CH635347A5 - Stable solutions of hydrogenated ergot alkaloids or their synthetic derivatives in a mixture of alcohols and water - Google Patents

Description

The invention relates to stable solutions of hydrogenated ergot alkaloids or their synthetic derivatives of the formula I,

OH

O

H

-R

wherein R is hydrogen or alkyl with 1 -4 carbon atoms with the exception of tert. Butyl, Ri for methyl, ethyl or isopropyl, R2 for isopropyl, sec. Butyl, isobutyl or benzyl and X represents hydrogen or methoxy,

as well as their pharmacologically acceptable salts in a mixture of pharmacologically acceptable alcohols or their mixtures and water with a dielectric constant of not more than 50, and processes for the preparation of the stable solutions.

The above meaning not covered by the substituent R tert. Butyl has been excluded for technical reasons.

Preferred compounds of the formula I are those in which R is methyl, X is hydrogen and R is isopropyl or methyl, where R is expediently methyl if R 2 is benzyl. Particularly preferred compounds of the formula I in which R is methyl and X is hydrogen are dihydro-a-ergocryptin (Ri = isopropyl, R2 = isobutyl), dihydro-jS-ergocryptin (Ri = isopropyl, R2 = sec. Butyl) , Dihydroergocornin (Rj = R2 = isopropyl), dihydroergocristine (Ri = isopropyl, R2 = benzyl) and dihydroergotamine (Ri = methyl, R2 = benzyl) and their salts. Suitable salts are salts with pharmacologically acceptable acids, for example methanesulfonates, maleates and tartrates.

Particularly preferred compounds are dihydroergotamine (DHE) and a 1: 1: 1 molar mixture of dihydroergocryptin (a: β = 2: 1), dihydroergocornin and dihydroergocristine (dihydroergotoxin).

Pharmaceutically acceptable alcohols include pharmacologically acceptable monofunctional alcohols with at most 18 carbon atoms, preferably at most 10 carbon atoms, and especially at most 3 carbon atoms. Of these, ethanol is particularly preferred. Furthermore, pharmacologically acceptable polyhydric alcohols with at most 6, but in particular 2 or 3 hydroxyl groups and at most 6, in particular however 2 or 3 carbon atoms, in particular glycerol and propylene glycol, can be used, but also polyhydric alcohols in the form of pharmacologically acceptable polyalcohols, preferably polyalkylene glycols, in particular polyethylene glycol and / or polypropylene glycol or their copolymers with a molecular weight of 200 to 20,000, in particular from 200 to 600. Of these, a polyethylene glycol with a molecular weight of 400 is particularly preferred.

According to the invention, the abovementioned monohydric and polyhydric alcohols can be used either alone or preferably in the form of their mixtures. If one of these monohydric or polyhydric alcohols is solid at the use temperature, an alcohol which is liquid at this temperature is expediently used as an additional solvent.

If a mixture consisting of a monohydric and a polyhydric alcohol is used, for example a mixture of ethanol and propylene glycol, the monohydric and polyhydric alcohols should be used in a weight ratio of 1: 0.1 to 1: 100, preferably 1: 1 to 1: 10, in particular from 1: 1 to 1: 4, be present. A particularly preferred weight ratio is from 1: 1 to 1: 2, preferably 1: 2.

Mixtures of ethanol and propylene glycol or ethanol, propylene glycol and glycerin are particularly preferred.

The solutions according to the invention can also be added as pharmacologically acceptable organic esters and ethers, in particular the abovementioned mono- and polyhydric alcohols with fatty acids having 12 to 18 carbon atoms. atoms, for example stearic acid, palmitic acid or oleic acid, or fatty alcohols with 12 to 18 carbon5

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contain atoms, for example lauryl alcohol, cetyl alcohol and stearyl alcohol.

The dielectric constant of the solution can be determined using conventional measurement methods. An immersion capacitor, model DFI4, modified in accordance with ASTM D 1531 -595, made by Wissenschaftlich-Technischen Werkstätten GmbH in Weilheim, has proven its worth. (FRG) is offered. The preferred dielectric constant of the solution should be less than 50, in particular between 30 and 46, very particularly between 34 and 46.

The water content is determined by the proviso that the dielectric constant is not more than 50. The dielectric constant of water is approximately 80 and that of alcohols generally between 25 and 40. It has been found that solutions containing a mixture of water and one or more alcohols as solvents have a water content of no more with a dielectric constant of not more than 50 than 40% by weight. The above-mentioned preferred values of the dielectric constant of the solutions are achieved if the water content of the solutions is from 15 to 40% by weight, in particular from 25 to 40% by weight, preferably from 30 to 40% by weight.

Although the concentration of the hydrogenated ergot alkaloids or their derivatives and their salts in the solutions is not critical, it is advisable to use solutions with an active compound concentration of 0.01 to 1% by weight, preferably 0.1 to 0.5 % By weight to use. It goes without saying that the concentration used depends on the intended use.

The solutions can also contain solubility-promoting additives, for example acids, in particular methanesulfonic acid, maleic acid, tartaric acid, etc. However, it goes without saying that such additives which can be dissociated in ions are not taken into account when measuring the dielectric constant.

The solutions according to the invention are expediently prepared by dissolving the hydrogenated ergot alkaloids or their derivatives or their salts in a mixture of the above-described solvents and water with a dielectric constant of not more than 50, expediently in an inert gas atmosphere, for example a nitrogen atmosphere, expediently usually in the absence of daylight at room temperature (15 to 25 ° C) with stirring. The use of an inert gas atmosphere and the exclusion of daylight are only preferred measures which are not necessary in view of the high stability of the solution. The mixture is then filtered under pressure, preferably — but not necessarily — under inert gas pressure and the solution is filled into suitable vessels.

The solvent mixtures are prepared in a manner known per se, it being expedient to prepare them at higher temperatures, i.e. up to approx. 80 ° C, if one of the solvent components is solid at room temperature. The mixing ratios are not critical. Ethanol is advantageously chosen as the mixing partner, but this is not absolutely necessary.

A solvent mixture suitable for oral administration consists of ethanol and propylene glycol or ethanol, propylene glycol and glycerin and contains water in a proportion of up to 40% by weight, preferably from 15 to 40% by weight, in particular from 25 to 40% by weight. %, and especially from 30 to 40% by weight. Solutions containing at least 15% by weight of water have a taste that is favorable for oral administration. For parenteral administration, it is inappropriate to use solvent mixtures containing more than 5% by weight of ethanol. A preferred solvent is propylene glycol containing up to 40% by weight, preferably from 15 to 40% by weight, of water. The presence of at least 15% by weight of water also lowers the viscosity of the solution and allows easier and less painful injection of the solution.

The compounds of formula I to be administered in the stable solution and their therapeutic effects are known.

The following examples illustrate the invention: Example 1

A) Preparation of solvent mixtures

The solvent mixtures given in the table below under 1-4 are prepared by mixing together the solvents described in the table below. The table shows the water content in% by weight (taking into account the 6% water content of the 94% ethanol) and the dielectric constant determined. All four mixtures contain ethanol, glycerin and propylene glycol in a weight ratio of 33:26:41.

Mixture No. 12 3 4

Quantities (g)

Ethanol (94%)

1183

1051

1992

1728

glycerin

869

773

1464

1272

Propylene glycol

1391

1236

2344

2040

Dest. Water

303

686

2256

3056

% By weight of water

10.0%

20.0%

29.5%

39.

Dielectric constant

32.2

37.7

41.6

45.

aunt

B) Preparation of solutions

1 g of dihydroergotoxin methanesulfonate is dissolved in one liter of solvent mixture 1 with stirring at room temperature (25 ° C.) and in a nitrogen atmosphere. It is then filtered under pressure (nitrogen pressure) and the filtrate is used to fill dropper bottles.

Example 2

2 g of dihydroergot amine methanesulfonate are dissolved in 1 liter of solvent mixture 1, which was prepared under sterile conditions, with stirring at room temperature. After filtering off under nitrogen pressure, the filtrate is used to fill dropper bottles.

Examples 3-8

Using the processes described in Examples 1 and 2, using the solvent mixtures 2-4 instead of the solvent mixture 1, solutions of the active compounds described in Examples 1 and 2 are prepared and processed as described.

Example 9

0.1 g of dihydroergotamine methanesulfonate is dissolved in 100 ml of a mixture of 80 parts by weight of sterile propylene glycol and 20 parts by weight of water (for injections) at room temperature with stirring. After filtration under nitrogen pressure, the solution is filled into sterile ampoules, which then each contain 1 ml of the solution with a dielectric constant of 41. The ampoules are then closed.

Example 10

10 g of polyethylene glycol with a molecular weight of 400 are in a mixture of 40.0 g of 94% ethanol and

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23.0 g of propylene glycol dissolved. 20.0 g of water are then added, 100 ml of a solvent mixture having a dielectric constant of 38 being obtained. 0.1 g of dihydroergotoxin methanesulfonate are dissolved therein with stirring at room temperature. After filtering under nitrogen pressure, the solution is filled into dropper bottles.

Example 11

6.0 g of a mixture of cetyl and stearyl alcohol are dissolved in 68.6 g of 94% ethanol. 8.5 g of water are added to the solution, 100 ml of a solvent mixture having a dielectric constant of 30 being obtained. 0.1 g of dihydroergotoxin methanesulfonate are dissolved therein with stirring at room temperature. After filtering under nitrogen pressure, the solution is filled into dropper bottles.

s Example 12

A mixture of 330 g of propylene glycol, 280 g of ethanol (94% pure), 206 g of anhydrous glycerol and 188 g of water (demineralized) is prepared, and 1.0 g of a mixture of the methanesulfonates of Dihydroergocristin, dihydroergocryptin and dihydroergocornin (1/1/1) dissolved. The solution obtained has a dielectric constant of 35.5. After pressure filtration, they are filled in dropper bottles.

B

Claims (5)

635347 2. Process for the preparation of stable solutions according to claim 1, characterized in that hydrogenated ergot alkaloids or their synthetic derivatives and their salts in a mixture of pharmacologically acceptable alcohols or their mixtures and water with a dielectric constant of not more than 50 at temperatures of 15 to 25 ° C dissolves. 2nd PATENT CLAIMS 1. Stable solutions of hydrogenated ergot alkaloids or their synthetic derivatives of the formula OH NH - O H -R wherein R is hydrogen or alkyl of 1-4 carbon atoms with the exception of tert. Butyl, Ri for methyl, ethyl or isopropyl, R2 for isopropyl, sec. Butyl, isobutyl or benzyl and X represent hydrogen or methoxy, and their pharmacologically acceptable salts in a mixture of pharmacologically acceptable alcohols or their mixtures and water with a dielectric constant of not more than 50. 3. Stable solutions according to claim 1, characterized in that the mixture has a dielectric constant from 30 to 46, in particular from 34 to 46. 4. Stable solutions according to claim 1, characterized in that the mixture contains water in a proportion of up to 40% by weight. 5. Stable solutions according to claim 1, characterized in that the proportion of water in the mixture is expediently from 15 to 40% by weight, in particular from 25 to 40% by weight, preferably from 30 to 40% by weight.