DK146194B - PROCEDURE FOR THE PREPARATION OF A SOLID SUBSTANCE CONTAINING ONE OR MORE HYDROGENERATED MIDDLE ALCOALOIDS - Google Patents

Description

1 146194

The present invention relates to a process for the preparation of a solid containing one or more hydrogenated melon alkaloids or synthetic derivatives thereof selected from dihydroergotamine, dihydroergocristine, dihydroergocryptin and dihydroergocornin or salts thereof, the process of which dissolves the hydrogenated melon compound with a pharmaceutically tolerable polymer and optionally surfactants in a solvent consisting, for example, of a lower alcohol, and vaporizing the solvent from the solution obtained, optionally after further addition of the polymer, wherein the polymer is at least slightly soluble in an aqueous medium and consists of a non-crosslinked poly (N-vinyl) pyrrolidone having a molecular weight of 10,000 - 100,000, and wherein the ratio of the hydrogenated molybdenum alkaloid component to the polymer and any additional other additives present is 0.1: 99.9 - 50:50.

Suitable salts of tolerable organic acids such as methanesulfonates, maleinates and tartrates, or inorganic acids, e.g. hydrochlorides, are suitably used as salts of the hydrogenated melon alkaloids.

In particular, the non-crosslinked poly (N-vinyl) pyrrolidone-2 having a molecular weight of between 10,000 and 100,000 has a molecular weight of 11,500-40,000, preferably 20,000-30,000.

As the pharmaceutically tolerable additives present, there may be mentioned surfactants such as sodium lauryl sulfate and polyethylene glycol fatty acid esters, especially polyethylene glycol stearate, and stability-enhancing additives, for example acids, especially methanesulfonic acid, maleic acid and tartaric acid, to obtain a pH value of about 4-5, with the weight ratio of the hydrogenated mildew alkaloid component to the polymer and the optionally additional additives used being in the range 0.1: 99.9-50: 50, preferably 5: 95-15: 85. The weight ratio of the surfactants alone to the amount of active substance used must be 1: 45-10: 1.

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In the process of the invention, a substance is prepared which can also be referred to as a solid solution in which the polymer is used in solid form. The solid solutions thus obtained have the surprising advantage that the salts embedded therein of hydrogenated ergot alkaloids, which are themselves water soluble, have a significant improvement in the resorption quotient.

It is known to produce solid solutions of water-insoluble active substances, e.g., griseofulvin in polymers, eg polyvinylpyrrolidone, but here it is an attempt to improve water solubility in improved in vivo absorption (cf. e.g. Stupak and T. Bates "Enhanced Absorption of Digitoxin from Orally Administered Digitoxin - Polyvinylpyrrolidone Coprecipitates" in Journal of Pharmaceutical Sciences 62 (1973), 1806-1809). This article establishes a clear link between solubility and absorption of the active substance. It is found that with good water solubility, faster absorption occurs and at poorer water solubility slower absorption of the active substance in the body.

Contrary to the prior art, by advancing the invention, a significant improvement in the absorption of water-soluble compounds is obtained by conversion to the solid solution. This surprising effect, which could not be deduced from the teachings of the above literature, has been found in studies in which the resorption of water-soluble dihydro-ergotamine methanesulfonate as aqueous solution (in ampoule) and as a solid (solid solution prepared by the method of invention) has been compared using the jejunum loop from rats. The relevant data is shown in the following report with tables: 3 µm-m In jejunum loops on anesthetized rats 0.25 mg of dihydro-ergotamine methanesulfonate is administered as pure substance, respectively, in a vial aqueous solution and in the form of a solid solution. The solid solution and the pure substance are administered in aqueous boiling salt solution. Mesenterial blood is collected and the amount of dihydroergotamine methanesulfonate (1 µg) is measured after 15, 30, 45 and 60 minutes. The results are shown in Table I below.

Table I

yug in blood after 15 30 45 60 minutes

Pure 0.92 2.72 4.28 5.76

Ampoule 2.75 5.36 7.42 9.30

Solid 3.71 9.51 15.07 19.78

It can be seen from Table I that the resorption of dihydroergotamine-methanesulfonate as a solid is ca. 4 times better than the resorption of the pure substance, as evidenced by the resorption after 15 minutes (3.71, 0.92yug in the blood, respectively). Dihydroergotamine methanesulfonate in solution (as ampoule) is twice as well resorbed as the pure substance, but never reaches the resorption of the substance in solid solution.

In addition, a comparison of blood levels after oral administration of 5 mg / kg dihydroergotamine methanesulfonate as solid, per se and ampoule, respectively was performed.

1/2, 1, 2 or 4 hours after oral administration, the animals were killed and the dihydroergotamine content determined fluorimetrically. The results (in ng / ml) are shown in the table below, where "n" indicates the number of rats.

4 14 619 Λ

- Table II

η 0.5 1 2 4 hours

Solid 12 66.5 127.3 52.8 22.3

Substance 9 14.7 49.0 36.0 8.7

Ampoule 3 16.0 28.0 30.0 13.0

By comparing the blood level maximum values, it is seen that at least twice the blood level is achieved by using the solid solution substance over the substance per se.

In British Patent Specification No. 1,175,430, U.S. Patent No. 3,557,287 and German Patent Publication No.

23 11 071 and German Publication No. 23 57 503 disclose mixtures which, in addition to the active substance, also contain the polymers used in the process according to the invention for the preparation of solid solutions. Here, in each case, these are so-called physical mixtures in which the active substance and the polymer occur side by side and do not form an inner mixture, as is the case with the solid solution.

The above ingredients are dissolved in a suitable solvent, for example a lower alcohol, eg ethanol or methanol, with stirring and heating to temperatures between 30 and 70 ° C, preferably between 40 and 60 ° C to give a clear solution. Then, the solvent is removed in vacuo at temperatures between 30 and 70 ° C, preferably between 40 and 60 ° C. It is also possible that only part of the polyvinylpyrrolidone or other additives is used in the preparation of the solution and addition of the remaining amount is done while evaporating the solution. The obtained clear liquid is allowed to solidify at room temperature (15-25 ° C). The obtained product is ground to a fine powder and dried in vacuo at ca. 30 ° C to completely remove the solvent.

U6194 5

The solid obtained in the manner described above can be processed together with the usual additives in a manner known per se, for galenic preparations, for example tablets, hard and soft gelatin capsules and dragees.

In the manufacture of tablets, as additives, organic or inorganic adjuvants such as binders, lubricants, fillers and wetting agents can further be used. In addition, the pharmaceutical composition may also contain dyes, flavors and sweeteners. As auxiliaries in the preparation of tablets may be used calcium carbonate, sodium bicarbonate lactose, starch species and talc, as granulating and disintegrating starch and alginic acid, as binder starch and gelatin and as lubricant magnesium stearate, stearic acid and talc, and as a pharmaceutically useful retarder. waxes, fats, cellulose derivatives and other polymers. The tablets may be coated or uncoated, the coating being applied in a manner known per se.

For the preparation of soft gelatin capsules, the above-mentioned solid is processed in a manner known per se with a mixture of e.g. glycerol, sorbitol, water and a preservative and optionally dye, and to prepare hard gelatin capsules, the above-mentioned solid is worked up in a manner known per se with pharmaceutically useful excipients.

The preparation of dragees is carried out in a manner known per se by drageing of e.g. tablet cores.

A suitable tablet composition consists of 16.3 mg of the solid obtained in the manner described above, 104.0 mg of lactose, 15.0 mg of corn starch and 12.0 mg of talc, 32.0 mg of cellulose powder and 0.7 mg of silica.

A suitable mixture for filling in soft gelatin capsules is obtained by mixing 16.3 mg of the solid obtained in the manner described above, 9.0 mg of glycerol and 74.7 mg of polyethylene glycol 400.

A suitable mixture for loading into hard gelatin capsules is obtained by mixing 16.3 mg of the solid obtained in the manner described above, 0.7 mg of silica, 13.0 mg of corn starch and 65.0 mg of lactose.

146194 6

The invention is further illustrated by the following examples:

Example 1.

Into a flask with a volume of 4 liters is poured 34.6 g of dihydroergotamin-methanesulfonate, 195.4 g of polyvinylpyrrolidone (average molecular weight 25000) and 500 ml of methanol. The flask is connected to a rotary evaporator. At a bath temperature of 60 ° C, the contents of the rotary flask are heated to approx. 60 ° C. A clear solution is thus formed.

Evaporate from the solution at reduced pressure (about 250 mm Hg) and a bath temperature of 60 ° C so much methanol that the residue assumes a syrupy consistency. This mass is placed in an evaporating bowl and kept for approx. 2 hours at room temperature. Then dry (vacuum drying cabinet, 30 ° C, about 1 mm Hg, about 12 hours), grinding and post-drying.

The powder produced is processed together with usual pharmaceutically used excipients into a pharmaceutical form.

Example 2.

Into a flask with a volume of 4 liters is poured 34.6 g of dihydroergotamine methanesulfonate, 193.165 g polyvinylpyrrolidone (average molecular weight 25000), 2.26 g polyethylene glycol 1800 stearate and 500 ml methanol. The flask is connected to a rotary evaporator. At a bath temperature of 60 ° C, the contents of the rotary flask are heated to approx. 60 ° C. Thereby a clear solution is formed.

Evaporate from the solution at reduced pressure (about 250 mm Hg) and a bath temperature of 60 ° C so much methanol that the residue assumes a syrupy consistency. This mass is placed in an evaporating bowl and kept for approx. 2 hours at room temperature. Then dry (vacuum drying cabinet, 30 ° C, about 1 mm Hg, about 12 hours), grinding and post-drying.

The powder produced is processed together with usual pharmaceutically used excipients into a pharmaceutical form.