DE2555481C3 - Production of stable drop solutions of hydrogenated ergot alkaloids - Google Patents

Description

In the case of drop solutions of the aforementioned hydrogenated ergot alkaloids or their salts in a predominantly aqueous medium it occurs in the course of storage Loss of active ingredient as a result of, for example, oxidation and rearrangement reactions. To this adverse To counteract this effect, the solution is often fumigated with inert gas when it is filled into the for sale certain vessels carried out By these technically complex measures, the desired Purpose, however, can only be achieved incompletely, since the active substance concentration after opening the vessels drops sharply

Surprisingly, it has been found that solutions of the aforementioned hydrogenated ergot alkaloids or of the salts of which remain stable over longer periods of time after opening the storage vessels, if one is used as Solvent used the aforementioned mixtures

DD Patent 43 402, especially page 1, lines 12-19, was indeed already been described that alcohols, especially polyols, a stabilizing effect exerted on ergotamine tartrate, but is does not tell us in this specification, how big and what kind is the stabilizing effect that is achieved. It is only said that the ergotamine tartrate stabilized in this way is better suited as a uterotonic for domestic animals. However, comparative studies have shown that there are so considerable differences in the stability behavior of ergotamine, which is a characteristic representative of the natural ergot alkaloids, and dihydroergotamine, which is a characteristic representative of the hydrogenated ergot alkaloids, that the content of the DD patent does not apply to the present one Invention can be closed. In these investigations it was found that ergotamine (in the form of its tartrate) is more stable in aqueous solutions than in predominantly organic solutions, that is to say in particular in the mixtures of monohydric and polyhydric alcohols and optionally water claimed according to the invention. It has been shown that in predominantly organic solutions the equilibrium with ergotamine is established more quickly and the formation of degradation products is accelerated. In these investigations, dihydroergotamine shows a stability behavior that is completely different from that of ergotamine. This is expressed in the fact that dihydroergotamine has an extremely high stability in predominantly organic solutions, this stability remains practically unchanged up to a water content of approx. 40% by weight and only when water is added above approx. 40% by weight (i.e. L at a water content between 40 and 50%), there is also a sharp drop in stability or an increase in the amount of decomposition products (see enclosed Figures 1 and 2). Because of this unpredictable realization, it has become possible. Solutions of the aforementioned hydrated ergot alkaloids, which are so important in medicine, which after opening the storage vessels - in contrast to the previous ones

ίο known, especially aqueous solutions - over remain stable for long periods of time.

In Chem. Zentralblatt 1963, page 2164. is a Finnish work by P. Heinänen cited in which the extraction of ergot alkaloids (in particular

is ergotamine) with alcohols. Here Attention is drawn to the fact that absolute alcohol is ergotamine better stabilized than aqueous alcohol (70%), the addition of ascorbic acid being able to significantly increase the stability of ergotamine. These Reference also states that when using 70% alcohol after six weeks only 15% of the original ergotamine content are present.

A similar extraction method from ergot is in Hager's Handbook of Pharmaceutical Practice, Berlin 1949, page 683, described in which the extractant is a mixture of glycerol, ethanol and Water is used. This extraction procedure is only for secale alkaloids, i.e. natural Ergot alkaloids, especially described for ergotamine. Since, as in connection with the above DD patent and the o. E. in the Chem. Zentralblatt reported work shown Ergotamine one of Dihydroergotamine shows different stability behavior, this reference appears for the present Invention not obvious.

British patent specification 11 75 430 describes in example 3 a solution of a combination of dihydroergocristine methanesulfonate Rutin and esculin in a mixture of ethanol, glycerine and propylene glycol.

This combination is stated to have a synergistic peripheral vasodilatory effect owns

This known mixture, which achieves a different object than the present invention, has an im Compared to the hydrogenated ergot alkaloid, an extraordinarily high proportion of rutin and esculin. Accordingly the stability behavior of the known mixture is strongly determined by rutin and esculin and a stabilizing effect of the solvent mixture on the hydrogenated ergot alkaloid is not necessary here recognize and not described in the patent.

The mixtures of ethanol and the polyhydric alcohols used according to the invention for the stabilization of dihydroergocristine, dihydroergocryptine, dihydroergocornine or their mixtures and / or dihydroergotamine should be in a weight ratio of in particular 1 to 2.
The drip solutions according to the invention can also be used as additional pharmacologically harmless organic esters and ethers, in particular the aforementioned monohydric and polyhydric alcohols with fatty acids having 12 to 18 carbon atoms, for example stearic acid, palmitic acid and oleic acid, or fatty alcohol

(, contain len with 12 to 18 carbon atoms, for example lauryl alcohol, cetyl alcohol and stearyl alcohol.
The hydrogenated ergot stabilized according to the invention

alkaloids can also be in the form of their salts. The salts used are advantageously salts with harmless acids, such as, for example the methanesulfonates, maleinates, tartrates, etc.

Although the concentration of the hydrogenated ergot alkaloids specified in the claim or of their salts is not critical in the solutions, it is advisable to To use solutions with an active ingredient concentration of preferably 0.1 to 0.5% by weight. Ee is it goes without saying that the concentration used depends on the particular application

In addition, the solutions can also contain additives which promote solubility, for example acids, in particular Contain methanesulfonic acid, maleic acid, tartaric acid, etc.

The solutions are expediently prepared by dissolving the hydrogenated ergot alkaloids specified in the claim or their salts in the solvent mixture specified in the claim, expediently in an inert gas atmosphere, for example a nitrogen atmosphere, expediently with exclusion of daylight, usually at room temperature (15 to 25 ° C) with stirring.

example 1

A mixture of 40.0 g of propylene glycol, 34.0 g of ethanol (94% pure) and 25.0 g of anhydrous Glycerine prepared and in this mixture with stirring and nitrogen gas at room temperature 0.1 g of a mixture of dihydroergocristine, dihydroergocryptine and dihydroergocornine (1/1/1) dissolved after After pressure filtration, the filling takes place in dropper bottles.

Example 2

A mixture of 330 g propylene glycol, 280 g ethanol (94% pure), 206 g anhydrous glycerine is used and 183 g of water (demineralized) and in this mixture while stirring and gassing with nitrogen 1.0 g of a mixture of the methanesulfonates of dihydroergocristine, dihydroergocryptine and dihydroergocornine (1/1/1) dissolved at room temperature. After Pressure filtration, the filling takes place in dropping bottles. cryptine and dihydroergocornine (1/1/1) dissolved after the Pressure filtration, the filling takes place in dropping bottles.

Example 5

A mixture of 268 g of propylene glycol, 227.70 g of ethanol (94% pure), 167.6Og of anhydrous Glycerine and 335.70 g of water (demineralized) represents and in this mixture with stirring and Nitrogen gassing at room temperature 1.0 g of a mixture of the methanesulfonates of dihydroergocristine, dihydroergocryptine and dihydroergocornine (1/1/1) solved After the pressure nitration, the

Filling in dropper bottles. Example 6

A mixture of 245.8 g of propylene glycol, 261.8 g of ethanol (94% pure), 245.80 g of anhydrous glycerine and 245.80 g of water (demineralized) is prepared and 1.0 in this mixture, with stirring and nitrogen gassing at room temperature g one

Mixture of the methanesulfonates of dihydroergocristine, dihydroergocryptine and dihydroergocornine (1/1/1) dissolved After pressure filtration, it is filled into dropper bottles.

Example 7

A mixture of 350 7 g propylene glycol, 297.8 g ethanol (94% pure), 219.0 g anhydrous Glycerine and 131.5 g of water (demineralized) and in this mixture while stirring and Nitrogen gassing at room temperature 1.0 g of a mixture of the methanesulfonates of dihydroergocristine, dihydroergocryptine and dihydroergocornine (I / l / l) dissolved After pressure filtration, it is filled into dropper bottles.

Example 8 Example 3

It is a mixture of 293 g propylene glycol, 249 g ethanol (94% pure), 183 g anhydrous glycerine and 282 g of water (demineralized) and in this mixture while stirring and gassing with nitrogen 2.0 g of dihydroergotamine methanesulfonate dissolved at room temperature Filling in dropper bottles.

Example 4

It is a mixture of 255 g propylene glycol, 216 g ethanol (94% pure), 159 g anhydrous glycerine and 382 g of water (demineralized) prepared and in this mixture with stirring and nitrogen gassing at room temperature 1.0 g of a mixture of the methanesulfonates of dihydroergocristine, dihydroergo- A mixture of 391.70 g of propylene glycol, 332.80 g of ethanol (94% pure), 244.9Og of anhydrous glycerine and 29.60 g of water (demineralized) and prepared in this mixture with stirring and Nitrogen gassing at room temperature 1.0 g of a mixture of the methanesulfonates of dihydroergocristine, dihydroergocryptine and dihydroergocornine (1/1/1) dissolved After pressure filtration, it is filled into dropper bottles.

Example 9 A mixture of 403.80 g propylene glycol,

342.90 g of absolute ethanol (99.8%) and 25230 g anhydrous glycerine and in this

Mixture with stirring and nitrogen gassing Room temperature 1.0 g dihydroergotamine methanesulfo-

nat dissolved. After pressure filtration, the

Filling in dropper bottles.

The solutions described in Examples 1 to 9 above have, in terms of their components, the from the table below

Subsidence. Therein with the additional examples up to 16 further solutions according to the invention are given, while Examples 17 bis, which are also cited, serve for comparison purposes. All of these additional inventive examples or comparative examples each contain 0.1 g of a 1: 1: 1 mixture of Me thansulfonate of dihydroergocristine, dihydroergocryptine and dihydroergocomin or 0.2 g each of the Methanesulfonate of dihydroergotamine as active ingredients, as indicated in detail in the symbols (box or asterisk) contained in Figures 1 and 2 can be found

example

% Water

% Propylene glycol % Ethanol

% Glycerine

2.0 40.4 20.4 32.8 29.5 29.1 39.0 25.2 35.0 26.8 OC O
4υμ. 24.6 15.0 35.1 5.0 39.2 0.06 30.4 5.0 39.2 9.9 37.1 9.9 37.1 20.4 32.8 39.1 23.9 29.5 29.1 183 32.8 423 23.9 49.9 20.6 49.9 20.6 743 10.3 74.9 103 90.0 4.1

32.2 26.2 23.2 20.0 21.4 24.6 28.0 313 343

313 29.8 29.8 26.2 13.1 23.2 283

9.9

16.6

16.6

8.4

8.4

3.4

25.2 20.5 18.2 15.7 16.7 24.6 2i, 9 24.5 25.3

24.5 23.2 23.2 20.5 23.9 18.2 20.6

23.9

12.9

12.9

6.4

6.4

In the following figures 1 and 2 the stability values of the active ingredients of the majority of the in the solutions described above are given. The numbers correspond to the respective example.

For this purpose 2 sheets of drawings

Claims (1)

Claim: Use of mixtures of ethanol and propylene glycol! and glycerine as a solvent Preparation of a stable drop solution of dihydroergocristine or dihydroergocryptine or dihydroergocornine or mixtures of these active ingredients or dihydroergotamine or the salts of these active ingredients with harmless acids in an active ingredient concentration of 0.1 to 1% by weight and a water content up to 40% by weight, the weight ratio of ethanol to the other alcohols being 1: 0.1 to 100