SE442265B - FIXED, ENTERAL TRANSFER COMPOSITION IN UNIT FORM ORAL SUPPLY INCLUDING AN ERGOTAL KALOID - Google Patents

Description

U '7910227-3 2 The pellets or granules can, after application of the enteral coating, be used as such or pre-filling of capsules, Lex. hard gelatin capsules. Suitable dosage forms for the compositions of the invention are therefore tablets, pellets, granules or capsules.

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

The active agents of particular interest for use in the invention are compounds of formula I wherein R 1 is hydrogen or halogen, R 2 is hydrogen or C 1-4 alkyl, R B is isopropyl, sec-butyl, isobutyl or benzyl, Ru is methyl, ethyl or isopropyl, and either R 5 is hydrogen and R 6 is hydrogen or methoxy or R 5 and 116 together represent an additional bond, or mixtures thereof.

When R 11 is halogen, it is preferably bromine.

Particularly preferred compositions of the invention contain reid-V hydroergotoxin, bromocryptine or dihydroergotamine in free base form or, preferably, in acid addition salt form as active agent.

Preferred sterol ethers for use in the compositions of the invention have a hydrophilic / lipoil balance value (HLB group number) of from about 10 to about 20, especially from 12 to 16. They are preferably ethers of lanosterol, the dihydrocholesterin «Éqoon fi oifitifi * -» í- w fl- wu-fß- 7910227-3 3 and, in particular, of cholesterol, or mixtures of such ethers. Particularly suitable sterol ethers are sterols etherified with an average of 8 up to 75, preferably 9 up to 30 alkylene oxide units. The hydroxy group in the terminal alkylene moiety of such sterol ethers may be partially or completely acylated, e.g. with acyl residue groups from aliphatic carboxylic acids such as acetyl. Particularly preferred are sterol ethers etherified with ethylene oxide and / or propylene oxide units.

The sterol ethers can be obtained in a conventional manner by etherification of sterol with a corresponding amount of epoxide and optionally acylation of the alcohols thus obtained. They are partly available on the market and are marketed, for example, by the company Amerchol under the brand name "Solulan". Examples of "Solulan" types which are commercially available and suitable for use in the compositions of the invention are those which can be obtained by alkoxylation of, for example, a) 1 mole of cholesterol with about 24 moles of ethylene oxide ("Solulan C- 21 + ") b) 1 equivalent of lanolin alcohols with about 16 equivalents of ethylene oxide (" Solulan 16 ") c) 1 equivalent of lanolin alcohols with about 25 equivalents of ethylene oxide (" Solulan 25 ") d) 1 equivalent of lanolin alcohols with about 75 equivalents of" Solulan 16 "Ethylene" e) 1 equivalent of lanolin alcohols with about 10 equivalents of propylene oxide ("Solulan PB - 10"), and also the f) partially acetylated derivatives of 1 equivalent of lanolin alcohols ethoxylated with about 10 equivalents of ethylene oxide ("Solulan 98"), and g) the fully acetylated derivatives of 1 equivalent of lanolin alcohols ethoxylated with about 9 equivalents of ethylene oxide ("Solulan 97") - The expression "approximately" under a) to g) above indicates that the given number of ethylene oxide or propylene oxide equivalents is an average, ie that Some sterol ethers have more and others fewer ethyleneoxy or propyleneoxy groups.

Lanolin alcohols are also known as wool fatty alcohols' (Handbuch der Kosmetika und Riechstoífe, 2nd ed. 1950, Vol. 1, page llOl Clanistyn »and are a mixture of, among other things, cholesterol, dihydrocholesterol and lanosterol.

The term "enteral coating" includes any pharmaceutically acceptable coating that prevents the release of the active agent into the stomach and is sufficiently broken down in the intestinal tract (by contact with approximately neutral or alkaline intestinal juice) to allow resorption of the active agent through the walls of the intestinal tract. Various in vitro tests to determine whether a coating is classified as an enteral coating have been published in different countries' pharmacopoeias.

More particularly, the term "enteral coating" according to the present invention refers to a coating which remains intact for at least 1 hour, e.g. for 2 hours, in contact with artificial gastric juice such as HC! with pH 1.2 at 36 to 38 ° C, and which is then decomposed within 30 minutes in artificial intestinal juice, e.g. 366 w ...- ... w -... w i? .pni ,, ._ mm_ A 'n. orm YUI. my; ..fi 7910227-5 KH2PO4 buffered solution with pH 6.8.

The thickness of the coating can vary and depends, among other things, on its permeability to water and acids and the desired delay effect. In general, satisfactory results are obtained with a coating with a thickness of 5 - 100 μm, preferably 20 to XOum. The coating is suitably selected from macromolecular polymers. Suitable polymers are stated in e.g. l-lagers l-landbuch der pharmazeutischer Praxis, 4: e upplagan Vol 7a, sid. 739 to 742 and 776 to 772 (Springer Verlag, 1971) and Remingtows Pharmaceutical Sciences, 13th edition, p. 1689 to 1691 (Mack Publ. Co., 1970), and these include e.g. cellulose ester derivatives, cellulose ethers, acrylic resins such as methyl acrylate copolymers and copolymers of maleic acid and phthalic acid derivatives.

The preferred films are made of cellulose acetate phthalate, copolymers derived from methyl acrylic acid and esters thereof, containing at least 140% methyl acrylic acid, and especially hydroxypropyl methylcellulose phthalate. An example of a suitable cellulose acetate phthalate is the marketed product CAP (Eastman Kodak, Rochester N.Y., USA). Examples of suitable hydroxypropyl methylcellulose phthalates are the marketed products HP 50 and HP 55 (Shinetsu, Tokyo, Japan).

Since a coating, which essentially consists of CAP, decomposes at a higher p1-1 than e.g. a coating consisting essentially of HP 50, the release of the active agent from compositions provided with the former coating will be delayed more than from compositions provided with the latter coating. In this way, a suitable retarding effect can be achieved by appropriate selection of the coating, which takes into account the properties of the active agent in an optimal manner.

The method according to the invention can be carried out in a manner analogous to known methods for applying an enteral coating.

For the production of coated tablets, pellets or granules, one can e.g. proceed so that the kernels are sprayed with a solution of the enteral coating. Suitable solvents for the enteral coating are, for example, organic solvents, e.g. an alcohol such as ethanol, a ketone such as acetone, halogenated hydrocarbons such as CH 2 Cl 2 or mixtures of such solvents, e.g. ethanol / acetone, 1: 1. A plasticizer such as di-n-butyl phthalate is conveniently added to such a solution. g The cores are suitably heated up to 250 to lmoC, e.g. using hot air of 40 ° to 70 ° C, before spraying. In order to avoid sticking of the cores, the spraying procedure can preferably be interrupted at certain intervals and .-- »v ~. ~ ..-.... 4. ~ __ .. ...___. -___.... ¿.......,. eoosgoïfïitšïif * l0 720 7910227-3 the kernels are then reheated. The spray pressure can vary within wide limits, but in general satisfactory results are obtained with a spray pressure from about 1 to about 1.5 bar. However, it is also possible to proceed without interruption in the spraying procedure, e.g. by automatic control of the amount sprayed as a function of the temperature of the outgoing air and / or cores.

The enteral-coated compositions of the invention have the beneficial property that after po-administration to humans the maximum concentration of the active agent in blood plasma is reached after about 4 to 6 hours, while the initial peak after administration of a conventional composition, e.g. ex. one tablet, is achieved already after 0.5 to 1 hour.

The delayed release effect of the compositions of the invention is also illustrated by determining the concentration of the active agent (and metabolites) in excreted urine: the maximum concentration in the urine occurs about 6 hours after administration, while this maximum is reached after about 2 hours when administering a normal composition.

In addition, the plasma level after administration of the compositions of the invention between 6 and 24 hours after application is higher than after administration of a normal composition, e.g. A pill. This is illustrated by the surface below the plasma level (AUC) and is a measure of the excellent bioavailability of the compositions of the invention.

Accordingly, the compositions of the invention show a therapeutically desirable antitussive effect, together with excellent blot availability, and they consequently allow treatment with one unit dose per day.

In addition, the compositions of the invention, especially the tablets, may be coated with an outer drug layer. This outer layer may, in addition to an active agent such as an ergot alkaloid, contain carriers and / or fillers which are soluble or dispersible in the intestinal juices, e.g. talc, microcrystalline cellulose, magnesium stearate, mannitol, polyvinylpyrrolidone, etc. Such compositions can be used, for example, when a rapid onset of activity is required.

The high initial concentration of the ergot alkaloid in the blood is then maintained by the delayed release thereof out of the nucleus in the intestinal tract.

The optimal weight ratio of ergot alkaloid / sterol ethers in the core depends largely on the physical properties of the sterol ether in question, the Thus, the amount of the above-mentioned sterol ethers of the type "Solulan 16", the adjuvants used and the type and size of the composition are used.

"Solulan 25" and "Solulan (2-24") of their waxy nature. However, in general, satisfactory results are obtained using the stated weight ratio of ergot alkaloid / sterol ether from 1: 1 to 1:25, preferably from 1; 2 Pó fl š aßyv-w fl The range 1: 2 to 1: 8 is especially preferred when the core is in the form of a solid solution of the ergot alkaloid and especially when using polyvinylpyrrolidone as the solid solvent. .

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

The use of cores in the form of a solid solution constitutes a special embodiment of the invention, and such cores can be prepared in the following manner.

An ergot alkaloid, a sterol ether and a pharmaceutically acceptable polymer which are at least partially soluble in an aqueous medium, especially a polyalkylene glycol, polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate or a mixture thereof, are mixed together. Suitable polyalkylene glycols include polyethylene glycol and polypropylene glycol and their copolymers having a molecular weight of 200 to 20,000, preferably 0.000 to 15,000, especially 6,000 to 13,000. By "polyvinylpyrrolidone" is meant non-crosslinked poly- (N-vinylspyrrolidone-2, preferably having a molecular weight between 10,000 and 100,000, preferably 11,500 to 00,000, especially 1,000 to 30,000. The copolymer of vinylpyrrolidone and vinyl acetate preferably contains 60 weight-96 vinylpyrrolidone and 40-weight-96 vinyl acetate and preferably has a molecular weight of 30,000 to 100,000, especially 140,000 to 90,000.

If desired, stabilizers such as acids, preferably methanesulfonic acid, maleic acid and tartaric acid, are added to adjust the pH of the composition. The preferred pI-L range for the composition is pH 4-6, preferably pH 4-5.

The weight ratio of ergot alkaloid / sterol ether / pharmaceutically acceptable polymer can vary widely, but in general satisfactory results are obtained with ratios between 1: 1-10: 0, 1-10, especially between 1: 2-8: 0, -1 0, and especially between 1: 2-5: 0, 1-5.

For the preparation of the solid solutions according to the invention, the polymers are used in solid form. In the event that one of the polymers used is liquid at room temperature, e.g. a polyalkylene glycol having a molecular weight of about 200, it is obvious that such a polymer. not used alone but in combination with a: polymer, which is solid at room temperature. The above-mentioned components are dissolved by stirring in a suitable solvent, for example in a lower alcohol such as ethanol or methanol, or in. § __ \ ___ i / wr-: A _ r- www “w ffi ''" '1' * '- ~~ Lai) -šig,'. "" -., »Fj / U-“ šf _: æighfxél Chloroform, at a temperature of from 30 to 70 ° C, preferably 40 to GOOC, and the solvent can be removed by evaporation in vacuo at the same temperature.

In the preparation of the solution, it is also possible to add only a part of the polymer and the additional components, if used, and to add the residue during the evaporation of the solvent. The clear solution formed is allowed to solidify at room temperature (15 to 25 ° C), and the solid solution or dispersion can then be ground to a fine powder and dried, preferably under vacuum at 30 ° C, to remove all traces of the solvent.

The solid solution obtained according to the above procedure (the core of the composition) is then compounded in a known manner with pharmaceutically acceptable diluents or carriers, optionally with an added amount of a sterol ether, whereby the total content of sterol ethers in the core should preferably be within the above limits. .

The invention is illustrated in the following examples, in which all temperatures are given in degrees Celsius.

Example 1 Tablet cores consisting of 3 g of dihydroergotamine, 75 g of cholesterol ethoxylated with about 24 moles of ethylene oxide ("Solulan C-24") and 22 g of dispersed silica gel are heated to 30 ° for 10 minutes by means of hot air of 50 ° in a coating pan. , which is rotated repeatedly. The tablet cores are then sprayed using a spray gun with a solution of 5.4 g of hydroxypropyl methylcellulose phthalate (HPSO) and 1.35 g of di-n-butyl phthalate in a 1: 1 mixture of ethanol and acetone at a spray pressure of 1 to 1. 5 bar using conventional interval spray coating methods. The coated tablets thus obtained are then dried.

Example 2 The procedure is analogous to Example 1, but 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 24 moles of ethylene oxide. ____ L_E> g dihydroergotoxin methanesulfonate, 1.05 g cholesterol ethoxylated with about 24 molethylene oxide, ("Solulan C-24"), 33.95 g polyvinylpyrrolidone (molecular weight 25,000) and 250 ml methanol are charged to a one liter round bottom flask. The piston is attached. a rotary evaporator and rotated at a bath temperature of 60 ° until the flask content reaches 600, whereby a clear solution is obtained.

The bath temperature is maintained at 60 ° and the solvent is evaporated under reduced pressure until the residue has a syrupy consistency. The remainder decante- - - 'WWW-un v ~ v ..._ _ ..>.

P °° R Qvszzïtf 7910227-3 8 is placed in an evaporation bowl and allowed to solidify for 2 hours at room temperature. i The solid residue is dried in a vacuum oven at 30 ° and about 1 dry for about 12 hours, ground to a fine powder and dried again. 26.8 g of the solid solution thus obtained are then mixed with the following adjuvants: silica 1.0 g of 1Aerosi® 200, Degussa) polyvinylpyrrolidone 8.0 g (crosslinked) corn starch 20.0 g Talc 30.0 g Solulan C -24 "30.0 g of cellulose granules 42.0 g (Elcema G 250) lactose 122.0 g until a homogeneous mixture is obtained, which is then pressed in a conventional manner into faberl kernels of 140.0 mg (hardness io-zzw). The cores thus obtained are then sprayed analogously 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 21.0 g dichloromethane 526.5 g 900 0 g until the cores are coated with about 10 mg of the cellulose acetate phthalate / di-n-butyl phthalate mixture per core. The coated tablets thus obtained are resistant to gastric juices, since the core remains intact after treatment for 1 hour with artificial gastric juice of pH = 1.2. The decomposition time in artificial intestinal juice at pH 5.5 is more than 1 hour, is at pH 6.0 between 23 and 28 minutes and is at pH 6.8 between 12 and 16 minutes.

Example 4 The procedure is analogous to Example 3, but spray the 140 mg tablet cores with a solution of 100.0 g of hydroxypropyl methylcellulose phthalate (HP 50) and 28 g of di-n-butyl phthalate in a mixture of 6 16 g of ethanol and 6 16 g of acetone until the cores are gy-coated with about 9 mg of hydroxypropyl methylcellulose phthalate / di-n-butyl phthalate mixture (ratio 10: 2) per core.

Example 5 In analogy to Example 3, a solid solution of 1 g of dihydroergotoxin methanesulfonate, 0.3 g of "Solulanan 16" and 9.1 g of polyvinylpyrrolidone (average molecular weight 2000) is obtained.

This solid solution is then mixed with 1: silica 0.5 g of polyvinylpyrrolidone 4.0 g (average molecular weight zooo) of corn starch 10.0 g of talc 15.0 g of "Solulan 16". 15.0 g of cellulose powder 21.0 g (Emma c 250131 lactose 61.1 g and this mixture is compressed into 140.0 mg tablets.

The tablet cores thus obtained are then sprayed analogously to Example 4 until each core is coated with either about 10 mg or about 15 mg of the mixture of hydroxypropyl methylcellulose phthalate and di-n-butyl phthalate.

In analogy to the procedure described in the above Examples, tablets are obtained according to the list in Table I below.

If Ib and Ic (see table) are used, the tablet cores are in the form of a solid solution. ïöšsš Qvzan-t t 7910227-3 TABLE 1 EXGIHPP-l 6 'I 8 9 1.0 11 12 13 Ia Dihydroergot- 4.0 4.0 4.0 4.0 4.0 4.0 4.0in-oxylate Dihydroergot-oxin- nxesilate 6-0 6.0 Ib Solulan C24 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 C24 15.0 15.0 31.7 7.3 23.7 15.3 22.9 22.5 xisemioxide 2- .4 2.4 '0.5 0.5 0.5 0.5 3.6 3.6 Maize starch 124.0 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 21.0 108.1? 10310 Lactose 110.6 110.8 44.4 68.6 52.4 61.1166.4166.4 Magnesium- 2.4 2.4 3/6 3.5 stearate x ° 111a0n 4.0 4.0 * 4.0 4.0 CE 5050 Polyvinylpyr - 9,1 13,5 rolidone (25) * Igalk 15,0 15,0 15,0 1191402 * 26,0 7,0 7,2 9.0 9.0 9.0 7.2 7.2 Di-n-butyl- _fta1ar- 1,6 - -. - 1- 1-8 _ _ _96 gl) frotalvlkt .. 266.0 247.0 149.0 149.0 149.0 149.030, 36 .0 (me) '- x HPMCP = hydroxypropyl methylcellulose phthalate (1) the cores of these tablets pressed to a hardness of 50-60N.

V W-w -... m.-_.____.

P fl ß fl ïààiïï fi f * 0 l0 7910227-3 11 ___ P__EX ° m el I ”Idßlstfifæš ef: xtlfs lækemséelsëkik: l fl laßfsllëleifl- a) The kernels are prepared analogously to Example 3 by mixing 26.8 g of a solid solution of 8,0 g of 0.6 g of "Solulan C-24" and 18.2 g of polyvinylpyrrolidone) together with 1.0 g of highly dispersed silica gel, 8.0 g of crosslinked 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 until the mixture is homogeneous. The mixture is then compressed into 140.0 mg cores. b) The cores thus obtained are sprayed with a solution of 140.0 g of hydroxypropyl methylcellulose phthalate and 28.0 g of di-n-butyl phthalate in a mixture of 616 g of ethanol and 616 g of acetone until the cores are coated with about 10 mg per tablet. c) The outer drug layer is prepared by mixing 4.0 g of dihydroergotamine mesilate with 4.0 g of dispersed silica gel, 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 of calcium starch. hydrogen phosphate until the mixture is homogeneous. This mixture is then compressed with the coated tablets (according to Example 14b) to produce tablets with an outer drug layer, having a total weight of 530.0 mg per tablet.

Example 15 The procedure is analogous to Examples 1 to 14 using 4 mg of bromocryptine, 4 mg of dihydroergovalin or 4 mg of dihydroergonin instead of dihydroergotoxin or dihydroergotamine to give tablets containing the corresponding ergot alkaloid as active agent.

Clinical Trials Example 16 The composition of Example 4 was compared with a solid solution of dihydroergotoxin mesylate and tartaric acid (Composition A) and a conventional composition of dihydroergotoxin mesylate (Composition B).

Each treated person received 4 mg of dihydroergotoxin mesylate.

The results are given in the table below 7910227-3 n Composition Example 4 AB Concentration in plasma after å '' o, o47fo, o12 * o, 37eÉo, o7a o, 21sÉo, os4 40 'o oszfo o3s *** o 472 + o * 1 0 1 ", 07O 0,506-0,049. + 'Uâx. Koílc. Lvl) o, e1s-o, o77 o, 5o7“ - ”o, o71 o, s3aï'o, o31 p asma ng.m... _ + from * + äidmiiiäiwsšlnås * Bi-MB ° 1 ° 4 ~ ° - ° fi O flfl fo fl _ Bioavailability.

Auc (0-2íefimmar) '4,77sïo.41s * 3, ß7sfo, 279 3,7s4fo, 111 (ng. M1-) "_... -' + i: +% ïšsggdïäâmàrïrln 1, o1o-0,154 0,781-0,121 The significance of the differences between the composition according to Example 4 and the composition B was calculated according to Student T-Test (xp (_ 0.05, xip 4 0.01 and *** p). The good retardation effect and the excellent bioavailability of the composition according to the invention is clearly illustrated by the figures in the table above.

Furthermore, we found a clearly poorer bioavailability (60-7096 of composition B) when testing a marketed composition of dihydroergotoxin, which has been retarded in a conventional manner.

Analogous tests with other compositions according to the invention give similar good results. However, a marketed composition of dihydroergotamine, retarded in a conventional manner, showed a bioavailability which was about 30- 11096 lower than that observed with the corresponding non-retarded reference.

MP1 ”. 'ïšoonišàiïfslsifï

Claims (12)

10 15 20 25 7 9 1 0 2 2 7 - 3 13 PATENTKQA! A solid, entered-coated composition in unit dosage form for oral administration, characterized in that its core contains an ergot alkaloid and a polyalkoxyalkylene sterol ether in a weight ratio of ergot alkaloid to polyalkoxyalkylene sterol ether ranging from 1: 1 to 1:25. 2. A composition according to claim 1, characterized in that the ergot alkaloid is a compound of formula I wherein R 1 is hydrogen or halogen, R 2 is hydrogen or C 1-4 alkyl, R 3 is isopropyl, sec-butyl, isobutyl or benzyl, R a is methyl, ethyl or isopropyl, and either R 5 is hydrogen and R 6 is hydrogen or methoxy or R 5 and R 6 or mixtures thereof. together form an additional bond, Composition according to Claim 1 or 2, characterized in that the ergot alkaloid is dihydroergotamine, dihydroergotoxin or bromergocryptine. Composition according to any one of claims 1 to 3, characterized in that the polyalkoxyalkylene sterol ether has a hydrophilic / lipophilic in pallans, from lciylllëo, speclell: from 12 nu le. Composition according to any one of Claims 1 to 4, characterized in that the sterol moiety in the polyalkoxyalkylene sterol ether is lanosterol, dihydrocholesterol and / or cholesterol. PÛÖR QïÃÃflf '} "ie 10 15 20 25 30 7910227-3 lll Composition according to any one of claims 1 to 5, characterized in that the polyalkoxyalkylene sterol ether is a sterol lined with about 8 to about 75 alkylene oxide units, especially with from about 9 to about 30 alkylene oxide units. Composition according to any one of Claims 1 to 6, characterized in that the polyalkoxyalkylene sterol ether is a sterol etherified with ethylene oxide or propylene oxide. Composition according to any one of Claims 1 to 7, characterized in that the enteral coating is selected from cellulose ester derivatives, cellulose ethers, acrylic resins or copolymers of maleic acid and phthalic acid derivatives. 9. A composition according to claim 8, characterized in that the enteral coating is of cellulose acetate phthalate, hydroxypropyl methylcellulose ethylate, or methacrylic acid and esters thereof containing at least 4096 methacrylic acid. 10.. Composition according to any one of claims 1 to 9, characterized in that the enteral coating contains a plasticizer, e.g. di-n-butyl phthalate. 11.. Composition according to any one of claims 1 to 10, characterized in that the composition is in the form of tablets, optionally further surrounded by an outer drug layer, granules, pellets or capsules. Composition according to any one of claims 1 to 11, characterized in that the core is in the form of a solid solution, the core preferably containing a polyalkylene glycol, polyvinylpyrrolidone and / or a copolymer of vinylpyrrolidone and vinyl acetate as solid solvent, and wherein the weight ratio in the core between ergot alkaloid: polyalkoxyalkyl sterol ether: solid solvent is preferably between 1: 1-10: 0, 1-10, especially 1: 2-8: 0.1-10, especially 1: 2-5: 0.1. 5. A composition according to claim 12, characterized in that the core contains a stabilizer, the core being preferably stabilized by adjusting its pH to pH 4-6 with an acid.