DE3602577A1 - PHARMACEUTICAL COMPOSITIONS CONTAINING 9,10-DIHYDROGENATED ERGOTAL CALOIDS - Google Patents

Description

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Pharmaceutical products containing 9,10-dihydrogenated ergot alkaloids Compositions

The invention relates to pharmaceutical compositions containing 9,10-dihydroergot alkaloids contain. The group of 9,10-dihydroergot alkaloids not only includes 9,10-dihydro derivatives of the natural ergot alkaloids, but also ergot alkaloids, which can be produced by fermentation or chemical synthesis. The ergot alkaloids can Have substituents, e.g. those which are common in the chemistry of ergot alkaloids. They can appear as isomers, e.g. as 8R- and 8S isomers. All of this information is in "Ergot alkaloids and related compounds" edited by B. Berde and H.D. Shield, Springer-Verlag, Berlin, Heidelberg, New York 1978, included. This book is indicated in the following as a berde and a shield.

The most preferred compounds are dihydroergocornine, dihydroergocristine, Dihydro-a-ergocryptin, dihydro-ß-ergogryptin, co-dergocrin and Dihydroergotamine.

Co-Dergocrine is the generic name of a mixture of dihydroergocornine, Dihydroergocristin, dihydro-a-ergocryptin and dihydro-ß-ergocryptin with the molar ratio of 3: 3: 2: 1 of these components.

Co-dergocrin can be used in pharmacy as an acid addition salt, e.g. as Ethane sulphonate, maleate, fumarate, tartrate, hydrochloride or preferably can be used as mesylate. These salts have approximately the same activity as the free base form and can be prepared in a known manner will.

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The methanesulphonate is listed under the brand name in The Merck Index, 1983 HYEERGIN mentions. Reference is made to reference 3596 on pages 526-527. The pharmacological and clinical properties have been discussed at length in the book by Berde and Schild. Codergocrin alters and improves cerebral neurotransmission decreased cerebral metabolic function. It has a stabilizing effect on the tension in the cerebral vessels and is antihypertensive Activity.

Co-dergocrin is therefore used in the treatment of cerebral insufficiency the elderly and in cerebrovascular disorders, especially when associated with high blood pressure. Also the product is used for prevention used by migraines.

The daily oral dosages are usually 3-6 mg, whereby 4.3 mg is specifically recommended. This amount is preferably distributed in smaller doses of 1.5 mg, which are taken three times a day.

Dihydroergocornine, Dihydroergocristine, Dihydro-α-ergocryptine and Dihydro-ß-ergocryptin can be used individually for the same indications in approximately the same dosages.

The pharmacological and clinical properties of dihydroergotamine have also been described in Berde and Schild.

Dihydroergotamine can be used in pharmacy as a free base or as a pharmaceutical acceptable acid addition salt can be used. A typical one The addition salt is the methanesulphonate (the mesylate) described in "The Merck Index "1983, reference 3151, and is used under the brand name DIHYDER-GOT sold. Dihydroergotamine is used for treating hypotensia

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and from. orthostatic circulatory disorders and both in treatment used for acute migraine attacks and related vascular headaches, as well as for their interval treatment. In the further Dihydroergotamine is mentioned to be effective in treating herpes zoster. The medicine is usually found in daily dosages of about 1-10 mg taken orally.

The invention relates to a composition for oral administration with controlled release of the active ingredient, characterized by a 9,10-dihydroergot alkaloid as active ingredient, a pharmaceutically acceptable one hydrophilic swellable substance and a pharmaceutically acceptable one inert fatty material.

The invention particularly relates to a composition with controlled Release wherein the 9,10-dihydroergot alkaloid is a peptide alkaloid is.

Hydrophilic swellable substances include, for example, one or more natural, partially or completely synthetic, preferably nonionic hydrophilic resins, modified cellulosic substances or proteinaceous substances, such as acacia, tragacanth resin, acacia bean resin, guar resin, karaya resin, Agar, pectin, carrage, soluble and insoluble alginates, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, Sodium carboxymethyl cellulose, carboxypolymethylene and Gelatin suitable.

Cellulose hydrocolloids such as methyl cellulose and hydroxypropyl cellulose are preferred and especially hydroxypropylmethyl cellulose and sodium carboxymethyl cellulose.

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Usable pharmaceutically acceptable inert fatty materials are, for example, beeswax, fatty acids, long-chain fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, esters, for example glycerides such as glyceryl esters of fatty acids or of hydrogenated aliphatic carboxylic acids, such as glyceryl monostearate such as glyceryl monostearate, glyceryl distearate, glyceryl distearate, such as glyceryl distearate Mineral oil. Preferred fatty materials are those with a melting point between 30 and 90 ^° C.

Particularly preferred fatty materials are those having a melting point between 45 and 65 ⁰ C, for example, glycerides such as Glycerilpalmitate and stearates; Fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.

The composition preferably includes both hydroxypropylmethyl cellulose as a swellable substance and cetyl palmitate as a fatty material.

The formulation can also contain other soluble or insoluble pharmaceuticals Auxiliaries such as calcium sulphate, calcium phosphate, lactose, mannitol, Contain sucrose, sorbitol, colloidal silicon dioxide or magnesium stearate. Preferably a soluble excipient, especially lactose, available. The weight ratio of the hydrocolloid to these other excipients can then be between 1: 0.5 and 1: 2.

The composition can be prepared in a conventional manner by mixing the Components are prepared, wherein the fatty material is preferably melted. The resulting mixture is in powder form. The powder can be compressed into a tablet, but is preferably filled in: capsules.

If the fatty material is melted, the active ingredient and the other excipients such as lactose, silicon dioxide, calcium sulphate or

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Calcium phosphate will be absorbed into the molten fatty material. The mixture is then cooled until it solidifies and divided into small particles (granules).

The resulting granules can with a, preferably porous, hydrophilic swellable substance and with other auxiliary substances, e.g. magnesium stearate, are mixed and the mixture can be compressed into a tablet or, preferably, filled into capsules.

The invention is preferably a composition of a 9,10-dihydroergot alkaloid in a pasty matrix granulate in which the Granules are in contact with a hydrophilic swellable substance.

Preferably the swellable substance is present in a porous form. It was found that the composition has excellent stability, although the alkaloids against many chemical reagents are sensitive. In addition, the compositions are excellent pharmacodynamic and pharmacodynamic profile.

The resulting retarded compositions have in clinical Standard tests have a bioavailability similar to that of conventional non-sustained release formulations with the same amounts of alkaloids are comparable. The compositions according to the invention can even, when taken once a day, have a therapeutic effect cause for at least 24 hours and even up to 35 hours. The composition therefore only needs once a day in approximately the same daily dosage for the known indications of the alkaloids in question than the conventional non-sustained release forms to be taken.

The 9,10-dihydroergot alkaloids particularly include the 9,10-dihydropeptidergot alkaloids of formula I.

Case 100-6572

H-JM-MH ^

l OH

The groups R and R can be the same or different, e.g.

^R l ^{= (C} l-4) alkyl, and

= (C -.) Alkyl, or benzyl, and

X = CH or S.

9,10-dihydroergot alkaloids include 9,10-dihydropeptidergot alkaloids of the formula I in which the carbon atom in position 9 ^{1 has been} replaced by a sulfur atom, as described in British Patent 2,109,795 B. The compounds are preferably used in pharmaceutical form as acid addition salts.

The preferred compound of formula I in which X = S is that 9'-thia-9,10-dihydroergotamine, which is preferably used as a malonate will. The preferred indication is for the prevention and treatment of vascular headache and for the treatment of the orthostatic Syndrome. There have not yet been any publications on the clinical use of these active ingredients and no specific forms for them delayed release of these agents has been described.

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Epicryptin is the general name of a compound of the formula I, in which R = isopropyl, R = 2R-butyl and X = CH, and is used in British U.S. Patent 2,114,980. The chemical name is: (5R, 8R, 10R) -N - [(2R, 5S, HS, 12S) -5- (2R-butyl) -octahydro-12-hydroxy-2-isopropyl-3,6-dioxo- 8H-oxazolo [3,2-a] pyrrolo [2,1-c! Pyrazinyl] -6-methyl-ergoline-8-carboxamide. Epicryptin is also called epicriptin.

The compound can be used as a pharmaceutically acceptable acid addition salt be taken. However, the free base is preferably used.

It is used for the treatment of lactation, galactorrhoea, hyperprolactinaemic Hypogonadism using acromegaly or prolactinorna.

Epicryptine is also used for the treatment of cerebral insufficiency, e.g. senile dementia, especially its early forms and used to improve alertness. In addition, the epicryptin used for the treatment of hypertension, especially in geriatrics, and for stroke. The preferred indication is that of hypertension. The compound is taken in a daily dosage of about 0.1 to 15 mg, preferably from 2 to 5 mg.

The administration of the ergot alkaloids used according to the invention can occasionally be associated with undesirable side effects » and thereby affect e.g. the heart, the blood vessels, the central nervous system or the autonomic and peripheral nervous system and the glands. Please refer Berde and Schild, pages 815-820. Preferably, the concentration of the ergot alkaloids is at a therapeutically effective level, however kept between narrow limits and thereby an explosion of drug release avoided, which occurs just after ingestion of non-release controlled compositions, resulting in high plasma

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mirror and correspondingly strong side effects. In this The compositions according to the invention are tolerated well. They also have similar effect profiles in experiments

in which the manipulation of food is examined, e.g. before and after taking breakfast in empty subjects.

In particular, the invention relates to a delayed composition Release of the active ingredient, for oral ingestion, which co-dergocrin, dihydroergotamine or epicryptin as active ingredients in uniform dosage forms contains. The pharmaceutical compositions according to the invention preferably contain 1 to 15 mg of 9,10-dihydroergot alkaloid. Preferred weight ratios of 9,10-dihydroergot alkaloid to swellable substance are about 1: 4 to 1:50, e.g. 1: 4 to 1:25.

Preferred weight ratios of 9,10-dihydroergot alkaloid to fatty Material are from about 1: 0.5 to 1:10. Preferred amounts of co-dergocrin in uniform dosage form are from 2 to 10 mg, especially 3 to 6, e.g. 4.5 or 3 mg. The co-dergocrine is preferably present as a mesylate.

Preferably the weight ratio of co-dergocrine to swellable is Substance from 1:50 to 1:10, especially from 1:10 to 1:30, e.g. from 1:15 until 1:25. The weight ratio of co-dergocrin to fatty material is preferably from 1: 1 to 1:10, especially from 1: 1 to 1: 5. If other excipients such as lacose or magnesium stearate are present, is the most favorable weight ratio of; ΐΟο-dergocrin to the other weight aids from 1: 5 to 1:40, especially from 1:15 to 1:40.

Preferred amounts of dihydroergotamine in unit dosage form are from 4-15 mg, e.g. 5 or 7.5 mg, especially 8-12, e.g. 10 mg. The dihydroergotamine is also preferably present as the mesylate. The weight ratio from dihydroergotamine to swellable substance is preferable

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preferably from 1: 4 to 1:20, e.g. 1: 5 to 1:20, especially from 1: 4 to 1:12, e.g. 1: 5 to 1:12.

The weight ratio of dihydroergotamine to fatty material is preferably from 1: 0.5 to 1: 2, preferably from 1: 0.5 to 1.5, e.g. from 1: 0.8 to 1: 1.5. If other auxiliaries, e.g. lactose, silicon dioxide, Magnesium stearate or tartaric acid are present, the weight ratio of dihydroergotamine to the other auxiliaries is appropriate from 1: 3 to 1:20, preferably from 1: 4 to 1:15.

Epicryptine can also be used as an acid addition salt. In the It is preferably present as a free base in a controlled release composition. The unit dosage form preferably contains an amount of 2-7 mg, especially 5 mg of active ingredient. The invention relates for the first time to an oral pharmaceutical Dosage form containing 9'-thia-9,10-dihydroergocryptine or epicryptine for once daily intake. The compositions for once daily intake can be produced in a manner known per se as a capsule or tablet and contain 1 to 15 mg of active ingredient. she have a release profile similar to that obtained from in vivo or vitro dissolution rate experiments can be determined, e.g. a release of 50 to 90, e.g. 50 to 60, 70 to 80 or 80 to 90%, distributed over 7 hours, in 0.1 N HCl, as described, for example, in the experimental results in the examples. In the following examples, all temperatures are in degrees Celsius and are uncorrected.

More information about the properties of pharmaceutical excipients, which are named hereafter can be obtained from the manufacturer mentioned or taken from his brochures or other sources, especially H.P. Fiedler Lexicon of auxiliaries for pharmacy, cosmetics and adjacent areas, 2nd edition 1981, Edito Cantor, Aulendorf. FRG.

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Silicon dioxide is e.g. the branded product Aerosil200, available from ... der Deutsche-Gold und Silberscheideanstalt, Frankfurt, FRG. Glycerol tripalmitostearate is e.g. the branded product Precirol Ato 5, available from ETS Gattefosse 929100 Boulogne-Brillancourt, France. Hydroxypropylmethylcellulose 15000 CPS and 4000 CPS are the branded products Methocel K15M and Methocel 4EM, available from DOW Chemical Company, Michigan, 48640 USA.

Cetyl palmitate is e.g. the branded product Cutina CPA, available from HENKEL 4000, Düsseldorf, Germany, or is available from Gattefosse or from A / S Johan C. Martens and Company, Bergen, Norway.

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EXAMPLE 1; Capsule composition

Ingredient mg

a) Co-dergocrine as mesylate 4.5

b) lactose 124.265

c) silica 10

d) Glycerol tripalmitostearate 40

e) Hydroxypropyl methyl cellulose 4000 CPS 110

Capsule (hard gelatin) 78

Production (amount of 6000 capsules)

Components a), b) and c) were sieved and mixed. Component d) was brought by heating to 56 ⁰ C (melting point of 54 ⁰ C) and melted and added erwärmtenGemisch at 55 ° C. The mass was stirred for 2 minutes until a homogeneous mixture resulted and cooled overnight. The cooled mass was comminuted by sieving (through openings of 250 micrometers). Component e) was also sieved (through openings of 360 micrometers) and mixed in for 10 minutes. The mixture was encapsulated.

Case 100-6572

EXAMPLES 2 to 5:

Capsule compositions: ingredient

a) Co-dergocrine as mesylate

b) lactose

c) cetyl palmitate

dl) Hydroxypropylmethylcellullose (15000 CPS)

d2) hydroxypropylmethyl cellulose (4000 CPS)

e) magnesium stearate

Capsule (hard gelatin; 78 mg)

Ex. 2 Ex. 3 Ex. 4 Ex. 5

mg mg mg mg

4.5 4.5 3.0 3.0 165.5

10.0 8.0 8.0 8.0

90.0 70.0 70.0

1.0 1.0

90.0

Manufacturing

The constituents are mixed in a manner analogous to that described in Example 1, with the exception that constituent d) is replaced by an equivalent
Amount of cetyl palmitate is replaced, the silicon dioxide c) is omitted and the hydroxypropylmethyl cellulose d) is mixed with magnesium stearate.

Release in vitro

In in vitro tests (USP XXI, pages 1243-1244, apparatus 1, 1000 ml
0.1 N HCl, 100 revolutions per minute) the following release results were obtained:

Case 100-6572

Time (hours) Release of the
Co-Dergocrins Ex. 3 Time (hours) Release of the
Co-Dergocrins Ex. 5 Ex. 2 16% Ex. 4 20% 1 15% 37% 1 19% 37% 3 32% 52% 2 32% 49% 5 50% 64% 4th 48% 73% 7th 66% 86% 7th 67% 101% 24 99% 24 100%

EXAMPLE 6: Capsule composition

component

Dihydroergotamine as a mesylate Lactose

Silicon dioxide

Glycerol tripalmitostearate

mg

10.0

88.0

1.0

10.0

Hydroxypropyl methyl cellulose 4000 CPS 90.0 Magnesium stearate 1.0

Capsule (hard gelatin)

62.0

Production (amount of 6000 capsules)

Components a), b) and c) are sieved and mixed. Component d) is ^{melted by heating to 56 °} C. (melting point 54 ^° C.) and is added to the mixture heated ^{to 55 ° C.} The mass was stirred for 2 minutes until a homogeneous mixture was obtained and over

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Chilled night. The cooled mass was crushed by sieving (through 800 micrometer opening. Components e) and f) were sieved (through openings of 500 micorometers) and mixed in in 10 minutes. The mixture was encapsulated.

Release in vitro (the experimental conditions were as

in example 2)

Time (hours) release of dihydroergotamine (%)

1 9

2 17 4 29 6 41

24 96

EXAMPLE 7; Capsule composition

Ingredient mg

a) Dihydroergotamine (as mesylate) 10.0

b) lactose 107.0

c) cetyl palmitate 10.0

d) hydroxypropyl methyl cellulose (15,000 CPS) 70.0

e) silicon dioxide 1.0

f) Magnesium stearate 2.0

Capsule (hard gelatin) 62.0

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Manufacturing

The constituents were described in a manner analogous to that in Example 6 mixed, with the exception of component d), which was replaced by an equivalent amount of cetyl palmitate.

Release in vitro

Time (hours) release of dihydroergotamine (%)

1 24

2 41 4 65 6 80 8 100

EXAMPLES 8 to 10:

Capsule composition Ex. 8 Ex. 9 Ex.

Components mg mg mg a) Dihydroergotamine (as mesylate) 7.5 7.5 7.5 b) Tartaric acid 0.18 0.2 0.18 c) Lactose 81.32 144.3 81.32 d) Cetyl palmitate 8.0 -5.0 8.0 e) Hydroxypropyl methyl cellulose 80.0 40.0 80.0

(4000 CPS)

The constituents are described in a manner analogous to that in Example 6, mixed.

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Components a), b) and c have been included in component d), the solidified mixture granulated and mixed with component e).

Release in vitro (experimental conditions as in example 2)

Time (hours) release of the dihydroergotamxn

Ex. 8 Ex. 9 Ex.

1 10% 14% 10%

2 19% 26% 22% 4 33% 49% 41% 6 46% 67% 56%

24 96% 99% 101%

Comparative clinical trial

From a capsule A taken orally by healthy volunteers according to Example 2, which releases the co-dergocrmin in a controlled manner, the bioavailability was compared with that of a conventional tablet B also orally taken with the following composition:

Conventional composition of tablet B

Ingredient mg

1. Co-dergocrine (mesylate) 1.0

2. Stearic Acid 2.0

3. Talk 4.0

4. Polyvinyl pyrrolidone 4.0

5. Strength 8.0

6. Lactose 141.0

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Ingredients 1 to 6 were mixed together with one mixture granulated from alcohol and water, dried and pressed into a tablet.

A dosage of two capsules containing 4.5 mg of co-dergocrine mesylate A (= 9 mg) was administered with a dosage of 4 conventional tablets B, which contained 1 mg co-dergocrine mesylate in (= 4 mg), compared. The low dosage of the tablet was chosen so as to be expected Side effects due to the high plasma concentration explosions of the uncontrolled release from conventional tablets are avoided would. The experiment consisted of three treatments with a random arrangement of the subjects and had a marked distribution pattern. Ten healthy Male volunteers were given capsules A and tablets B in two different treatments in the fasted state, after which a third treatment took place with capsule type A which was taken with breakfast. The subjects were given at certain time intervals Blood samples taken up to 24 hours after dosing. The co-dergocrin concentrations after taking capsules A and tablets B. were measured graphically as the corresponding average curves A (without food), A 2 (with food) and B (without food) (in picograms / ml, time / in hours) shown in FIG. The co-dergocrin concentrations measured became as follows Parameters calculated as arithmetic mean values.

Retard capsule A Retard capsule A Oral tablet B with food without food without food

(Area under the 2066 2066 2042 *

curve, 0-24 hours)

Peak value (in 172 162 511 *

Picograms / ml)

^Time (in hours) 5.9 3.9 0.9

*
Extrapolated from 4 mg to 9 mg

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The extrapolation is permissible since codedergocrine mesylate is a linear Dependence of the plasma concentration in the dose range from 0 to 9 mg.

The extended-release capsule A has approximately the same bioavailability (AUC) as Tablet B at the same dosage, taken both on an empty stomach and with breakfast. Compared to tablet B, the retard capsule has A has a statistically significantly lower peak value. The peak at capsule A is also reached later (a delay from less than 1 hour after ingestion to up to 3.9 hours on an empty stomach or up to 5.9 hours with a meal). In general is However, the profile with capsule A in an empty state is about the same as with capsule A with a meal, apart from the delay in absorption of the active ingredient in a filled stomach (presumably through a delay in gastric emptying).

Capsule A shows whether the subject is fasted, whether with a Meal a delayed release of the active ingredient, whereby, and this is particularly noteworthy, no significant loss of bioavailability, can be determined compared to the oral reference tablets B.

Side effects such as headache and gastrointestinal upset were temporary and mild to moderate in their effects. Single doses of Extended-release capsules A, taken as 2 χ 4.5 mg extended-release capsules A are safe and well tolerated.

EXAMPLE 11:

The co-dergocrine and dihydroergotamine in the previous examples can with an equivalent amount of epicryptine or 9'-thia-9,10-dihydroergotamine be replaced.

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Claims (23)

SANDOZ-PATENT-GMBH Lörrach Case 100-6572 Patent to s ρ r ü c h e 1. A composition for controlled release oral administration of the active ingredient, characterized by - a 9,10-dihydroergot alkaloid as an active ingredient - a pharmaceutically acceptable hydrophilic swellable substance a pharmaceutically acceptable inert fatty material. 2. Composition according to claim 1, wherein the active ingredient is a peptide alkaloid is. 3. Composition according to claim 2, wherein the peptide alkaloid Codergocrin, Dihydroergotamine, epicryptine or 9 * -Thia-9,10-dihydroergotamine is. 4. Composition according to any one of the preceding claims, wherein the swellable SuDStanz is a cellulose hydrocolloid. 5. Composition according to any one of the preceding claims, wherein the swellable substance is hydroxypropylmethyl cellulose. 6. Composition according to one of the preceding claims, wherein the fatty material is a hydrophobic material with a melting point between 30 and 90 ^° C. 7. Composition according to any one of the preceding claims, wherein the fatty material is a fatty acid ester. 8. Composition according to one of the preceding claims, wherein the fatty material is cetyl palmitate. - 2 - Case 100-6572 9. Composition according to one of the preceding claims, which I - Contains 15 mg of ergot alkaloid per unitary dosage form. 10. A composition according to any one of the preceding claims, which contains 2 to 10 mg co-dergocrine. 11. Composition according to one of the preceding claims 1 to 9, which contains 4 to 15 mg of dihydroergotamine. 12. Composition according to one of the preceding claims 1 to 10, wherein the weight ratio of co-dergocrin to the swellable substance is from 1:10 to 1:50. 13. Composition according to one of the preceding claims 1 to 9 and 11, wherein the weight ratio of dihydroergotamine to swellable substance is from 1: 4 to 1:20. 14. Composition according to one of the preceding claims 1 to 10 and 12, wherein the weight ratio of codedergocrin to fatty material is from 1: 1 to 1:10. 15. Composition according to one of the preceding claims 1 to 9, 11 and 13, wherein the weight ratio of dihydroergotamine to fatty material is from 1: 0.5 to 1: 2. 16. Composition according to one of the preceding claims, which Hydroxypropylmethylcellulose as a swellable substance and cetyl palmitate contains as a greasy material. 17. Composition according to one of the preceding claims, which the 9,10-dihydroergot alkaloid enclosed in a fatty matrix granulate contains and the granulate particles with the hydrophilic - 3 - Case 100-6572 swellable substance are encased. 18. Composition according to one of the preceding claims, based to co-dergocrin, for use in the treatment or prevention of cerebral insufficiency or cerebral disorders, hypertensia or migraines, in unit dosage form containing 2 to 10 mg of co-dergocrine. 19- Composition according to one of the preceding claims to dihydroergotamine, for use in treatment or prevention of hypotensia, orthostatic circulatory disorders or migraines, in uniform dosage form, 4 to 15 mg dihydergotamine containing. 20. Process for the preparation of a composition for oral administration with controlled release of the active ingredient, characterized by the mixing of a 9,10-dihydroergot alkaloid active ~ stoffeSj with a hydrophilic, swellable substance and a greasy material. 21. The method according to claim 20, characterized in that the Active ingredient mixed with the melted fatty material, the mixture solidified by cooling and granulated and the Granulate particles are mixed with the swellable substance. 22. A once-daily oral use of an epicryptine containing Composition for the treatment of cerebral insufficiency, hypertension or stroke. 23. A once daily oral use of a 9'-thia-9,10-dihydroergotamine containing composition for the treatment or prevention of hypotensia, orthostatic circulatory disorders or migraines.