NO144468B - PROCEDURE FOR THE PREPARATION OF A SOLID SUBSTANCE CONTAINING A DRY-ALKALOID COMPONENT - Google Patents

Description

The present invention relates to a method

for the production of a solid substance containing an alkaloid component, consisting of one or more alkaloids, their synthetic derivatives or hydrogenated forms, respectively their salts or mixtures thereof,

and the peculiarity of the procedure according to up-

the invention is that the ash alkaloid components together with a pharmaceutical tolerable polymer and possibly surfactants are dissolved in a solvent, consisting of e.g. a lower alcohol, and from the resulting solution the solvent is optionally evaporated after further addition of polymer, the polymer being at least slightly soluble in an aqueous medium and consisting of an uncrosslinked poly(N-vinyl)pyrrolidone with a molecular weight of 10,000 - 100; 000, and as the ratio between the moth alkaloid component and polymer and any other additives present is from 0.1 : 99.9 to 50 : 50..

In an advantageous embodiment of the invention, polyethylene glycol fatty acid esters are used as surfactant.

These features of the invention appear from the patent claims.

The method according to the invention is carried out as described in the following: Meldrøye alkaloids, such as e.g. ergotamine, ergocristine, ergo-cryptine, ergocornine, respectively their synthetic derivatives, such as e.g. ergovaline, respectively their hydrogenated forms and their mixtures respectively their salts, the salts being suitably used with tolerable organic acids, such as e.g. methanesulfonates, maleinates, tartrates, etc. or inorganic acids such as hydrochlorides, are mixed with pharmaceutically acceptable in an aqueous medium at least slightly soluble polymers of poly-N-vinylpyrrolidone-2 (uncrosslinked) with molecular weights between 10,000 and 100,000, preferably 20,000 to 30,000, optionally together with pharmaceutically acceptable additives such as surfactants, such as sodium lauryl sulfate, polyethylene glycol fatty acid esters, especially polyethylene glycol stearate, as well as stability-promoting additives, such as e.g. acids, especially methanesulfonic acid, maleic acid, tartaric acid to achieve a pH value in the preparation form of 4 to 5, with the weight ratio between the alkaloids and their salts and the polyvinylpyrrolidone used as well as any additional additives used being from 0.1 : 99 .9 to 50 : 50, preferably 5 : 95 to 15 : 85. The weight ratio between the surfactants alone and the amount of active ingredient used must be from 1:45 to 10:1.

The above-mentioned components 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, whereby a clear solution is obtained. The solvent is then removed in vacuo at temperatures . from 30 to 70°C, preferably 40 to 60°C. Hereby, it is possible that only a part of the polyvinylpyrrolidone and any other additives are used in the preparation of the solution and the addition of the remaining quantity takes place during the evaporation of the solution. The mixed clear liquid is allowed to solidify at room temperature (15 to 25°C). The product obtained is ground to a fine powder and dried in a vacuum at approx. 30°C until complete removal of the solvent.

The solid substance obtained according to the above-mentioned method can be combined with common additives in a manner known per se for galenic preparations, e.g. tablets, hard and soft gelatin capsules as well as dragees.

In the production of tablets, organic or inorganic auxiliaries such as binders, lubricants, fillers and wetting agents can also be used as additives.

In addition to this, the pharmaceutical preparation may further contain colourings, aroma components, sweeteners etc.

As excipients for the production of tablets can be used: Calcium carbonate, sodium bicarbonate, milk sugar, starch, talc, as granulating agent and disintegrant starch and alginic acid can be used, as binder starch, gelatin,

and as a lubricant magnesium stearate, stearic acid and talc as well as pharmaceutically common retarders, e.g. waxes, fats, cellulose derivatives and other polymers.

The tablets may optionally be coated, the possible coating being applied in a manner known per se.

For the production of soft gelatin capsules, the above is processed. said solid substance in a manner known per se with a mixture

ding of e.g. glycerol, sorbitol, water as well as a preservative and possibly colouring, and for the production of hard gelatin capsules, the above-mentioned solid substance is processed in a manner known per se with pharmaceutical common excipients.

The production of dragees takes place in a manner known per se

when dragging e.g. tablet cores.

EXAMPLE 1:

34.6 g of dihydroergotamine methanesulfonate, 195.4 g of polyvinylpyrrolidone (average molecular weight 25,000) and 500 ml of methanol are added to a 4 l flask. The flask is connected to a rotary evaporator.

At a bath temperature of 60°C, the contents are heated with a rotating flask to approx. 60°C and thereby a clear solution is formed.

The solution is distilled off at reduced pressure (approx. 250 torr)

and a bath temperature of 60°C so much methanol that the residue achieves a syrupy consistency. This mass is brought into an evaporation dish and kept for about 2 hours at room temperature. Then the drying takes place (vacuum drying cabinet, 30°C, approx. 1 torr,

about. 12 hours), the painting and subsequent drying.

The produced powder is processed with common pharmaceutical excipients into preparation form.

EXAMPLE 2:

34.6 g of dihydroergotamine methanesulfonate, 193.16 g of polyvinylpyrrolidone (average molecular weight 25,000), 2.26 g of polyethylene glycol 1800 stearate and 500 ml of methanol are introduced into a flask with a volume of 4 1. The flask is connected to a rotary evaporator. At a bath temperature of 60°C, the contents are heated with a rotating flask to approx. 60°C. This creates a clear solution.

From the solution, so much methanol is distilled off at reduced pressure (approx. 250 torr) and a bath temperature of 60°C that the residue has achieved a syrup-like consistency. This mass is brought into an evaporation dish and kept for about 2 hours at room temperature. Then the drying takes place (vacuum drying cabinet, 30°C,

about. 1 torr, 12 hours), the paint and subsequent drying.

The produced powder is processed with common pharmaceutical excipients into preparation form.

In Hager's Handbuch der pharm. Praxis, volume VII, part A, pages 689 - 690, the section regarding "Tabletten mit verzogerter Wirtschaftsabgabe", deals with the manufacture of pharmaceutical delivery forms with delayed active ingredient release. On page 690, lines 9-14, administration forms are mentioned which contain the active substances embedded in insoluble skeletal substances such as polyvinylpyrrolidone and from which (according to the previous paragraph) the active substances are released delayed. As the skeletal substances must be insoluble, it is obvious that this is three-dimensionally cross-linked polyvinylpyrrolidone.

In comparison with the delivery forms according to the relevant state of the art, no insoluble skeletal substances are used in the present invention, such as e.g.

a three-dimensionally crosslinked polyvinylpyrrolidone, but in contrast a water-soluble non-crosslinked polyvinylpyrrolidone. Thereby, the solid is given completely different properties. In contrast to the delivery forms with delayed active substance release according to the state of the art in question, the delivery forms made possible by the invention improve the dissolution rate and resorption of the active substance to a considerable extent.

Correspondingly, the above-mentioned literature pertains to delivery forms for therapeutically active compounds which differ in principle from the delivery forms which can be achieved by the present invention.

British patent document 1,175,437 contains examples of dragee recipes for various mealybug alkaloids, where polyvihyi pyrrolidori only fulfills the function as a binder for the granulation. This literature site has no connection with the present invention, where the addition of polyvinylpyrrolidone takes place for a different purpose and with a different result than in the present invention, as the inventive use of polyvinylpyrrolidone leads to a surprising improvement in the solubility and resorption properties of the active substance , which is then neither intended nor achieved at this state of the art.

In Norwegian patent document 93,807, only the production of

tablets with controlled release time for the active ingredient, obtained by mixing the active ingredient with a polymer and pressing the mixture. In this way, the active substance is embedded in the porous structure of the polymer and is slowly washed out from there during use.

The aforementioned patent document describes a form of delivery which, like the above-mentioned forms of delivery in Hager's Handbuch, aims at a delayed release of the active substance and therefore, because of and also because of the different type of active substance-polymer combination constitutes a completely different form of delivery than the one achieved by the present invention.

In Pharmazie 1971, pages 72 and 73, page 72, right column, describes the embedding of active substances in polymers (similar to the Norwegian patent document 93,807 and Hager's Handbuch) by which preparations with a prolonged effect are obtained. This chapter and also the other chapters on pages 72 and 73 deal with the production of retard drug forms. This also applies to the one in Chem. Abstract 75, 40326r mentioned article in Pharmazie 1971, pages 170 - 172, whereby four methods are mentioned for the production of granules with a retarding effect, whereby the active substances are mixed with substances that delay resorption (retardants).

The present invention, in contrast to the features from the above-mentioned literature, does not consist in the preparation of a physical mixture of the active substance with polyvinylpyrrolidone, or in an entrapment of the active substance in a polymer skeleton, but in the preparation of a combination of the components, i.e.

a homogeneous solid, whereby the active substance is combined with the polymer, i.e. polyvinylpyrrolidone (in a similar way as in an alloy). When combined with polyvinylpyrrolidone, the originally crystalline compounds of formula I pass into an amorphous form, which has surprisingly good solubility properties as well as a much higher dissolution rate.

Surprisingly - and this constitutes in several ways the essential aspect of the invention - the active substance is absorbed much better from this combination than from the previously known physical mixtures. For proof of the surprising effect of the solid substance produced in accordance with the invention, reference is made to the subsequent test report.

TRIAL REPORT

When using the powdery mildew alkaloid-containing solid which is obtained by the method according to the invention i

tablets, hard and soft gelatin capsules as well as dragees, a favorable resorption improvement of the active ingredient is achieved.'

In the following tables, the results obtained from an examination of the resorption based on an examination of the blood level values with dihydroergotamine in the form of the methanesulfonate are reproduced.

In the resorption studies, total resorption was determined from the jejunum loop in rats. (9 animals) with help. ouch. the method of Ochsenfahrt and D. Winne "Der Einfiuss der Druchblutung. åu die Resorption von Arzneimitteln aus dem Jejunum der Ratte", Nauhyn-Schiedeberg's Arch. Pharm. 264, 55-75 (1969). IN

the following table lists the amounts of dihydroergotamine methanesulfonate detected in mesenteric blood after administration of this compound as a pure substance, in the form of a commonly used aqueous ampoule solution and in the form of the solid substance obtained by the present invention (the solid substance and the pure substance was added in aqueous sodium chloride solution).

Blood count

When administering 5 mg/kg DHE-ms p.o. (n=number of animals) it was after fluorimetric determination of the dihydroergotamine in plasma (the fluorimetric determination of the dihydroergotamine took place after reaction with o-phthalaldehyde (OPT) in the plasma, whereby a fluorescence with a maximum at approximately 335/ 420 nm and a somewhat lower blank value than with the intrinsic fluorescence) on average determined the following values (ng/ml):

The ampoule solution was only administered to some of the animals for orientation. The values largely agree with the values for the pure substance for 1 hour.

The previous numerical values allow a conclusion that dihydroergotamine from the solid substance of dihydroergotamine-methanesulfonate and polyvinylpyrrolidone is resorbed 3.4 to 4 times better than after administration of the pure substance.

Dihydroergotamine methanesulfonate in dissolved form (as an ampoule) is admittedly absorbed twice as well as in pure form. but ocp does not reach the resorption rate of the pure form. The solid substance obtained by the present invention thus entails a genuine resorption advantage.

The blood level values for dihydroergotamine are - as can be concluded from the preceding table - after administration of the solid substance significantly higher than after administration of the pure form, either in solid or liquid form. In general, it can be said that the degree of resorption. of dihydroergotamine from the solid substance amounts to 24% <p>g when using the pure substance 10%.' Consequently, 2.4 times more dihydroergotamine is resorbed from the solid substance than from the pure substance. When you compare the two blood level maxima after hours, you arrive at the very similar factor of 2.6. This factor lies in total resorption. for the solid substance • as stated above, surprisingly higher (3.4 to 4 times).

This is all the more surprising in light of the general recognition of how difficult it is to achieve good resorption of hydrogenated ergot alkaloids.

Claims (2)

1. Process for the production of a solid substance containing an alkaloid component, consisting of one or more alkaloids, their synthetic derivatives or hydrogenated forms, respectively their salts or mixtures thereof, characterized in that alkaloid components together with a pharmaceutically acceptable polymer and even tuelt surfactants are dissolved in a solvent, consisting of e.g. a lower alcohol, and from the resulting solution the solvent is optionally evaporated after further addition of polymer, the polymer being at least slightly soluble in an aqueous medium and consisting of a non-crosslinked poly(N-vinyl)pyrrolidone with a molecular weight of 10,000 - 100,000, and in that the ratio between the ash alkaloid component and polymer and any other additives present is from 0.1 : 99.9 to 50 : 50. 2. Method as stated in claim 1, characterized in that polyethylene glycol fatty acid esters are used as surfactants.