

Preparation of a solution of heparin (5000 IU) dihydroergotamine (0.5 mg) for injection 15 a) Preparation of a dihydroergotamine-1 run 18.4 kg of propylene glycol and 1.84 kg of glycerin are placed anhydrous in a 50 liter stirrer and the mixture is stirred under a CCl atmosphere. 10 min. I drive. With further stirring and using CC> 2, a shielding gas is added for about 30 min.

20, a mixture of 0.0286 kg of dihydroergotamine esilate and 0.426 kg of lidocaine hydrochloride (2- (diethylamino) -N- (2,6-dimethylphenyl) acetamide hydrochloride) is dissolved and dissolved therein.

b) Preparation of the heparlin-1 run 18.4 kg of water 25 (for injection) are placed in a 30 liter mixer and mixed for 10 min. time in the CO2 atmosphere. With further stirring and using CCl 4 shielding gas, about 30 min is added. containing 1.898 kg of heparin sodium (corresponding to 285.7 million IU) and 0.114 kg of Calcium titriplex (calcium salt of ethylenediaminetetraacetic acid) and dissolved therein.

(c) Mixture of the solutions prepared in (a) and (b)

The solution prepared according to b) is added to the solution prepared according to a) under CCl 4 atmosphere. The vessel in which solution b) was prepared is then rinsed with 1 kg of water (for injection) and this is likewise added to the solution prepared according to a). The combined solutions are stirred for 10 minutes under 4 72045 CO2 (the pH of the combined solutions should then be about 5.7) and then made up to a final weight of 42.810 kg (equivalent to 40 liters of liquid) by adding water (for injection).

5 d) Filtration d ^) Pre-filtration; Pre-filtration takes place through a membrane filter (0.2 μm - Ultipor nm Pali).

d2) Sterile filtration: The solution prepared and pre-filtered according to c) is filtered directly in the filling device 10 using CC> 2, through a sterilized pressure filtration device with a membrane filter (0.2 μm - Ultipor nm Pali) at a pressure of 1.7 bar.

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

15 Example 2

Preparation of a solution of heparin (2500 IU) dihydroergotamine (0.5 mg) for injection a) Preparation of a dihydroergotamine-1 run

The solution is prepared using the method described in Example 1a) and using 15.3 kg of propylene glycol, 1.53 kg of glycerin, 0.03 kg of dihydroergotamine mesilate and 0.32 kg of lidocaine hydrochloride (2- (diethylamino) -N- (2,6-dimethyl- phenyl) -acetamide hydrochloride).

b) Preparation of the heparin solution The solution is prepared using the method described in Example 1b) and using 0.997 kg of heparin sodium (corresponding to 150 million IU) and 0.12 kg of Calciumtitriplex · 6H 2 O.

c)

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

d) Filtration 35 Pre-filtration:

Membrane filter 0.2 nm (Ultipor um Pali) 11

Claims (4)

5 72045 Sterile filtration: The solution is filtered directly into a filling device using CO 2 through a sterilized pressure filtration device with a membrane filter 0.2 μm (Ultipor uin Pali) at a pressure of 1.7 bar. The sterile filtered solution is filled under aseptic conditions into 1 ml ampoules. A process for preparing a stable solution of dihydroergotamine methanesulfonate and sodium heparinate containing dihydroergotamine (in mg) and heparin (in IU) in a ratio of 1: 500 to 70,000, characterized in that the dihydroergotamine methanesulfonate is dissolved in 2-propylene glycol In the presence of N- (2,6-dimethylphenyl) acetamide and the solution is combined with an aqueous solution of sodium heparinate in the presence of monocalcium disodium ethylenediamine tetraacetate and the pH of the combined solutions is adjusted to about 5.7. Process according to Claim 1, characterized in that the solution contains dihydroergotamine (in mg) and heparin (in IU) in a ratio of 0.5 to 2500 or 5000. Process according to Claim 1, characterized in that the stabilizing medium has a water content of 45 to 72% and a propylene glycol / glycerol content of 28 to 55%. Process according to Claim 1, characterized in that 2- (diethylamino) -N- (2,6-dimethylphenyl) acetamide is present in a concentration of 1 to 2%, based on the total amount of the finished solution.