CH642259A5 - GALENIC PREPARATIONS FOR ORAL APPLICATION OF ERGOTAL CALOIDS. - Google Patents

Description

The invention relates to pharmaceutical preparations for oral application of ergot alkaloids, which are characterized by a prolonged action and good bioavailability.

It is undisputed in the medical community that in many cases a single daily application of a drug is preferable to a multiple daily application. This can generally be achieved with so-called «retard systems», by delaying and delaying the release of the active ingredient, and aims to prolong the therapeutic effect. In the area of ergo t therapy, however, retardation with classic systems, e.g. with a matrix system or with the help of microcapsules, each brings about a considerable reduction in bioavailability.

It is also known that ergot compounds are acid stable, i.e. are not broken down in gastric juice and that the absorption of the ergot alkaloids takes place predominantly in the intestinal tract. One would then also not expect that the bioavailability of ergot alkaloids could be influenced favorably by means of a stomach-resistant coating.

It is therefore surprising that with the help of an enteric coating not only a significant lengthening

45 the duration of action of an ergot alkaloid can be observed, but that, moreover, the total bioavailability of the active ingredient is significantly improved if the cores provided with an enteric coating also contain a polyalkoxyalky-50 len sterol ether in addition to the ergot alkaloide.

The invention is therefore, more specifically, a preparation provided with an enteric coating for oral application, the core of which contains an ergot alkaloid and a polyalkoxyalkylene sterol ether. 55 According to the invention, the preparations are obtained by providing an enteric coating on a core which contains ergot alkaloid and a polyalkoxyalkylene sterol ether (hereinafter referred to as sterol ether).

60 The term “core” encompasses any mixture of an ergot alkaloid and a sterol ether, optionally with other physiologically compatible aids, which can be coated with a stomach-resistant coating. It follows that the expression "core", in the broadest sense, not only tablets, pellets and granules, but also capsules, e.g. B. soft gelatin capsule or hard gelatin capsule filled with a liquid or waxy mixture of an ergot alkaloid, a sterol ether and given

3rd

642 259

if includes pharmacologically acceptable excipients. Such capsules can then be coated with an enteric film, for example analogously to known methods. If tablet cores are used, they preferably have a hardness of approximately 10 to approximately 70N.

The pellets or granules can, after application of the enteric coating, be used as such or in capsules, e.g. B. Hardgelatin capsules are filled. Suitable forms of use of the preparations according to the invention are therefore tablets, pellets, granules or capsules.

The term “ergot alkaloids” includes natural ergot alkaloids such as ergotamine, ergocristin, a-ergocryptin, “ß-ergocryptin and ergocornin, synthetic or semisynthetic derivatives thereof such as ergovalin, dihydroergotoxin (also known as co-dergocrin) and dihydroergotamine in free form or in Form of their salts with pharmacologically acceptable organic or inorganic acids such as methanesulfonic acid, maleic acid, tartaric acid or hydrogen chloride.

The active ingredients to be administered in particular are compounds of the formula I

NH -

HN

wherein

R, for hydrogen or halogen,

R2 represents hydrogen or an alkyl group with 1-4 carbon atoms,

R3 for isopropyl, sec-butyl, isobutyl or benzyl,

R4 for methyl, ethyl or isopropyl,

R5 for hydrogen, and

R6 represents hydrogen or methoxy, or R5 and R6 together form a further bond or mixtures thereof.

If R! Halogen means it is preferably bromine.

Particularly preferred embodiments of the present invention contain dihydroergotamine, bromocryptin or dihydroergotoxin in free form or preferably in salt form as the active ingredient.

The sterol ethers according to the invention preferably have an average HLB value (hydrophilic-lipophilic balance = hydrophilic-lipophilic equilibrium value) of approximately 10 to approximately 20, in particular 12 to 16. They are preferably ethers of lanosterol, dihydrocholesterol and in particular of cholesterol or mixtures of such ether. Particularly suitable sterol ethers are sterols which are etherified with an average of 8 to 75, preferably an average of 9 to 30, alkylene oxide equivalents. The hydroxyl substituent of the last alkylene part of such sterol ethers can optionally be partially or completely acylated, for example with an acyl radical or aliphatic carboxylic acid such as acetyl.

Sterol ethers which are etherified with ethylene oxide or propylene oxide are particularly preferred.

Analogously to known methods, the sterol ethers can be obtained by etherification of the sterol with the appropriate amount of epoxide and, if appropriate, subsequent acylation of the hydroxy ethers thus obtained.

Some of them are commercially available, and these are among others distributed by Amerchol under the name Solulan®. Examples of types of Solulan® which are commercially available and can be used in the preparations according to the invention are those which are obtained and alkoxylation of a) 1 mol of cholesterol with an average of 24 mol of ethylene oxide (Solulan® C-24)

b) 1 equivalent of lanolin alcohols with an average of 16 equivalents of ethylene oxide (Solulan® 16)

c) 1 equivalent of lanolin alcohols with an average of 25 equivalents of ethylene oxide (Solulan® 25)

d) 1 equivalent of lanolin alcohols with an average of 75 equivalents of ethylene oxide (Solulan® 75)

e) 1 equivalent of lanolin alcohols with an average of 10 equivalents of propylene oxide (Solulan® PB-10)

or by f) partial acetylation of the reaction product of 1 equivalent of lanolin alcohols with an average of 10 equivalents of ethylene oxide (Solulan® 98)

g) complete acetylation of the reaction product of 1 equivalent of lanolin alcohols with an average of 9 equivalents of ethylene oxide (Solulan® 97).

The term "average" in connection with the specification of the equivalent amount of alkylene oxide which can or will be converted per mole of sterol indicates that the stated amount represents an average value, i.e. that there may be a mixture of sterol ethers, some more and some less

Alkyleneoxy groups carries.

Lanolin alcohols are also known as wool fatty alcohols (Handbook of Cosmetics and Fragrances, 2nd Ed. 1950, Vol. I, page 1101 (Janistyn)) and are a mixture of cholesterol, dihydrocholesterol and lanosterol, among others.

The term "enteric coating" includes any pharmacologically acceptable coating that prevents the release of the active ingredient in the stomach when the preparation passes through the stomach and that is sufficiently disintegrated in the intestinal tract (through contact with the approximately neutral to alkaline intestinal juices) to prevent the absorption of the Allow active ingredient through the walls of the intestinal tract.

A number of in vitro tests have been described in the pharmacopoeia of various countries, which make it possible to determine whether a coating is gastro-resistant.

More specifically, the term enteric coating within the meaning of the invention includes a coating that has been on for at least 1 hour, e.g. B. 2 hours in artificial gastric juices such as a hydrogen chloride solution of pH 1.2 and at a temperature of 36 to 38 ° C and then in artificial intestinal juices e.g. dissolved in a pH 6.8 buffered solution with KH2P04 within 30 minutes. The thickness of the film depends on the degree of permeability of the film for water and acid and the desired retarding effect. In general, satisfactory results are obtained with a film thickness of 5-100 µm and especially 20-80 µm. The film conveniently orders from a macromolecular polymer.

Suitable polymers are listed, for example, in Hager's Handbook of Pharmaceutical Practice, 4th edition, vol. 7a, pages 739-742 and 776-778, and in Remingtons' Pharmaceutical Sciences, 13th edition, pages 1689-1691 and um5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

642259

4th

include in particular cellulose ester derivatives, cellulose ethers, acrylic resins such as methacrylate copolymers and copolymers of maleic acid and derivatives of phthalic acid.

Preferred films are made from cellulose ethers such as cellulose acetate phthalate or hydroxypropyl methyl cellulose phthalate, and from copolymers of methacrylic acid and its esters, which contain at least 40% methacrylic acid. An example of a suitable cellulose acetate phthalate is CAP (trade name) sold by Eastman Kodak, Rochester N.Y., USA. Examples of suitable hydroxypropyl methyl cellulose phthalates include the commercial products HP50 and HP55 distributed by Shinetsu, Tokyo, Japan.

Since a CAP film only goes into solution at a higher pH than e.g. an HP50 film, the administration form provided with CAP film will have a comparatively longer lasting effect. In this way, by suitable choice of the coating, a retardation can be achieved which optimally takes into account the properties of the active ingredient used.

The method according to the invention can be carried out analogously to methods known for applying a coating.

For the production of coated tablets, pellets or granules, e.g. so that the cores are sprayed with a solution of the film-forming material.

Suitable solvents for the film-forming material are e.g. organic solvents, for example an alcohol such as ethanol, a ketone such as acetone, a halogenated hydrocarbon such as CH2C12 or solvent mixtures such as ethanol / acetone 1: 1. A plasticizer such as di-n-butyl phthalate is expediently added to the solution.

The cores are expediently heated to 25 to 40 ° C. before spraying, for example using warm air of 40 to 70 ° C. In order to prevent the cores from sticking, the spraying process is advantageously interrupted at certain time intervals and the cores warmed up again. The spray pressure can vary, generally good results are obtained with a spray pressure of 1 to 1.5 bar. However, the spraying process can also be carried out without interrupting the working process, for example by automatically regulating the spraying quantity as a function of the exhaust air or core temperature.

The forms according to the invention provided with an enteric coating are characterized in that

that according to p. o. administration to humans the maxima of the active substance concentration in the plasma can only be reached approx. 4-6 hours after application, while the initial peak occurs after administration of a normal tablet after only 0.5-1 hour. The retarding effect achieved is also evident in the determination of the amount excreted in the urine: after application of the form according to the invention, the maximum rate of excretion with urine is shifted from about 2 to 6 hours compared to a normal tablet. In addition, the plasma levels after application of the form according to the invention are between 6-24 hours higher than after application of a normal tablet. This is based on the area under the plasma level (AUC) and is a measure of the excellent bioavailability that is achieved with the preparations according to the invention.

The dosage form according to the invention accordingly leads to a therapeutically desired sustained-release effect, which permits a single application per day. This increases the patient's comfort of use and the level of safety

The forms provided with an enteric coating, in particular the tablets, can additionally be coated with an outer layer of active substance. In addition to an active ingredient, this outer active ingredient layer contains e.g. an ergot alkaloid that is soluble or dispersible in the gastric juices and / or fillers, such as talc, microcrystalline cellulose, magnesium stearate, mannitol, polyvinylpyrrolidone, etc. Here, the active ingredient is rapidly absorbed through the stomach walls, initially a high concentration of the active ingredient in the bloodstream is achieved. The level of the active substance blood level is maintained by the delayed release of the active substance from the tablet core in the neutral or alkaline juices of the intestinal tract.

The optimal weight ratio of ergot alkaloid: sterol ether in the cores depends to a large extent on the physical properties of the sterol ether, the auxiliaries used and the type and size of the chosen administration form.

For example, the above-mentioned sterol ethers of the types Solulan® 16, Solulan® 25 and Solulan® C-24 cannot be tabletted in unlimited quantities due to their waxy nature.

In general, however, good results are obtained with an ergot alkaloid: sterol ether weight ratio of 1: 1 to 1:25, in particular 1: 2 to 1: 8, preferably 14. The range 1: 2 to 1.8 is particularly preferred if the nuclei in the form of a solid solution of ergot alkaloid, especially when polyvinylpyrrolidone is used as the solid solvent.

Depending on requirements, other auxiliaries such as binders, lubricants, fillers and wetting agents are processed in the cores.

The use of the cores in the form of their solid solution is a special embodiment of the invention. To produce such cores, one goes, for. B. As follows:

An ergot alkaloid is mixed with a sterol ether and a pharmaceutically acceptable polymer which is at least slightly soluble in an aqueous medium, in particular one or more polyalkylene glycols, polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate or a mixture thereof.

Suitable polyalkylene glycols include i.a. Polyoxyethylene or polyoxypropylene polymers and their copolymers with a molecular weight of 200 to 20,000, in particular 4,000 to 15,000, preferably 6,000 to 13,000. With polyvinylpyrrolidone are uncrosslinked poly-N-vi-nyl-pyrrolidone-2 compounds with molecular weights of 10,000 to 100,000, in particular 11,500 to 40,000, preferably 20,000 to 30,000. The copolymers of vinyl pyrrolidone and vinyl acetate preferably consist of approximately 60 parts by weight of vinyl pyrrolidone and 40 parts by weight of vinyl acetate and preferably have a molecular weight of 30,000 to 100,000, in particular 40,000 to 90,000.

If desired, stability-demanding additives such as acids, in particular methanesulfonic acid, maleic acid, tartaric acid, are added. The preferred pH of the preparation is between 4 and 6, in particular between 4 and 5. The weight ratio ergot alkaloid: sterol ether: to polyalkylene glycols and / or polyvinylpyrrolidone and / or copolymers of vinyl acetate and vinylpyrrolidone used can vary between wide limits; in general, however, good results are achieved with ratios which vary between 1: 1-10: 0.1-10, in particular between 1; 2-8: 0.1-10, preferably between 1: 2-5: 0.1-5 .

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

642 259

The polymers are used in solid form to prepare the solid solution. If one of the polymers, for example a polyalkylene glycol with a molecular weight of about 200, which is liquid at room temperature, is used to produce the solid, it goes without saying that this is not used alone, but together with a solid polymer.

The above ingredients are in a suitable ^ solvent, for example a lower alcohol, e.g. As ethanol or methanol or chloroform, with stirring and heating to temperatures of 30 to 70 ° C, preferably 40 to 60 ° C, dissolved, a clear solution being obtained. The solvent is then removed in vacuo at temperatures from 30 to 70 ° C., preferably 40 to 60 ° C. It is possible here that only part of the polyalkylene glycol and / or polyvinylpyrrolidone and / or copolymer of vinyl acetate or the other additives is used in the preparation of the solution, and the remaining amount is added during the evaporation of the solution. The resulting clear liquid is allowed to solidify at room temperature (15-25 ° C). The product obtained is ground to a fine powder and dried in vacuo at about 30 ° C. until the solvent has been completely removed.

The solid solution obtained by the above process (core of the administration form) is processed in a manner known per se together with pharmacologically acceptable auxiliaries and, if appropriate, further proportions of the sterol ether. The proportion of sterol ether added here, but also during the previous operation, should overall remain within the above numerical limits.

The following examples illustrate the invention. Temperatures are given in degrees Celsius.

example 1

Tablet cores consisting of 3 g dihydroergotamine, 75 g cholesterol (Solulan® C-24) ethoxylated with approx. 24 mol ethylene oxide and 22 g disperse silicic acid are placed in a coating pan with repeated turning of the pan, using supply air from 50 ° for 10 minutes to approx. 30 ° warmed. The tablet cores are then blended with a solution of 5.4 g hydroxypropylmethyl cellulose phthalate (HP-50) and 1.35 g di-n-butyl phthalate in a 1: 1 ethanol / acetone mixture using a hand spray gun and at a spray pressure of 1-1.5 bar, sprayed using known interval spraying methods. The coated tablet cores thus obtained are then dried.

Example 2

The procedure is analogous to Example 1, but tablet cores are used which contain instead of 75 g of cholesterol ethoxylated with approx. 24 mol of ethylene oxide, 75 g of lanolin alcohols ethoxylated with 25 equivalent ethylene oxide.

Example 3

Tablet core in the form of a solid solution

15 g of di-hydroergotoxin methanesulfonate, 1.05 g of Solulan® C-24 and 33.95 g of polyvinylpyrrolidone (average molar weight 25,000) and 250 ml of methanol are placed in a flask with a volume of 11. 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. The solvent is evaporated at a reduced pressure 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 about 2

Stored at room temperature for hours. This is followed by drying in a vacuum drying cabinet at 30 ° C, approx. 1 torr., Approx. 12 hours, grinding and drying. 26.8 g of the powder produced are then mixed with the following auxiliaries

Silicon dioxide (Aerosil® 200, Degussa) 1.0 g

Polyvinyl pyrrolidone (cross-linked) 8.0 g

Corn starch 20.0 g

Talc 30.0 g

Solulan® C-24 30.0 g

Cellulose granules 42.0 g

Milk sugar 122.0 g and then compressed to tablets of 140.0 mg (hardness 10-32N) in a manner known per se.

The tablet cores obtained in this way are analogous to Example 1 with a solution of

Cellulose acetate phthalate (CAP) 90.0 g

Di-n-butyl phthalate 22.5 g

Acetone 240.0 g

Ethanol 21.0g

Dichloromethane 526.5 g

Spray 900.0 g until the tablet cores are coated with about 10 mg of the mixture of cellulose acetate phthalate and di-n-butyl phthalate per tablet core.

The tablets thus obtained are enteric-resistant, i.e. the cores remain unharmed after 1 hour of treatment with artificial gastric juices of pH 1.2.

The intestinal juice disintegration time is longer than 60 minutes at pH 5.5 and between 23-28 minutes at pH 6.0 and between 12 and 16 minutes at pH 6.8.

Example 4

The procedure is analogous to Example 3, but the tablet cores of 140 mg are sprayed with a solution of 140 g of hydroxypropylmethyl cellulose 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 coated with 9.0 mg of the mixture hydroxypropyl methylcellulose phthalate and di-n-butyl phthalate (weight ratio 10: 2) per tablet core.

Example 5

Analogously to Example 3, a solid solution of 4 g of di-hydroergotoxin methanesulfonate, 0.3 g of Solulan® 16 and 9.1 g of polyvinylpyrrolidone (average molar weight 25,000) is prepared.

The powder thus obtained is then mixed with the excipients

Silicon dioxide 0.5 g

Polyvinylpyrrolidone (average mole weight 2000) 4.0 g

Corn starch 10.0 g

Talc 15.0 g

Solulan® 16 15.0g

Cellulose powder 21.0 g

Lactated sugar mixed 61.1 g and compressed into tablets of 140.0 mg.

The tablet cores obtained in this way are then sprayed analogously to Example 4 until the cores are coated with about 10 mg or about 15 mg of the mixture of hydroxypropylmethyl cellulose phthalate and di-n-nutyl phthalate per tablet core.

Analogously to the processes described in the examples above, the tablets obtained are summarized in Table I below.

If Ib or Ic (see table) are used, the tablet cores are in the form of a solid solution.

5

10th

is

20th

25th

30th

35

40

45

50

55

60

65

642 259

6

Table I

example

6

7

8th

9

10th

11

12

13

Ia dihydroergotoxin mesilate

4.0

4.0

4.0

4.0

4.0

4.0

Dihydroergotamine mesilate

6.0

6.0

Ib Solulan® C-24

0.3

0.3

0.3

0.3

0.3

0.4

Ic polyvinyl pyrrolidone

9.1

9.1

9.1

9.1

9.1

13.5

II Solulan® C-24

15.0

15.0

31.7

7.3

23.7

15.3

22.9

22.5

Silicon dioxide

2.4

2.4

0.5

0.5

0.5

0.5

3.6

3.6

Cornstarch

24.0

24.0

10.0

10.0

10.0

10.0

36.0

36.0

Cellulose

72.0

72.0

21.0

21.0

21.0

21.0

108.0

108.0

Lactose

110.8

110.8

44.4

68.8

52.4

61.1

166.4

166.4

Magnesium stearate

2.4

2.4

3.6

3.6

Kollidon CE 5050

4.0

4.0

4.0

4.0

Polyvinyl pyrrolidone (25)

9.1

13.5

talc

15.0

15.0

15.0

HPMCP *

26.0

7.0

7.2

7.2

7.2

7.2

7.2

7.2

Di-n-butyl phthalate

1.8

1.8

1.8

1.8

1.8

1.8

Total weight (mg) 266.0 247.0 149.0 * HPMCP = hydroxypropyl methyl cellulose phthalate

(1) The tablet cores were pressed until they had a hardness of 50-60N.

149.0

149.0

149.0

(1) 369.0

(1) 369.0

Example 14 Preparation of coated tablets a) To produce the cores, 26.8 g of solid solution (containing 8.0 g of dihydroergotamine mesilate, 0.6 g of Solulan® C-24 and 18.2 of polyvinylpyrrolidone) together with 1.0 g of highly disperse silicon dioxide are used. 8.0 g of cross-linked polyvinylpyrrolidone, 20 g of corn starch, 47.4 g of Solulan® C-24, 42.0 g of cellulose granules, 104.8 g of lactose and 30.0 g of talc are mixed to form a homogeneous mass and this mixture is converted into cores of 140.0 mg full weight pressed.

b) The cores contained in a) are sprayed in a suitable apparatus with a solution of 140.0 g of hydroxypropyl methyl cellulose phthalate and 28.0 g of di-n-butyl phthalate in a mixture of 616 g of ethanol and 616 g of acetone until an amount of solids is applied of an average of 10.0 mg per tablet, which gives the cores a stomach-resistant coating.

c) To produce the casing mass, 4.0 g of dihydroergotamine mesilate together with 4.0 g of highly disperse silicon dioxide, 6.0 g of magnesium stearate, 166.8 g of cellulose powder, 40.0 g of talc, 191.2 g of corn starch and 348.0 g Cal-

ciumhydrogenphosphat ver-30 works to a homogeneous mixture. This mixture is pressed together with the coated cores obtained according to paragraph to coated tablets of full weight 530.0 mg.

Example 15

The procedure is analogous to that of Examples 1 to 14, and tablets containing the appropriate amount of ergot alkaloid as the active ingredient are obtained using 4 mg bromocryptin, 4 mg dihydroergalin or 4 mg dihydroergonins instead of dihydroergotoxin or dihydroergotamine.

40

Example 16 Clinical Trials In a clinical trial, the preparation according to Example 4 was compared with a solid solution of dihydroergo-45 toxin mesilate (A) and with a classic preparation of dihydroergotoxin mesilate (B).

Each of the 12 subjects treated was treated with 4 mg di-hydroergotoxin mesilate.

The result is summarized in Table II below-50.

Table!!

preparation

Example 4

Concentration in plasma after

20 '0.047 ± 0.012

40 '0.092 + 0.039

Maximum concentration 0.615 + 0.077 (ng. Ml "!)

Time (in hours) after the

The maximum achieved is 3.33 +0.48 bioavailability

AUC (0-24 hours) 4.778 + 0.415 (ng. Ml_1h)

% Urine elimination (0-96 hours) 1.010 + 0.154

0.376 ± 0.078 0.472 ± 0.070 0.507 ± 0.071

0.64 ± 0.06

3.875 ± 0.279 0.787 ± 0.121

0.215 ± 0.064 0.506 ± 0.049 0.538 ± 0.037

0.78 ± 0.12

3.754 ± 0.171 0.740 ± 0.081

The good retardation and bioavailability of the preparation according to the invention is clearly shown in the table above. On the other hand, a commercially available slow release preparation of dihydroergotoxin showed a clearly weaker bioavailability (60-70% of preparation B used as reference).

7 642 259

Experiments with the other preparations according to the invention give comparably good results. A commercially available sustained-release preparation of dihydroergotamine, on the other hand, also showed a 30 to 40% weaker bioavailability than the corresponding non-delayed reference.

Claims (12)

642 259 2nd PATENT CLAIMS 1. Preparations for oral application provided with an enteric coating, the core of which contains an ergoal alkaloid and a polyalkoxyalkylene sterol ether. 2. A preparation according to claim 1, wherein the er-Gotalkaloid a compound of formula I, wherein Rj for hydrogen or halogen, R2 represents hydrogen or an alkyl group with 1-4 carbon atoms, R3 for isopropyl, sec-butyl, isobutyl or benzyl, R4 for methyl, ethyl or isopropyl, R5 for hydrogen, and R6 represents hydrogen or methoxy, or Rs and R6 together form a further bond, or is a mixture of compounds of the formula I. 3. A preparation according to claims 1 and 2, wherein the active ingredient is dihydroergotamine, dihydroergotoxin or bromoergocryptine. 4. A preparation according to any one of claims 1 to 3, wherein the sterol ether is a multiple with ethylene oxide or Propylene oxide is an etherified derivative of cholesterol, dihydro-cholesterol or lanosterol. 5. A preparation according to claims 1 to 4, wherein the coating is a film made of a macromolecular polymer from the series cellulose ester derivatives, cellulose ethers, acrylic resins, copolymers or maleic acid with phthalic acid derivatives. 6. A preparation according to claim 5, wherein the coating is a film of cellulose acetate phthalate. 7. A preparation according to claim 5, wherein the coating is a film of hydroxypropyl methyl cellulose phthalate. 8. A preparation according to claims 1 to 7, wherein the weight ratio of the components contained in the core ergot alkaloid: sterol ether between 1: 1 and 15 1:25 lies. 9. A preparation according to claims 1 to 8, wherein the core is in the form of a solid solution. 10. A preparation according to claim 9, wherein the core is one or more polyalkylene glycols and / or poly- 2o contains vinyl pyrrolidone and / or a copolymer of vinyl pyrrolidone and vinyl acetate. 11. A preparation according to claims 9 and 10, wherein the weight ratio ergot alkaloid: sterol ether: polyalkylene glycol and / or poly vinyl pyrrolidone 25 and / or copolymers of vinyl acetate and vinyl pyrrolidone is 1: 1-10: 0.1-10. 12. A method for producing a preparation according to claim 1, characterized in that a core containing an ergot alkaloid as an active ingredient and a polyalkoxy Contains 30 alkylene sterol ether, provided with an enteric coating. 13. The method according to claim 12, characterized in that the cores are sprayed with a solution of the film-binding material. 14. The method according to claim 13, characterized in that the cores are heated to 25 to 40 ° C before spraying.