NO147901B - PROCEDURE FOR PREPARING STABLE LIQUID SOLUTIONS OF HYDROGENERED ERGOTAL CALOIDS - Google Patents

Description

The present invention relates to a method for producing stable liquid solutions of hydrogenated ergot alkaloids with formula I

in which

R stands for hydrogen or alkyl with 1-4 carbon atoms,

with the exception of tert.butyl,

R^ stands for methyl, ethyl or isopropyl,

R2 stands for isopropyl, sec. butyl, isobutyl or benzyl,

and X stands for hydrogen or methoxy, such as dihydroergotamine, dihydroergocryptine, dihydroergocornine and dihydroergocristine, respectively their salts or their mixtures, by dissolving the compounds of formula I in a mixture of pharmacologically tolerable monohydric alcohols with no more than 18 carbon atoms,

such as ethanol, and polyhydric alcohols) with no more than 6 carbon atoms or polyalcohols with a molecular weight of up to 20,000

such as propylene glycol and/or glycerol, as well as water, and the peculiarity of the method according to the invention is that the solvent mixture is a mixture with a dielectric constant of 34-46 (corresponding to an amount of water, of 15-40 percent by weight) .

These features of the invention appear in the patent claim.

A water content limited to 15-40% by weight constitutes i

in relation to the quantity of water of 0 to 40 weight 2S referred to in Norwegian patent document 145,262 a selection invention. On

on the one hand, it has been shown that in the case of the solvent mixtures described in the aforementioned patent in the case of a relatively high proportion of alcohols, e.g. ethanol, with a longer storage time for the solution, an alkylation occurs, e.g. ethoxylation of the cyclol group in the hydrogenated ergot molecule, whereby the activity conditions for the active substance change in a harmful direction. In order to exclude these disadvantages, it has then proved appropriate to keep the water content in the solvent mixture so that the above-mentioned carboxylation of the active substance molecule does not take place, but the good stability of the solution as such is still maintained.

On the other hand, it has been found that a solution containing a hydrogenated ergot alkaloid according to formula I and a solvent mixture with a dielectric constant of 34-46 (corresponding to a water content of 15-40% by weight) produces a surprising favorable stabilization of these hydrogenated ergot alkaloids. For this matter, a report was drawn up which was published in December 1977 in the journal "Arzneimittel-Forschung 27, Hefte 12, (1977)", where particular reference is made to the

page 22 81, left column, first paragraph contained mention of the optimal range of the dielectric constant, in which it is stated that this lies between 35 and 45, when one assumes a chemical shelf life for the hydrogenated ergot alkaloids at room temperature of

more than 5 years. The solvent mixture used according to the invention prevents - as can be seen from table 7 in this publication - as a significant factor the

exposure to air oxygen resulted in oxidative breakdown of the hydrogenated ergot alkaloids, while in the other breakdown reactions, such as e.g. the hydro-

lytic degradation of the peptide part and the rearrangement in the peptide part of the molecule (at C^) by the so-called Aci rearrangement, the influence of the solvent mixture is less pronounced. The advantage achieved by the use of the present solvent mixture with a dielectric constant of 34 - 46 is then correspondingly due to the prevention of the oxidative breakdown of the hydrogenated ergot alkaloids, which until now could only be achieved with the elaborate treatment of the solutions with inert gas . As the protective effect of the gas after opening the container was quickly lost, the solutions had to be consumed quickly, while this is no longer necessary with the products from the method according to the invention.

Particularly preferred compounds of formula I, wherein R

stands for methyl and X stands for hydrogen, is dihydro-α-ergo-cryptine (R1 = isopropyl, R2 = isobutyl), dihydro-3-ergocryptine (R1 =isopropyl, R2 = sec. butyl), dihydroergocornine (R-j^ = R2 = isopropyl) , dihydroergocristine (R.^ = isopropyl, R2 = benzyl) and dihydroergotamine (R1 = methyl,

R2 = benzyl) as well as their salts.

Suitable salts are salts with pharmacologically tolerable acids, e.g. methanesulfonates, malates and tartrates.

Particularly preferred compounds are dihydroergotamine (DHE) and a 1:1:1 molar mixture of dihydroergocryptine (a:B = 2:1), dihydroergocornine and dihydroergocristine (dihydroergotoxin).

Pharmaceutically tolerable alcohols include pharmacologically tolerable monofunctional alcohols with no more than 18 carbon atoms, preferably no more than 10 carbon atoms and especially no more than 3 carbon atoms. Of these, ethanol is particularly preferred. Furthermore, pharmacologically tolerable polyhydric alcohols with a maximum of 6, especially with two or three carbon atoms and preferably two or three hydroxy groups are used, especially glycerol and propylene glycol, but pharmacologically tolerable polyalcohols, preferably polyalkylene glycols, especially polyethylene glycol and/or polypropylene glycol or their mixed polymers, with a molecular weight of up to 20,000, especially 200 to 600, can also be used. Of these, a polyethylene glycol with a molecular weight of 400 is particularly preferred.

The mentioned monohydric and polyhydric alcohols respectively polyalcohols can thus be used in the invention in the form of their mixtures. If one of the alcohols used is solid at the application temperature, an alcohol that is liquid at this temperature is suitably used as an additional solvent.

If a mixture consisting of a monovalent is used

and a polyhydric alcohol, e.g. a mixture of ethanol and propylene glycol, the monohydric and polyhydric alcohols must be present in a weight ratio of 1:0.1 to 1:100, preferably 1:1 to 1:10, especially from 1:1 to 1:4. A particularly preferred weight ratio is from 1:1 to 1:2, preferably 1:2.

Particularly preferred are mixtures of ethanol and propylene glycol or ethanol, propylene glycol and glycerol.

The solutions can also contain, as additives, pharmacologically tolerable organic esters and ethers, especially of the previously mentioned mono- and polyhydric alcohols with fatty acids with 12 to 18 carbon atoms, e.g. stearic acid, palmitic acid or oleic acid, respectively fatty alcohols with 12 to 8 carbon atoms, e.g. lauryl alcohol, cetyl alcohol and stearyl alcohol.

The dielectric constant of the solution can be determined

using standard measuring methods in and of themselves. An immersion condenser, model DFI 4, modified according to ASTM D 1531-595, supplied by Wissen-schaftlich-Technische Werksttten GmbH of Weilheim (BRD) has been found suitable. The dielectric constant must be between 34 and 46, and a water proportion of 15-40% by weight in the mixture. corresponds to this dielectric constant.

The proportion of water is thus determined by the regulation that the dielectric constant must lie within the specified range.._

The dielectric constant of water is about 80.

and of alcohols usually between 25 and 40. It was found that solutions containing a mixture of water and of the specified alcohols as solvent, at a dielectric constant within the specified range, have a water content within the specified range, so that the specified values for the dielectric constant of the solutions is obtained by tuning the water content of the solutions.

Although the concentration of the hydrogenated alkaloids resp. their derivatives and their salts in the solutions is not critical, it is recommended to use solutions with an active ingredient concentration of 0.01 to 1% by weight, preferably 0.1 to 0.5% by weight. It goes without saying that the concentrations used depend on the intended application.

In addition to this, the solutions may contain solubility-promoting additives, e.g. acids, especially methanesulfonic acid, maleic acid, tartaric acid etc. It is clear, however, that such additions which dissociate ions are not taken into account when measuring the dielectric constant.

The preparation of the solutions takes place appropriately by dissolving the hydrogenated alkaloids

their derivatives or their salts in a mixture of the previously described solvents and water with a dielectric constant within the specified range suitably

under inert gas atmosphere, e.g. under a nitrogen atmosphere, conveniently in the exclusion of daylight, usually at room temperature (15 to 25°C) with stirring. The use of an inert gas atmosphere as well as the exclusion of daylight are only preferred precautions which, in view of the high stability of the solution, are not absolutely necessary. It is then filtered under pressure, preferably but not necessarily under inert gas pressure,

and the solution is filled into suitable containers.

The preparation of the solvent mixtures takes place in a manner known per se, as it is appropriate to carry out the preparation at higher temperatures, i.e. up to approximately 80°C if one of the solvent components is solid at room temperature. The mixing ratios are not critical. Ethanol is advantageously chosen as a mixing partner, although this is not absolutely necessary.

A solvent mixture suitable for oral administration consists

of ethanol and propylene glycol or ethanol, propylene glycol and glycerol and contains water in a proportion in accordance with the invention of 15 to 40 by weight, especially 25 to 40 by weight and especially from 30 to 40 by weight. Solutions containing the specified amounts 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. The presence of water in the indicated amounts also reduces the viscosity of the solution and allows an easier and less painful injection of the solution.

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

The following examples illustrate the invention.

Example 1:

A) Preparation of solvent mixtures

The solvent mixtures indicated in the following table under 1-3: are prepared by mixing the solvents described in the following table with each other. The table indicates the water content in weight percent in 94% ethanol) as well as the measured dielectric constant. In all four mixtures, ethanol, glycerol and propylene glycol occur in a weight ratio of 33:26:41.

B) Preparation of solutions

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

Example 2:

In a liter of solvent mixture in combination with Ex. 1,

under sterile conditions, dissolve 2 g of dihydroergotamine methanesulfonate with stirring at room temperature. After filtration under nitrogen pressure, the filtrate is used for filling dropper bottles.

Examples 3 - 8

Using the method described in examples 1 and 2, different preparation solutions are prepared using solvent mixtures 1-3 in the form of different solutions of the active substances described in examples 1 and 2 and further processed as described.

Example 9

10 g of polyethylene glycol with a molecular weight of 400 are dissolved

1 a mixture of 40.0 g 94* ethanol and 23.0 g propylene glycol. 20.0 g of water are then added, whereby 100 ml of a solvent mixture with a dielectric constant of 38 is obtained. Then 0.1 g of dihydroergotoxine methane sulphate is dissolved while stirring at room temperature. After filtration under nitrogen pressure, the solution is filled into dropper bottles. ;Example 10: ;A mixture of 330 g propylene glycol, ;2 80 g ethanol (9 4* pure), 206 g anhydrous glycerol and 188 q water (demineralized) is prepared and dissolved in this mixture with stirring and nitrogen gas supply at room temperature 1, 0 g of a mixture of the methanesulfonates of dihydroergocristine, dihydroergocryptine and dihydroergocornine (1/1/1). The resulting solution has a dielectric constant of 35.5. After pressure filtration, filling is carried out in dropper bottles.

Claims (1)

Process for the production of stable liquid solutions of hydrogenated ergot alkaloids of formula I in which R stands for hydrogen or alkyl with 1-4 carbon atoms, with the exception of tert.butyl, R^ stands for methyl, ethyl or isopropyl, R2 stands for isopropyl, sec. butyl, isobutyl or benzyl, and X stands for hydrogen or methoxy, such as dihydroergotamine, dihydroergocryptine, dihydroergocornine and dihydroergo-cristine, respectively. their salts or their mixtures, in that the compounds of formula i are dissolved in a mixture of pharmacologically tolerable monohydric alcohols with a maximum of 18 carbon atoms, such as ethanol, and polyhydric alcohols with a maximum of 6 carbon atoms, respectively polyalcohols with a molecular weight of up to 20,000, such as propylene glycol and/or glycerol, and water, characterized in that a mixture with a dielectric constant of 34-46 (corresponding to a water proportion of 15-40 percent by weight) is used as the solvent mixture.