CS205023B2 - Process for preparing stable solutions of hydrogenated ergot alkaloids - Google Patents

Abstract

STABLE SOLUTIONS AND PROCESSES FOR THEIR PREPARATION Solutions of hydrogenated ergopeptide alkaloids in pharmacologically acceptable organic solvents have improved stability. Preferred solvents are alcohols, particularly mixtures of ethanol and propylene glyool.

Description

The present invention relates to a process for the preparation of stable solutions of hydrogenated ergot alkaloids and their synthetic derivatives, as well as their salts, wherein pharmacologically acceptable organic solvents or mixtures thereof are used as stabilizers.

The object of the invention is a process for preparing stable solutions of hydrogenated ergot alkaloids or synthetic derivatives thereof, e.g. The pharmacologically acceptable organic solvents use pharmacologically acceptable mono- and / or polyhydric alcohols, for example ethanol, propylene glycol and / or glycerin, and optionally up to 40% by weight of water.

According to the invention, pharmacologically acceptable monovalent alcohols having, for example, at most 18 carbon atoms, preferably at most 10 atm, can be used as pharmacologically harmless organic solvents which simultaneously serve as stabilizers. in particular not more than 3 carbon atoms. Of these alcohols, ethanol is particularly preferred. Furthermore, pharmacologically acceptable polyhydric alcohols having a maximum of 6, in particular 2 or 3 hydroxyl groups and a maximum of 6, in particular 2 or 3 carbon atoms, in particular glycerin and propylene glycol, can also be used according to the invention. but also polyhydric alcohols in the form of pharmacologically harmless polyalcohols, preferably polyalkylene glycols, in particular polyethylene glycol and / or polypropylene glycol, or mixed polymers thereof having a molecular weight of from 200 to 20,000, in particular from 200 to 600. polyethylene glycol having a molecular weight of 400.

The abovementioned monovalent and polyhydric alcohols may be used according to the invention either alone or preferably in the form of mixtures thereof. If any of these monovalent or polyhydric alcohols is used. - a temperature - a solid, an alcohol which is liquid at this temperature is expediently used as an additional solvent.

When using a mixture consisting of a monovalent and polyhydric alcohol, for example a mixture of -ethanol and propylene glycol, the monovalent and polyhydric alcohols should be present in a weight ratio of from 1: 0.1 to 100, in particular from 1: 2.

The solutions may, of course, contain several monovalent and / or polyhydric alcohols.

The stabilized solutions produced according to the invention may further comprise. _: As additives pharmacologically · acceptable organic esters and ethers, in particular the above-mentioned monohydric and polyhydric alcohols with fatty acids containing from 12 · to 18 carbon · atoms, · as stearic acid, palmitic acid and oleic acid, or · fatty alcohols having 12 to These include, for example, lauryl alcohol, cetyl alcohol and stearyl alcohol.

The stabilized solutions produced according to the invention may also contain a small amount of water, but the proportion of water must not exceed 40% by weight, in particular not more than 3% by weight of the total weight of the mixture.

Hydrogenated ergot alkaloids and their synthetic derivatives which are useful according to the invention are, for example, dihydroergotamine, dihydroorgocristine, dihydroergocryptine, dihydroergocornine, and mixtures thereof, in particular a mixture of dihydroergocristine, dihydroergocryptine and dlhydroergocornine (1: 1: 1). Suitably, salts with non-toxic acids such as methanesulfonates, maleates, tartrates etc. are used as salts.

Although the concentration of hydrogenated ergot alkaloids and their synthetic derivatives - and their salts in solutions - is not critical, it is recommended to use solutions with an active compound concentration of 0.1 to 1% by weight, preferably 0.1 to 1% by weight. 0.5 weight percent. It goes without saying that the concentration used depends on the particular application.

In addition, solubility aids, for example acids, in particular acids, methanesulfonic acid, maleic acid, tartaric acid, etc. may also be used in the preparation of the solutions.

The stable solutions produced according to the invention are conveniently prepared by dissolving the hydrogenated ergot alkaloids and their derivatives or their salts, as well as methergin or its salts, in one of the abovementioned solvents or mixtures thereof, suitably in an inert gas atmosphere, e.g. nitrogen, conveniently avoiding daylight at room temperature (15-25 ° C), with stirring.

The preparation of the solvent mixtures is carried out in a manner known per se, it being convenient to prepare the mixtures. % of solvents at higher temperatures, ie. temperatures up to about 80 ° ^C, if any of the components of the solvent at room · solid. The ratios in which the individual components are present in a mixture with one another are not critical. Preferably, ethanol is selected as a component of the mixture, although this is not absolutely necessary.

Example 1

Prepare a sc mixture of 50.0 g propylene glycol and 41.9 g ethanol (94% pure) and dissolve 0.1 g of a mixture of dihydroergocristin, dihydroergocryptine and dihydroergocornine in the mixture under stirring and under nitrogen atmosphere at room temperature. (1: 1: 1). After pressure filtration, filling into dropper bottles is performed.

Example 2

A mixture of 40.0 g of propylene glycol, 34.0 g of ethanol (94% pure) and 25.0 g of anhydrous glycerin is prepared and dissolved in this mixture at room temperature under stirring and under a nitrogen atmosphere. 1 g of a mixture of dihydroergocristine, dihydroergocryptine and dihydroergocarnine (1: 1: 1). After pressure filtration, filling into dropper bottles is performed.

Example 3

A mixture of 50.0 g of propylene glycol and 41.9 g of ethanol (94% pure) was prepared and 0.1 g of dihydroergotamine methanesulfonate was dissolved at room temperature under stirring and under nitrogen. After pressure filtration, filling into dropper bottles is performed.

Example 4

A mixture of 330 g of propylene glycol, 280 g of ethanol (94% pure), 206 g of anhydrous glycerin and 188 g of water (demineralized) is prepared, and 1.0 g of the mixture is dissolved in this mixture while stirring under a stream of nitrogen. dihydroergocristine methanesulfonate, dihydroergocryptine and dihydroergocornine (1/1/1). After pressure filtration, filling into dropper bottles is performed.

Example 5

A mixture of 293 g of propylene glycol, 249 g of ethanol (94% pure), 183 g of anhydrous glycerin and 282 g of water (demineralized) is prepared, and 2.0 g of dihydroergotamine methanesulfonate are dissolved in this mixture while stirring under a stream of nitrogen. After pressure filtration, filling into dropper bottles is performed.

Example 6

A mixture of 255 g of propylene glycol, 216 g of ethanol (94% pure), 159 g of anhydrous glycerin and 382 g of water (demineralized) is prepared, and 1.0 g of a mixture of methanesulfonates is dissolved at room temperature under stirring and nitrogen flow. dihydroefgocritin, dihydroergocryptine and dihydroergocornine (1/1/1). After pressure filtration, filling into dropper bottles is performed.

Example 7

A mixture of 268 g of propylene glycol is prepared,

227.70 g of ethanol (94%, pure), 167.60 g of anhydrous glycerin and 335.70 g of water (demineralized), and 1.0 g of the methanesulfonate mixture are dissolved at room temperature with stirring and under a stream of nitrogen. dihydroergocristine, dihydroergocryptine and dihydroergocornine (1/1/1). After pressure filtration, filling into dropper bottles is performed.

Example 8

A mixture of 245.80 g propylene glycol, 261.60 g ethanol (94% pure), 245.80 g anhydrous glycerin and 245.80 g water (demineralized) is prepared and dissolved in this mixture while stirring under a stream of nitrogen at 1.0 g of a mixture of dihydroergocristine, dihydroergocryptine and dihydroergocornine methanesulfonates (1/1/1). After pressure filtration, filling into dropping vials is performed.

Example 9

A mixture of 350.70 g of propylene glycol, 297.80 g of ethanol (94%, pure), 219.0 g of anhydrous glycerin and 131.5 g of water (demirallized) is prepared and dissolved in this mixture with stirring and under a stream of nitrogen. at room temperature, 1.0 g of a mixture of dihydroergocrystine, dihydroergocryptine and dihydroergocornine methanesulfonates (1/1/1). After pressure filtration, filling into dropper bottles is performed.

Example 10

A mixture of 391.70 g propylene glycol is prepared,

332.80 g of ethanol (94%, pure), 244.90 g of anhydrous glycerin and 29.60 g of water (deminaralized) and 1.0 g of a mixture of dihydroergocritin methanesulfonates are dissolved in this mixture with stirring and under a stream of nitrogen. , dihydroergocryptine and dihydroergocornine (1/1/1). After pressure filtration, filling into dropper bottles is performed.

Example 11

A mixture of 403.80 g of propylene glycol, 342.90 g of absolute ethanol (99.8%) and 252.30 g of anhydrous glycerin is prepared and 1.0 g of dihydroergotamine is dissolved in this mixture with stirring and under nitrogen flow at room temperature. -methanesulfonate. After pressure filtration, filling into dropper bottles is performed.

Claims (1)

SUBJECT A process for the production of stable solutions of hydrogenated ergot alkaloids or their synthetic derivatives, for example dihydroergotamine, dihydroergocryptine, dihydroergocornine and dihydroergocristine, respectively. salts thereof, for example methanesulfonates, by dissolution in pharmacologically acceptable OF THE INVENTION according to the invention, characterized in that the pharmacologically harmless organic solvents used are pharmacologically harmless mono- and / or polyhydric alcohols, for example ethanol, propylene glycol and / or glycerine and optionally up to 40% by weight of water.