CH643737A5 - Preparation of a solid material composed of ergot peptide alkaloids and polyvinylpyrrolidone - Google Patents

Description

The invention relates to a process for producing a solid substance from ergot peptide alkaloids, their hydrogenated forms or their salts and polyvinylpyrrolidone according to claims 1 to 3.

The process according to the invention is carried out in detail as described below:

Ergot peptide alkaloids, such as, for example, ergotamine, ergocristin, ergocryptin, ergocornin, ergovalin, or their hydrogenated forms and their mixtures or their salts, the salts advantageously being salts with harmless organic acids, such as methanesulfonates, maleinates, tartrates, etc or inorganic acids, such as hydrochloride, are used together with polyvinylpyrrolidone in the form of poly-N-vi-nylpyrrolidon-2 (uncrosslinked) with molecular weights between 10,000 and 100,000, in particular 11,500 to 40,000, preferably 20,000 to 30,000, optionally together with pharmaceutically acceptable additives, for example surfactants, such as sodium lauryl sulfate, polyethylene glycol fatty acid esters, in particular polyethylene glycol stearate, and stability-promoting additives, such as acids, in particular methanesulfonic acid, maleic acid, tartaric acid, in order to achieve a pH of the dosage form of approx. 4-5, the weight ratio of Er gotpeptide alkaloids, the hydrogenated forms or the salts thereof for the polyvinylpyrrolidone used and the additives which may still be used should be from 0.1: 99.9 to 50:50, preferably from 5:95 to 15:85. The weight ratio of the surfactants alone to the amount of active ingredient used should normally be from 1:45 to 10: 1. Here, the polyvinyl pyrrolidone is used in solid form.

The above ingredients are dissolved in a suitable solvent, e.g. a lower alcohol e.g. Ethanol or methanol, with stirring and heating to temperatures of 30 to 70 ° C, preferably 40 to 60 ° C, dissolved, a clear solution being obtained. The solvent can then be removed in vacuo at temperatures from 30 to 70 ° C., preferably 40 to 60 ° C. It is possible here that only a part of the polyvinylpyrrolidone or the other additives is used in the preparation of the solution and the addition of the remaining amount takes place during the evaporation of the solution. The resulting clear liquid can be solidified at room temperature (15-25 ° C). The product obtained can be ground to a fine powder and then dried in vacuo at about 30 ° C. until the solvent has been completely removed.

The solid substance obtained by the above process is a complex which is formed in solution through the formation of intermolecular hydrogen bonds via secondary valence bonds and which is retained after the solvent has evaporated. This formation of intermolecular hydrogen bonds and the associated change s in the physical state of the ergot peptide alkaloids, their hydrogenated forms or their salts, i.e. Their transition from the crystalline to the X-ray amorphous form can be demonstrated with the help of Guinier-de-Wolff images using the example of dihydroergotamine methanesulfonate. io Due to the diffraction lines, it can be seen from the attached Fig. 1 that dihydroergotamine methanesulfonate before the reaction is in crystalline form (photo BH60), while polyvinylpyrrolidone (Kollidon 25) has an amorphous form (photo BH59). Processing the crystalline dihydroergotamine methanesulfonate with polyvinylpyrrolidone (Kollidon 25) to a solid material converts the dihydroergotamine methanesulfonate to an amorphous form (recordings BH68, 69, 70 and 71). The ratio of polyvinylpyrrolidone (Kollidon 25) 20 to dihydroergotamine methanesulfonate used is not critical within the above limits, since both solids containing 15% dihydroergotamine methanesulfonate (intake BH71) and solids containing 50% dihydroergotamine X-ray methanesulfonate (image BH70) -25 are amorphous. If the solid substances of the dihydroergotamine methane sulfonate are stored for 1 year at 5 ° C (BH52 image) and 35 ° C (BH53 image), the X-ray amorphous form of the dihydroergotamine methane sulfonate is retained.

30 In contrast to the above, the physical mixtures of the dihydroergotamine methanesulfonate with polyvinylpyrrolidone (Kollidon 25) clearly show the diffraction lines of the crystalline dihydroergotamine methanesulfonate (photo BH54). The crystalline form of the dihydroergotamine methanesulfonate is retained by storing the physi-35 mixtures for 1 year at 35 ° C. (photo BH55).

The solid substance can be processed together with the usual additives in a manner known per se to form galenical preparations, for example tablets, hard and soft gelatin capsules and dragees.

Organic or inorganic auxiliaries such as binders, lubricants, fillers and wetting agents can also be used as additives in the manufacture of tablets 45. In addition, the pharmaceutical preparation can also contain colorants, flavors, sweeteners, etc. Calcium carbonate, sodium bicarbonate, lactose, starch and talc as granulating agents, starch and alginic acid as disintegrants, starch and gelatin as binders, and magnesium stearate, stearic acid and talc as lubricants and pharmaceutically customary retardants, for example waxes, can be used as auxiliary substances for the production of tablets , Fats, cellulose derivatives and other polymers can be used. The tablets can be coated or uncoated, the coating being applied in a manner known per se.

To produce soft gelatin capsules, the solid substance mentioned above is processed in a manner known per se with a mixture of, for example, glycerol, sorbitol, 60 water and a preservative and, if appropriate, dye, and to produce hard gelatin capsules the solid substance mentioned above is processed per se known way with pharmaceutically common excipients.

65

Dragees are produced in a manner known per se by coating tablet cores, for example.

3rd

643 737

A suitable tablet composition consists of 16.3 mg of the solid obtained by the above process, 104.0 mg lactose, 15.0 mg corn starch, 12.0 mg talc, 32.0 mg cellulose powder and 0.7 mg silicon dioxide.

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

Suitable mixtures for filling hard gelatin capsules are obtained by mixing 16.3 mg of the solid obtained by the above process, 0.7 mg of silicon dioxide, 13.0 mg of corn starch and 65.0 mg of lactose.

example 1

34.6 g of dihydroergotamine methanesulfonate, 195.4 g of polyvinylpyrrolidone (average mol. Wt. 25,000) and 500 ml of methanol are placed in a flask with a volume of 41. The flask is connected to a rotary evaporator. At a bath temperature of 60 ° C the contents are heated to approx. 60 ° C with the piston rotating. This creates a clear solution.

As much methanol is distilled off from the solution under reduced pressure (approx. 250 torr) and a bath temperature of 60 ° C. until the residue has reached a syrup-like consistency. This mass is placed in an evaporating dish and kept at room temperature for about 2 hours. This is followed by drying (vacuum drying cabinet, 30 ° C, approx. 1 torr, approx. 12 hours), grinding and drying.

The powder produced is processed into the pharmaceutical form with customary pharmaceutically used auxiliaries.

Example 2

34.6 g of di-hydroergotamine methanesulfonate, 193.165 g of polyvinylpyrrolidone (average mol. Wt. 25,000), 2.26 g of polyethylene glycol s 1800 stearate and 500 ml of methanol are placed in a flask of 41 volume. The flask is connected to a rotary evaporator. At a bath temperature of 60 ° C the contents are heated to approx. 60 ° C with the piston rotating. This creates a clear solution.

10 A sufficient amount of methanol is distilled off from the solution under reduced pressure (approx. 250 torr) and a bath temperature of 60 ° C. until the residue has reached a syrup-like consistency. This mass is placed in an evaporation dish and kept at room temperature for about 2 hours. This is followed by drying (vacuum drying cabinet, 30 ° C, approx. 1 torr, approx. 12 hours), grinding and drying.

The powder produced is processed into common pharmaceutical form with customary pharma-20 adjuvants.

Example 3

Using the methods described in Examples 1 and 2 and replacing dihydroergotamine methanesulfonate with equivalent proportions of dihydroergocristine methanesulfonate, dihydroergocryptin methanesulfonate and dihydroergocornin methanesulfonate or mixtures thereof, solid substances of this hydrogenated ergot are obtained -30 peptide alkaloids.

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1 sheet of drawings

Claims (3)

643737 PATENT CLAIMS 1. A process for the production of a solid substance from er-peptide alkaloids, their hydrogenated forms or their salts and polyvinylpyrrolidone, characterized in that ergot peptide alkaloids, their hydrogenated forms or their salts and polyvinylpyrrolidone are dissolved in a solvent and the solvent is then removed. 2. The method according to claim 1, characterized in that the reactants are dissolved in a lower alcohol at temperatures of 30 to 70 ° C. 3. The method according to claim 1, characterized in that the residue obtained after removal of the solvent is ground to a fine powder.