CS207455B2 - Method of preparation of the new therapeutic mixture - Google Patents

Abstract

PHARMACEUTICAL COMPOSITION CONTAINING A HYDROGENATED ERGOT ALKALOID AND ETILEFRIN The invention provides novel pharmaceutical compositions useful as venotonics, comprising a mixture of dihydroergotamine or a related ergot alkaloid and etilefrin.

Description

The present invention provides a novel therapeutic composition comprising compounds of Formula I

in which

R represents a hydrogen atom or a (C 1 -C 4) alkyl group, with the exception of the tert-butyl group,

R 1 represents a methyl, ethyl or isopropyl group,

R2 represents an isopropyl, sec-butyl, isobutyl or benzyl group;

X is hydrogen or methoxy, and Etilephrine, as well as pharmaceutically acceptable carriers or diluents.

The term "compounds of formula I a

Etilefine 'also includes the pharmaceutically acceptable salts thereof. By pharmaceutically acceptable salts is meant those salts which do not have significantly higher toxicity than the corresponding free bases. Examples of such salts include the methanesulfonates, maleates or tartrates of the compounds of formula (I) and the hydrochloride, and Etilefrin sulfate.

Preferred compounds of Formula I are dihydroergotamine, 6-nor-6-isopropyl-9,10-dihydro-2 H, 3-methyl-5α-benzyl ergopeptin, and dihydroergovalin. The name Etilephrine refers to 2 - [(ethylamino) methyl] -3-hydroxyphenylmethanol of formula II

HOCHCH ^ NHC ^ Hs ·

A (ii)

Pharmaceutically acceptable diluents and carriers include, for example, polyvinylpyrrolidone and gelatin, glidants such as stearic acid, magnesium stearate and talc, fillers such as lacquer, calcium carbonate, disintegrants such as starches and alginic acid, as well as flavoring and coloring agents.

The present invention provides a process for the preparation of the above therapeutic composition, which generally comprises treating the compounds of formula I with polyvinylpyrrolidone to form a solid which is admixed with Etilefrine. In the present case, Etilefrine is preferably in the form of a granulate, together with the aforementioned pharmaceutically acceptable additives, for example lactase, starches and gelatin.

In accordance with the invention, it is expedient to first mix the compounds of formula I with polyvinylpyrrolidone. The polyvinylpyrrolidine is an unbranched poly (N-vinyl (4-pyrrolidone)) having an average molecular weight of from 10,000 to 100,000, preferably from 11,500 to 40,000, in particular 25,000. If desired, pharmaceutically acceptable additives such as wetting agents, e.g. polyethylene glycol with fatty acids, in particular polyethylene glycol stearate, and stabilizers, for example acids, in particular methanesulfonic acid, maleic acid and tartaric acid, k. The pH of the compounds of the formula I in the polyvinylpyrrolidone is preferably 1 to 30% by weight, preferably 5 to 15% by weight.

The mixture is dissolved in a suitable solvent, for example a lower alcohol such as methanol or ethanol at an elevated temperature, in particular at a temperature of 30 to 80 ° C, preferably 40 to 70 ° C. After complete dissolution (clear solution), the solvent is evaporated at a temperature of 50 to 80 ° C, preferably 40 to 70 ° C, only under normal pressure and then under vacuum. In this case, only part of the polyvinylpyrrolidone or other additives is used in the preparation of the solution, and the remaining part of the polyvinylpyrrolidone or other additives is added during the evaporation of the solution. Upon complete evaporation of the solution, a clear liquid is formed which solidifies at room temperature (15-25 ° C). The solid residue is ground in a conventional manner to a fine powder, which is then dried under vacuum at about 30 ° C to completely remove the solvent.

The resulting product is then mixed with an appropriate amount of Etilefrine, which is preferably in the form of a granulate and with pharmaceutically acceptable excipients usually used to prepare the granulates.

The weight ratio of the compounds of the formula I to Etilefrine in the therapeutic composition according to the invention should preferably range from 1: 5 to 1:15 and in particular should be 1:10.

Alternatively, the therapeutic compositions of the invention may be prepared by converting one of the above ingredients together with one or more pharmaceutically acceptable excipients into a granulate and then mixing the granulate with the other component.

This alternative process is preferably carried out by converting one of the components into a granulate in a manner known per se and mixing the granulate with the other component, optionally together with other conventional pharmaceutical ingredients, to obtain a solid mixture suitable for capsule filling And to compress the tablets. If desired, both components can be converted into granules prior to mixing.

The novel therapeutic mixture of the compounds of formula (I) and Etilefrine produced by the process of the invention is characterized by a potentiated effect on enhancing the tone of the large vessels. The incremental volume coefficient of elasticity E '(see M. Echt and L. Lange, "Das Orthostasesyndrom", 5th Rothenburger Gesprách, st. 109, FK Schattauer Verlag), achieved by the synergism of the compounds of formula I and Etilefrine, is on average more than 500%. Such an increase in tone cannot be achieved by the application of the individual compounds mentioned above.

Based on the above-mentioned beneficial effect, the therapeutic composition of the invention can be used to treat orthostatic and hypotonic circulatory disorders.

The beneficial effects in the treatment of orthostatic and hypotonic circulatory disorders are achieved by oral administration of the therapeutic composition of the invention in a daily dose corresponding to 0.5 to 5 mg of the compounds. and 5 to 50 mg of Etilefrine. Particularly preferred is a mixture of 2 mg of dihydroergotamine methanesulfonate and 20 mg of Etilefrine hydrochloride to be administered twice daily.

The invention also provides dosage forms of the composition of the invention suitable for oral administration such as tablets, hard gelatin capsules, soft gelatin capsules and dragees. These dosage forms are manufactured in a manner known per se using known organic or inorganic excipients such as binders (e.g. gelatin and polyvinylpyrrolidone), glidants (e.g. stearic acid, magnesium stearate and talc), fillers (e.g. lactose and carbonate) calcium disintegrating agents (e.g. starches and alginic acid) and optionally flavoring and coloring agents.

The preferred composition of the tablets is as follows:

Etilefrine hydrochloride 20.0mg dihydroergotamine methanesulfonate 2.0mg silicic acid 1.0mg gelatin 1.0mg corn starch 12mg, 3mg polyvinylpyrrolidone 1: 1, 3mg talc 17.0mg powdered cellulose 27.0mg milk sugar 89, 4mg

180.0 mg

The invention is illustrated by the following non-limiting examples.

Example 1

Mixtures for oral administration

Method 1:

a) Preparation of dihydroergotamine meth-ansulfonate and polyvinylpyrrolidone

In a 4-liter flask, add 34.6 g of dihydroeigotamine methanesulfonate,

195.4 g of polyvinylpyrrolidone (average molecular weight of 25,000 [mu] l and 500 ml of methanol) were connected to a rotary evaporator and rotated in a 60 [deg.] C bath until the contents of the flask became clear.

Sufficient methanol is distilled off from the solution under reduced pressure (ca. 33.33 kPa) at a bath temperature of 60 ° C until the residue reaches a syrupy consistency. This mass is transferred to an evaporation dish, where it is left at room temperature for about 2 hours, then dried for about 12 hours in a vacuum oven at 30 ° C under a pressure of about 133.3 Pa, then ground and dried.

b) Etilephrine hydrochloride granulate

In a planetary mixer, 346.0 grams of Etilefrine hydrochloride is mixed with 650.8 grams of milk sugar and 110.4 grams of corn starch, which is uniformly moistened with a solution of 17.3 grams of gelatin in 70 grams of water, granulated with a sieve. A mesh size of 1.3 mm and then dried in an oven at a temperature of 50 ^{° C for} 12 hours. The dried granulate is sieved through a 1.0 mm sieve.

• Mixing

230 · g of the preparation prepared in a) and 1124.5 g of the granulate prepared in b) are mixed together with 895.0 g milk sugar, 86.5 g maize starch, 467.0 g powdered cellulose in a free fall mixer , 294.0 g of talc and 17.0 g of silicic acid until homogeneous. The mixture thus obtained is processed in a pharmaceutical press into tablets weighing 180 mg.

Method 2:

1124.5 g připaaveného granules ¹ according to the procedure lb) was mixed with mixer 34.6 g dihydroergotamine methanesulfonate, 895.0 g of lactose, 86.5 g of corn 'starch 662.4 g powdered cellulose 294.0 talc and 17.0 g of silicic acid until a homogeneous mixture is obtained. The mixture thus obtained is formulated into 180 mg tablets in a pharmaceutical press.

Example 1 a d 2

Mixture for oral administration

Conveniently active mixture for oral use is obtained by the procedure of Example 1 was replaced by dihydroergotamine methanesulphonate equivalent, a quantity of ^{6-nor-6-isopropyl-9,10-dihydro-23'-methyl-5-t} -bvnzyl ergopeptin- methanesulfonate, optionally dihydrofluorovaline methanesulfonate.

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of a novel therapeutic composition comprising compounds of formula I - (phenylaminomethyl) -butyl alcohol, or salts thereof, together with pharmaceutically acceptable carriers or diluents, characterized in that the compounds of the above formula I, or salts thereof, together with a branched polyvinylpyrrolidone, wherein the proportion of the compound of formula I in the polyvinylpyrrolidone is 1 to 30% by weight, dissolved at 30 to 80 ° C in a lower alcohol such as ethanol, the solution is evaporated, the residue is ground to a fine powder which is mixed with m- hydroxy-.alpha .- (ethylamino-in-methyl) benzyl alcohol in a weight ratio of the compounds of formula I to m-hydroxy-.alpha.-methylaminoethyl benzyl alcohol of from 0.5 to 5: 5 to 50. 2. The method of claim 1, wherein pharmaceutically acceptable carriers or diluents are added to the therapeutic composition obtained. 3. The process of claim 1, wherein the m-hydroxy-.alpha .- (v-ylammomethyl) benzyl alcohol is used in the form of a granulate. 4. The method of claim 2, wherein the pharmaceutically acceptable carrier or diluent is gelatin and / or wherein: R represents a hydrogen atom or a (C1-C4) alkyl group, with the exception of a tert-butyl group, R 1 represents a methyl, ethyl or isopropyl group, R2 represents a propyl, sec-butyl, isobutyl or benzyl group; X represents a hydrogen atom or a methoxy group, or salts thereof and m-hydroxy-a207455 polyvinylpyrrolidone and / or stearic acid and / or magnesium stearate and / or talc and / or lactose and / or calcium carbonate and / or starch or and alginic acid. 5. A process according to claim 1, wherein a compound of formula I is used in which R and R1 are each methyl, X is hydrogen and R2 is benzyl.