NL7909105A - METHOD FOR PREPARING A GALENIC MEDICINE - Google Patents

Description

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Method of preparing a galenic drug.

The invention relates to a method of preparing galenic drugs for the oral administration of ergot alkaloids, which are distinguished by a long-lasting effect and a good bioavailability of the active ingredient.

It has long been recognized by medical specialists that in many circumstances it is recommended to administer a drug once a day rather than several times a day. This can be done using the so-called "retard systems" by delaying and delaying the release of the active ingredient, with the intention of a longer duration. effect of the therapeutic effect. In the field of ergot therapy, slowing down using classic systems, for example with a matrix-15 system or by microencapsulation, always entails a significant reduction in total bioavailability.

It is also known that ergot alkaloids are stable in the presence of acids, which means that they do not decompose in gastric juices and that the absorption of ergot alkaloids takes place mainly in the intestinal tract. Therefore, entero-coated drugs containing an ergot alkaloid were not expected to provide improved bioavailability.

Therefore, it is surprising that using an entero coating not only significantly extends the duration of action of an ergot alkaloid, but additionally improves overall bioavailability to a significant extent if the coated core contains a polyalkoxyalkylene sterol ether in addition to the ergot alkaloid. .

The invention is therefore particularly directed. 7909105 · *

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2 to a solid entero-coated drug in unit dosage form for oral use, the core of which contains an ergot alkaloid and a polyalkoxyalkylene sterol ether.

The invention also provides a method for preparing the medicaments of the invention by providing an entero-coating layer to a core containing an ergot alkaloid and a polyalkoxyalkylene sterol ether (hereinafter referred to as sterol ether ").

The term "core" includes any mixture of an ergot alkaloid and a sterol ether, optionally mixed with other physiologically acceptable material, which may be surrounded by an entero coating. The word "core" in a broad sense includes not only tablets, pellets or granules, but also capsules, for example soft capsules or capsules of hard gelatin filled with a liquid or waxy mixture of an ergot alkaloid, a sterol ether and optionally pharmaceutically acceptable material. Such capsules can then be entero-coated, for example in a conventional manner.

If tablet cores are used, they preferably have a hardness between about 10 and about 70N.

The pellets or granules can be used, after applying the entero coating layer, as such or for filling capsules, for example hard gelatin capsules. Thus, suitable uses of the medicaments of the invention are tablets, pellets, granules and capsules.

The term "ergot alkaloids" includes natural ergot alkaloids, such as ergotamine, ergocristine, α-ergocryptine, S-ergocryptine and ergocornine, and synthetic and semi-synthetic derivatives thereof, such as ergovaline, dihydroergotoxin (also known as co-dienocrine) and dihydroergotamine in free base form , or in the form of an acid addition salt thereof with pharmaceutically acceptable, organic or inorganic acids, such as methanesulfonic acid, maleic acid, tartaric acid or hydrochloric acid.

35 The active ingredients of particular interest 7909105 i _ A.

3 to be used in the process of the invention are compounds of formula 1, wherein a hydrogen or halogen atom, R 2 is a hydrogen atom or an alkyl group having at most k carbon atoms, R 1 is an isopropyl, sec-butyl, isobutyl-5 or benzyl group and a methyl, ethyl or isopropyl group and wherein a hydrogen atom and Rg represent a hydrogen atom or the methoxy group, or wherein R 1 and Rg together form an additional bond, and mixtures thereof.

If R 1 represents a halogen atom, it is preferably bromine.

Especially recommended drugs according to the invention contain dihydroergotoxin, bromocryptine and / or dihydroergotamine, in free base form, or, preferably in the form of an acid addition salt, as active ingredient.

Preferred sterol ethers for use in the medicaments of the invention have a hydrophilic-lipophilic equilibrium value (HLB group number) between about 10 and about 20, especially between about 12 and 16. They are preferably ethers of lanosterol , dihydro-20 cholesterol and, in particular, from cholesterol or mixtures of such ethers. Especially suitable sterol ethers are sterols etherified with an average of 8 to 75, preferably 9 to 30, alkylene oxide units. The hydroxyl group at the end of the alkylene chain of such sterol ethers can be acylated in whole or in part, for example by acyl residues of aliphatic carboxylic acids, such as recommended by the acetyl group pounder, sterol ethers etherified with ethylene oxide and / or propylene oxide units.

Sterol ethers can be obtained in a conventional manner by etherifying the sterol with a corresponding amount of epoxide and, if desired, acylating the alcohols thus obtained. They are partly available on the market and are for example offered for sale by the company Amerchol under the name Solulan. Examples of Solulan ® products that are on the market and suitable in the medicaments according to the invention 7909105

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k which may be used are those which can be obtained by alkoxylation of, for example, a) 1 mol of cholesterol with about 2k mol of ethylene oxide (Solulan C-2h), cb) 1 equivalent of lanolin alcohols with about ^ (3 \ 16 equivalents of ethylene oxide ( Solulan ^ 16), c) I equivalent of lanolin alcohols with about 25 equivalents of ethylene oxide (Solulan® 25), d) 1 equivalent of lanolin alcohols with about 10 75 equivalents of ethylene oxide (Solulanw 16), e) 1 equivalent of lanolin alcohols with about

Cr) 10 equivalents of propylene oxide (Solulan ^ PB-10) and also the f) partially acetylated derivative of 1 equivalent of lanolin alcohols ethoxylated with approximately (H) 15 10 equivalents of ethylene oxide (Solulan ^ 98 and the g) fully acetylated derivative of 1 equivalent of lanolin alcohols ethoxylated with about 9 equivalents of ethylene oxide (Solulan ^ 97)

The designation "about" in the above a) to g) indicates that the said number of ethylene oxide or propylene oxide equivalents in question is an average value, ie some sterol ethers contain more or less ethyleneoxy or propyleneoxy groups .

Lanolin alcohols are also known as wool fat-alcohols (Handbuch der Kosmetika und Riechstoffe, 2 ed. 1950, vol. I, p. 1101 (Janistyn)) are a mixture of cholesterol, dihydrocholesterol and lanosterol.

By the term "entero coating", any pharmaceutically acceptable coating that prevents the release of the active ingredient in the stomach and sufficient disintegration in the gut (through contact with approximately neutral or alkaline intestinal fluids) prevents the absorption of the active ingredient intended to enable the walls of the intestinal tract. Various in vitro tests to determine whether or not a coating can be considered an entero coating 7909105 fc.

5 have been published in the pharmacopoeias of different countries.

More specifically, the term "entero coating" according to the invention refers to a coating which remains intact for at least 1 hour, for example 2 hours, on contact with artificial gastric juices, such as HCl with a pH of 1.2 at a temperature between 36 and 38 ° C and then decomposes after 30 min into artificial intestinal fluids, such as a KEyPO 2 buffered solution with a pH of 6.8.

The thickness of the coating layer can vary depending on its permeability to water and acids and the desired retarding effect. In general, however, satisfactory results are obtained with a coating layer with a thickness between 5 - 100 µm, preferably between 20 - 80 µm.

The coating layer is suitably selected from macromolecular polymers. Suitable polymers are disclosed in, for example, Hagers Handbuch der pharmazeutischer Praxis, ke print, vol 7a, pages 739 to 7 ^ 2 and 776 to 778 (Springer Verlag, 1971) and in Remington's Pharmaceutical Sciences, 13th edition, pages 1689 to 1691 ( Mack Publ. Co., 1970) and include, for example, cellulose ester derivatives, cellulose ethers, acrylic resins, such as methyl acrylate copolymers, and copolymers of maleic acid and phthalic acid derivatives.

The recommended films are made from cellulose acetate phthalate, copolymers derived from methyl acrylic acid and its esters, which contain at least Ho% methyl acrylate-25 and especially hydroxypropyl methyl cellulose phthalate.

An example of a suitable cellulose acetate phthalate is the product CAP marketed (Eastman Kodak, Rochester N.I., USA). Examples of suitable hydroxypropyl methyl cellulose phthalates are the products marketed HP 50 and HP 55 20 (Shinetsu, Tokyo, Japan).

Since a coating mainly consisting of CAP disintegrates at a higher pH than, for example, a coating mainly consisting of HP 50, the release of the active ingredient from drugs provided with the first-mentioned coating will become more pronounced. 7909105 Λ

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6 then deprived of drugs after the latter coating. In this way, a suitable retarding effect can be obtained by suitably choosing the coating layer, which optimally takes into account the properties of the active agent concerned.

The method of the invention can be carried out in a manner similar to methods known for applying an entero-coating.

For example, to produce coated tablets, pellets or granules, the cores are sprayed with a solution of the entero coating layer.

Suitable solvents for this are, for example, organic solvents, for example an alkanol, such as ethanol, a ketone, such as acetone, halogenated hydrocarbons, such as CHgClg, or mixtures of comparable solvents, for example a mixture of equal amounts of ethanol and acetone. Suitably, an emollient, such as di-n-butylft salate, will be added to such a solution.

It is suitable, for example, to heat the cores to a temperature between 25 and * K) ° C before spraying, using warm air with a temperature of between 0 and 70 ° C. In order to avoid the cores sticking together, spraying is preferably interrupted at certain intervals and the cores are then reheated. The spray pressure can vary within wide limits and generally satisfactory results will be obtained with a spray pressure between about 1 and about 1.5 bar. However, it is also possible to carry out the method without interrupting the spraying, for example by automatically controlling the quantity to be sprayed as a function of the temperature of the blowing air and / or cores.

The enteric coated drugs of the invention have the beneficial effect that, after peroral administration to humans, the maximum concentration of the active ingredient in the blood plasma is reached after about U to 6 hours, while 7909105 is the starting site after administration of a conventional drug, for example one tablet, already reached after 0.5 to 1 hour.

The sustained releasing action of the medicaments of the invention is also illustrated by determination of the concentration of the active ingredient (and metabolites) in the excreted urine. The maximum concentration in the urine is found after about 6 hours after the administration, while this maximum concentration is reached after about 2 hours when a normal preparation is administered.

In addition, the plasma level after administration of the medicaments according to the invention will be between 6 and 2 hours after administration, which is higher than after administration of a normal medicine, for instance a tablet. This is illustrated by the area below the plasma level (AUC) and is a measure of the excellent bioavailability of the drugs of the invention.

Thus, the medicaments of the invention exert a therapeutically desired retarding action along with excellent bioavailability and thus allow treatment with one unit dose per day.

The medicaments according to the invention, in particular tablets, can additionally be provided with an external medicament layer. This outer layer may contain, in addition to an active ingredient, such as an ergot alkaloid, carriers and / or fillers which are soluble or dispersible in the gastric juices, such as talc, microcrystalline cellulose, magnesium stearate, mannitol, polyvinylpyrrolidone, etc. . Such drugs can be used, for example, if a quick start-up action is desired. The high initial concentration of the ergot-alkaloid in the blood is then maintained by slow release from the nucleus into the intestinal tract.

The optimum weight ratio in the core of the ergot alkaloid to the sterol ether depends to a great extent on the physical properties of the respective sterol ether, the additives used and the type and dimensions of the drug.

7909105 ka *, 8

For example, the amount of the aforementioned Sololan® 16, Solulan® 25 and Solulan® C-2k sterol ethers is limited by their waxy nature.

In general, however, satisfactory results are obtained if a weight ratio of ergot alkaloid to sterol ether between 1: 1 and 1:25, preferably between 1: 2 and 1: 8, especially 1: U, is used. The range 1: 2 to 1: 8 is especially recommended if the cores are in the form of a solid solution of the ergot alkaloid, especially if polyvinylpyrrolidone is used as a solid solvent.

The cores can be processed with conventional excipients, for example, binders, lubricants, fillers and disintegrants. Suitable fillers for the manufacture of tablet cores are, for example, silica gel, calcium carbonate, sodium carbonate, lactose, starch and talc, suitable granulating agents and disintegrating agents are, for example, starch and alginic acid, suitable binders are, for example, starch and gelatin and suitable lubricants are for example, stearic acid and talc.

The use of solid solution cores is a special embodiment of the invention. Such cores can be manufactured as follows.

An ergot alkaloid, a sterol ether and a pharmaceutically acceptable polymer, which is at least partially soluble in an aqueous medium, are mixed, in particular a polyalkylene glycol, polyvinylpyrrolidone, a copolymer of vinyl pyrrolidone and vinyl acetate, or a mixture thereof.

Examples of suitable polyalkylene glycols are polyethylene glycol and polypropylene glycol and their copolymers with a molecular weight between 200 and 20,000, preferably between U000 and 15 * 000, especially between 6000 and 13,000. With "polyvinylpyrrolidone", non-crosslinked poly (vinyl) pyrrolidone-2, suitably having a molecular weight of between 10,000 and 100,000, preferably between 11,500 to 1,000, especially between 20,000 and 7909105 9 30,000. The copolymer of vinyl pyrrolidone and vinyl acetate preferably contains 60 wt / s vinyl pyrrolidone and 40 wt% vinyl acetate and preferably has a molecular weight of between 30,000 and 100,000, in particular between 40,000 and 90,000.

If desired, stabilizers, such as acids, preferably methanesulfonic acid, maleic acid and tartaric acid, can be added to adjust the pH of the drug. The recommended pH range for the drug will be between 4 and 6, preferably between 4 and 5.

The weight ratio of ergot alkaloid to sterol ether to pharmaceutically acceptable polymer can vary within wide limits; in general, however, satisfactory results are obtained with ratios ranging between 1: 1-10: 0.1 - 10, especially between 1: 2 - 8: 0.1 - 10 and 15 especially between 1: 2-5 : 0.1-5.

The polymers in solid form are used to prepare the solid solutions used in the invention. If one of the polymers used is liquid at room temperature, for example a polyalkylene glycol with a molecular weight of about 200, it is obvious that such a polymer is used not only, but together with a polymer that is solid at room temperature.

The aforementioned components are dissolved by stirring in a suitable solvent, for example in a low alkanol, such as ethanol or methanol, or in chloroform, at a temperature between 30 and 70 ° C, preferably between 40 and 60 ° C. The solvent can be removed by evaporation under reduced pressure at the same temperature. When preparing a solution, it is also possible to add only a portion of the polymer and any additional ingredients used and the remainder during the evaporation of the solvent. The resulting clear solution is allowed to solidify at room temperature (15-25 ° C), after which the resulting solid solution or dispersion can be ground to a fine powder and, suitably under reduced pressure at 30 ° C, dried to give 7909105 *. 10 remove all traces of the solvent.

The solid solution (core of the drug) obtained by the above-described method is then processed in a known manner with pharmaceutically acceptable diluents and / or carriers, optionally with an additional amount of sterol ether, the total content of sterol ether the core will preferably lie within the aforementioned ranges.

Example I

Jq Tablet cores, consisting of 3 g of dihydroergotamine, 75 g of cholesterol, which has been ethoxylated with approximately 2k ml of ethylene oxide (Solulan® C-21 *) and 22 g of disperse silica gel, were heated at 30 ° C for 10 min. warm air at a temperature of 50 ° C in a coating pan, which was continuously turned. The tablet cores were then sprayed with a spray gun with a solution of 5 g of hydroxypropyl methylcellulose fValate (HP 50) and 1.35 g of di-n-butyl phalate in a mixture of equal parts. ethanol and acetone, at a spray pressure between 1 and 1.5 bar, according to the usual interval 20 spray coating methods, after which the coated tablets thus obtained were dried.

Example II

The procedure was the same as described in Example 1, but now using 75 g of lanolin alcohols ethoxylated with about 25 equivalents of ethylene oxide (Solulan® 25) instead of 75 g of cholesterol ethoxylated with about 2 moles of ethylene oxide.

Example III: coated tablets with cores in the form of a solid solution .__________________

15 g of dihydroergotoxin, methanesulfonate, 1.05 g (Solulan-C-2h), 33.95 g of polyvinylpyrrolidone (average molecular weight 25,000) and 250 ml of methanol were placed in a 1 liter round bottom. This flask was then connected to a rotary evaporator and rotated at a bath temperature of 60 ° C

7909105 11 until the temperature of the contents of the flask reached 60 ° C, whereby a countier solution was obtained.

The bath temperature was maintained at 60 ° C and the solvent evaporated under reduced pressure until the resulting residue had a syrup back consistency. This residue was then decanted in an evaporation bath and allowed to solidify for 2 hours at room temperature.

This solid residue was dried in a vacuum oven at a pressure of about 1 atmosphere 10 'at 30 ° C for about 12 hours, ground to a fine powder and dried again.

Then 26.8 g of the solid solution thus obtained were mixed with the following additives of silicon dioxide 1.0 g (Aerosil® 200, Degussa) polyvinylpyrrolidone 8.0 g (cross-linked) corn starch 20.0 g talc 30.0 g

Solulan ® C-2U 30.0 g 20 cellulose granules U2.0 g (Elcema G 250) lactose 122.0 g until a homogeneous mixture is obtained, which is then pressed in a usual manner to tablet cores weighing 140, 0 mg (hardness 10-32N).

The cores thus obtained were then sprayed, in a manner similar to that described in Example 1, with a solution of cellulose acetate phthalate (CAP) 90.0 g 30 di-n-butyl phthalate 22.5 g acetone 21 + 0.0 g ethanol 21.0 g of dichloromethane 526.5 g of 900.0 g of 35 until the cores containing about 10 mg of the cellulose acetate phthalate.

7909105 ƒ * 12 di-n-butyl phthalate mixture per core were coated.

The coated tablets thus obtained are resistant to gastric juices, since the cores remained intact after 1 hour of treatment with artificial gastric juices with a pH of 1.2. The disintegration time in artificial intestinal juices is at a pH of 5.5 over an hour, at a pH of 6.0 is between 23 and 28 minutes, and at a pH of 6.8 between 12 and 16 minutes.

Example IV

The procedure was the same as described in Example 3, but now the tablet cores of 100 mg were sprayed with a solution of 11 * 0.0 g of hydroxypropylmethylcellulose phthalate (HP 50) and 28 g of di-n-butyl phthalate in a mixture of 616 g of ethanol and 616 g of acetone, until the cores were coated with about 9 mg of the hydroxypropylmethylcellulose phthalate-di-n-butyl phthalate-15 mixture (ratio 10: 2) per core.

Example V

°. .e

In accordance with Example III, a solid solution of 1+ g of dihydroergotoxin, methanesulfonate, 0.3 g of Solulan® 16 and 9.1 g of polyvinylpyrrolidone (average molecular weight 2000) was prepared.

Then this solid solution was mixed with silicon dioxide 0.5 g polyvinylpyrrolidone 1 *, 0 g (average molecular weight 2000) corn starch 10.0 g talc 15.0 g

Solulan® 10 15.0 g of cellulose powder 21.0 g of (Elcema G 250) lactose 61.1 g and compressed this mixture into tablets weighing 11 * 0.0 mg.

Thereafter, the tablet cores thus obtained were sprayed, in a manner similar to that described in Example IV, until each core was coated with either about 10 rag or about 7909105 * & 13 15 mg of the mixture of hydroxypropylmethylcellulose phthalate and di-n-butyl phthalate ash. .

In accordance with the procedure described in the previous examples, the 5 tablets characterized in Table A were obtained.

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7909105

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HPMCP = hydroxypropylmethylcellulo sephthalate (1) The cores of these tablets were pressed until they had a hardness of 50-6ON.

Example XIV; Tablet with a drug-containing outer layer (coated tablet) a) Cores were prepared in a manner similar to that described in Example III by 26.8 g of a solid solution (containing 8.0 g of dihydroergotamine mesilate, 10 0.6 g of Solulan 0 -2h and 18.2 g of polyvinylpyrrolidone contained to be mixed with 1.0 g of very fine silica gel, 8.0 g of cross-linked polyvinylpyrrolidone, 20 g of corn starch, 1 * 7.1 * g of Solulan® C-2l *, 1 * 2.0 g of cellulose granules, 10 l *, 8 g lactose and 30.0 g talc, until a homogeneous mixture was obtained, after which this mixture was pressed into cores weighing 11 * 0.0 mg.

b) The cores thus obtained were sprayed with a solution of 11 * 0.0 g hydroxypropylmethylcellulose phthalate and 28.0 g di-n-butyl phthalate in a mixture of 616 g ethanol and 616 g acetone until the cores were at about 10 mg per tablet lined.

c) The outer layer containing drug was prepared by mixing 1.0 g of dihydroergotamine mesilate with 1.0 g of fine silica gel, 6.0 g of magnesium stearate, 166.8 g of cellulose powder, 1 * 0.0 g of talc, 191 * 2 g corn starch and 31 * 8.0 g of calcium hydrogen phosphate until a homogeneous mixture is obtained. Finally, this mixture was pressed with the coated tablets (according to Example XlVb), whereby tablets with an outer layer containing a drug and a total weight of 530.0 mg per tablet were obtained.

Example XV

Proceeding in a similar manner as described in Examples 1 - XIV, using 1 * mg bromocryptine, 1 * mg dihydroergovaline or 1 * mg dihydroergonin instead of dihydroergotoxin or dihydroergotamine, yielding tablets containing the corresponding ergot alkaloid as active 7909105} 16 component, obtained.

Example XVI:

Clinical research

The action of the drug according to Example IV was obtained with a solid solution of dihydroergotoxin mesilate and tartaric acid (drug A) and a conventional drug based on dihydroergotoxin mesilate (drug B).

Each treated subject obtained ^ mg of dihydroergotoxin mesilate.

The results obtained are shown in the following Table B.

Table B

Composition Example IV A B

concentration in plasma after 20 '0.01 ^ 0.012 ** 0.376 ^ 0.078 0.215 ^ 0.06¾ 1 * 0' 0.092 ^ 0.039 *** 0.1 * 72 ^ 0.070 0.506 ^ 0.01 * 9 maximum concentration 0.615— 0.077 0.507-0.071 0.538 ^ 0.037 in the plasma (ng.ml ”1) time (in hours) thereafter 3.33- Ο, ^ δ *** 0.6¾ +0.06 0.78 ^ 0.12 the maximum bioavailability AUC (0-2¾ hours) ^ 778-0, ^ 5 * 3,875-0,279 3.75 ^ 0.171 (ng. ml ”1)% was removed by 1.010 ^ 0.15 ^ 0.787-0.121 0.7 ^ 0.081 urine (0-96 hours)

The importance of the differences found between the action of the drug of Example IV and drug B was calculated according to the Student T-test (* P <0.05, ** P <0.01 and “p-C 0.001).

The values stated in the previous table show the good retarding effect and the excellent bioavailability of the medicaments according to the invention. On the other hand, a markedly less bioavailability (60-70% of drug B) was found when a commercial 7909105 * 17 formulation of dihydroergotoxin with delayed action was tested in a conventional manner.

Corresponding tests with other drugs according to the invention gave correspondingly good results.

However, a commercially available dihydroergotamine drug with delayed action in a conventional manner exhibited a bioavailability that was about 30 to 1% lower than that found with the corresponding undelayed comparator.

7909135

Claims (29)

A method of preparing a solid entero-coated medicament in unit dosage form for oral use, characterized in that a core 5 is used in the medicament containing an ergot alkaloid and a polyalkoxyalkylene sterol ether. 2. Process according to claim 1, characterized in that the ergot alkaloid used is a compound of formula 1, in which R1 is a hydrogen or halogen atom, Rg is a hydrogen atom or an alkyl group with at most 4 carbon atoms, R1 is an isopropyl-, sec.-butyl, isobutyl or benzyl group and R ^ represent a methyl, ethyl or isopropyl group and either represent a hydrogen atom and Rg represent a hydrogen atom or a methoxy group, or R ^ and Rg together form an additional bond, or mixtures thereof. Process according to any one of the preceding claims, characterized in that the ergot alkaloid used is dihydroergotamine. The method according to claim 1 or 2, characterized in that the ergot alkaloid dihydroergotoxin used is 20. Process according to claim 1 or 2, characterized in that the ergot alkaloid is bromergocryptine. 6. Process according to claims 1-5, characterized in that a polyalkoxyalkylene sterol ether with a hydrophilic-lipophilic balance between 10 and 20 is used. Process according to claim 6, characterized in that a polyalkoxyalkylene sterol ether with a hydrophilic-lipophilic balance of 12 to 16 is used. 8. A method according to any one of the preceding claims, characterized in that the sterol part of the polyalkoxyalkylene sterol ether is lanosterol, dihydrocholesterine and / or cholesterine. 9. Process according to any one of the preceding claims, characterized in that as polyalkoxyalkylene sterol ether a 7909105 V s sterol etherified with about 8 to about 75 alkylene oxide units is used. Method according to claim 9, characterized in. using a sterol etherified with about 9 to about 30 alkylene units. 11. Process according to any one of the preceding claims, characterized in that a sterol etherified with ethylene oxide or propylene oxide is used as polyalkoxyalkylene sterol ether. A method according to any one of the preceding claims, characterized in that the eifcero coating layer is selected from a cellulose ester derivative, a cellulose ether, an acrylic resin or a copolymer of maleic acid and phthalic acid derivatives. Method according to claim 12, characterized in. 15 which is the entero coating of cellulose acetate phthalate. 1¾. Process according to claim 12, characterized in that the entero-coating layer is of hydroxypropyl methylcellulose phthalate. __ 15. A method according to claim 12, characterized in that the entero-coating layer is of methyl acrylic acid and / or esters thereof containing at least ho% of methyl acrylic acid. A method according to any one of the preceding claims, characterized in that a plasticizer is included in the entero coating layer. Process according to claim 16, characterized in that di-n-butyl phthalate is used as a plasticizer. 18. Process according to claims 1-17, characterized in that the medicament is manufactured in the form of tablets, granules, pellets or capsules. Process according to claim 18, characterized in that tablets are manufactured, these tablets being additionally surrounded by an outer layer containing a medicament. 20. Process according to any one of the preceding claims, characterized in that a weight ratio of ergot 7909105 alk 4 alkaloid to polyalkoxyalkylene sterol ether between 1: 1 and 1:25 is used. 21. Process according to claim 20, characterized in that the weight ratio ergot alkaloid cj to polyalkoxyalkylene sterol ether is adjusted between 1: 2 and 1: 8. Process according to any one of the preceding claims, characterized in that a core in solid solution form is used. 23. Process according to claim 22, characterized in that a core is used which contains a polyalkylene glycol, polyvinylpyrrolidone and / or a copolymer of vinylpyrrolidone and vinyl acetate as a solid solvent. 2k. Process according to claim 23, characterized in that the weight ratio in the core of ergot alkaloid to polyalkoxyalkylene sterol ether to solid solvent is adjusted between 1: 1-10: 0.1-10. 25. Process according to claim 21, characterized in that a weight ratio between 1: 2-8: 0, Ι-ΙΟ is set. 26. Process according to claim 25, characterized in that the weight ratio is adjusted between 1: 2-5: 0.1-5. 27. Process according to claims 22-26, characterized in that a core is used which contains a stabilizer 25. 28. A method according to claim 27, characterized in that the core is stabilized by adjusting its pH with an acid between 1 and 6. 29. A process according to any one of the preceding claims, characterized in that a core containing an ergot alkaloid and a polyalkoxyalkylene sterol ether is entero-coated. A method according to claim 29, characterized in that the coating is carried out in a usual manner. 31. Process according to claim 30, 7909105, characterized in that entero-coated tablets, pellets or granules are prepared in which the cores are sprayed with a solution of the entero-coating material. 32. Process according to claim 31, characterized in that the core is heated before spraying to a temperature between 25 and 40 ° C. 33. Methods as described in the description and / or examples. 31 *. Formed medicaments obtained by a method according to claims 1 to 33. Λ 79 0 9 1 0 5 4 Jf * C-NH / 0V / N'N ^ Ri * \\ "VIH 'R, OCjNxRi HN-- * -R, 1 C Sandoz AG 7909105 SANDOZ AG ta Basel, Switzerland