NL8600161A - PHARMACEUTICAL PREPARATIONS CONTAINING 9,10-DIHYDROGOTALKALOIDS. - Google Patents

Description

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Pharmaceutical preparations containing 9,10-dihydroergot alkaloids.

This invention relates to pharmaceutical preparations containing 9,10-dihydroergotalkaloids.

9,10-Dihydroergot alkaloids include both the 9,10-dihydro derivatives of natural ergot alkaloids, and ergot 5 'alkaloids which can be obtained by fermentation or by chemical synthesis. For example, they may have substituents, for example, those commonly known from the chemistry of ergot alkaloids and may exist in the form of isomers, for example, as 8R and 8S isomers, for example.

10 as described in "Ergot alkaloids and related compounds,

Editors B. Berde and H.D.Schild, Springer Verlag, Berlin, Heidelberg,

New York 1978, hereinafter referred to as Berde and Shield.

The most recommended compounds are dihydroergo-comine, dihydroergocristine, dihydro-α-ergocryptine, dihydro-β-ergocryptine and co-dienocrine and dihydroergotamine.

Co -erdocrine is the general name of a 3: 3: 2: 1 mixture of dihydroergocomine, dihydroergocristine, dihydro-α-ergocryptine and dihydro-β-ergocryptine, (see Berde and Schild, p. 58).

For pharmaceutical use, co-dienocrine in the form of an acid addition salt, for example the ethanesulfonate, maleate, fumarate, tartrate, hydrochloride or preferably the mesylate, can be used. They have a similar degree of action as the free base form and are prepared or manufactured in a manner known per se.

The methanesulfonate salt is listed in the Merck index, 1983, under the trade name HYDERGIN, see reference 3596 on pages 526 and 527. This salt is also known as ergoloid mesylates.

i 30 «- * The pharmacological and clinical properties have been discussed in detail in the book by Berde and Schild.

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Co-Derdocrine modifies cerebral neurotransmission and improves. impaired cerebral metabolic function. In addition, it has a stabilizing effect on the tone of vessels in the skull and has an anti-hypertensive effect.

Co-Derdocrine is therefore indicated for the treatment of cerebral insufficiency in elderly people and of cerebrovascular disease, particularly when associated with hypertension, as well as to prevent migraine.

Usual oral, daily doses are between 3 and 6 mg. A recommended oral daily dose is 4.5 mg, preferably divided into smaller 1.5 mg doses administered three times a day.

Dihydroergocomine, dihydroergocristine, dihydro-ct-15 ergocryptine and dihydro-5-ergocryptine can be used separately, for the same indications and in the same dosage order of magnitude.

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

The compound can be administered in the form of the free base or of a pharmaceutically acceptable acid addition salt. Such acid addition salts are known. An example of an acid addition salt form is the methanesulfonate salt (the mesylate), described in The Merck Index 1983, reference 25 3151, and sold under the brand DIHYDERGOT.

Dihydroergotamine is indicated for use in the treatment of hypotension and orthostatic circulatory disorders, the treatment of acute migraine attacks and related vascular headaches, as well as in the interval treatment of migraine and other vascular headaches.

Furthermore, dihydroergotamine is indicated to be active in the treatment of Herpes Zoster.

The drug is usually administered orally in daily, * * * - 3 doses of about 1-10 mg.

The present invention provides a slow-release formulation for oral administration containing a 9,10-dihydroergotalkaloid, a pharmaceutically acceptable hydrophilic swelling agent, and a pharmaceutically acceptable inert fatty material.

In particular, the invention provides such a sustained-release preparation wherein the 9,10-dihydroergotalkaloid is a peptide alkaloid.

Preferred hydrophilic swelling agents include one or more natural, fully or fully synthetic, anionic, or, preferably, non-ionic hydrophilic gums, modified cellulosic or proteinaceous materials, such as, for example: acacia, tragacanth gum, cassava gum , guar gum, karaya gum, agar, peptin, carrageenan, soluble and insoluble alginates, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxypolymethylene, gelatin.

Cellulose hydrocolloids, including methyl cellulose, hydroxypropyl cellulose and in particular hydroxypropylmethyl cellulose and sodium carboxymethyl cellulose, are recommended.

Suitable pharmaceutically acceptable inert fatty materials include beeswax, fatty acids, long chain high alcohols, such as, for example, cetyl alcohol, myristyl alcohol, stearyl alcohol, esters, for example, glycerides, such as glyceryl esters of fatty acids or hydrogenated aliphatic acids, such as, for example, glyceryl mono-stearate glyceryl distearate, glyceryl esters of hydrogenated castor oil and so on; oils, such as mineral oil and so on. Fatty materials are preferably materials with melting points between 30 and 90 ° C.

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It is especially recommended that the fat materials have a melting point of 45-65 ° C and this includes glycerides, such as glyceryl palmitates. and stearates and fatty acids, such as hydrogenated castor oil and esters of fatty acids, such as cetyl palmitate.

The composition preferably contains both hydroxypropylmethylcellulose as a swelling agent and cetyl palmitate as a fat material.

It is also beneficial to include at least one or other soluble or insoluble pharmaceutical excipients, such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silicon oxide, and magnesium stearate, in the composition. A soluble excipient, in particular lactose, is preferably present. For example, the ratio of hydrocolloid to other excipient can be between 1: 0.5 and 1: 2.

The composition can be prepared or prepared in a conventional manner by mixing the ingredients together, preferably by melting the fatty material. The resulting mixture is in powder form and this powder can be pressed into a tablet, yet it is preferably placed in a capsule.

When the fat material is melted, the molten fat material can incorporate the drug and additional excipients, such as lactose, silica, calcium sulfate or calcium phosphate. The mixture is then allowed to solidify and divide it into small particles (granules).

The resulting granular product can be mixed with a preferably porous, hydrophilic swelling agent and further excipients, such as, for example, magnesium stearate, and the mixture can be pressed into a tablet or can be placed in a capsule.

According to a recommended aspect of the present invention, there is accordingly provided a composition containing a 9,10-dihydroergotalkoloid in a granular product of a fat material matrix, the granular particles being in. o i - 5 - contact with a hydrophilic swelling agent.

The swelling agent is preferably present in a porous form.

Surprisingly, it has been found that the formulation 5 has excellent stability, despite the fact that the alkaloids are sensitive to many chemical reagents.

In addition, the preparations have a satisfactory pharmacodynamic and pharmacokinetic profile.

The resulting sustained-release formulations generally have a comparable bioavailability, according to standard clinical trials, compared to conventional formulations containing the same amounts of alkaloids but not the active material with delayed release. The compositions of the invention, even when administered once a day, can exert a therapeutic effect for at least 24 hours and even up to 35 hours. Thus, the compositions can be administered only once a day in the known indications of the alkaloids in approximately the same daily doses as used in the conventional forms in which the active material is not released in a delayed manner.

The 9,10-dihydroergotalkaloids particularly include 9,10-dihydropeptidergotalkaloids of formula 1, wherein the substituents R 1 and R 2, which may or may not be the same, represent, for example, an alkyl group of 1-4 carbon atoms and R2 is an alkyl group of 1-4 carbon atoms or the benzyl group, and wherein X = CH or S.

The 9,10-dihydroergotalkaloids include 9,10-dihydro-30-peptidegotalkaloids of formula 1, wherein the carbon atom in 91 is replaced by a sulfur atom, as described in British Patent 2,109,795 B. The compounds are preferably pharmaceutical form as acid addition salts -6-- * «<t · ''.

The recommended compound of formula 1 wherein X represents a sulfur atom is 9'-thia., 9,10-dihydroergotamine.

This amine is preferably used in the form of the hydrogen malonate 5. The recommended indication is to prevent and treat vascular headaches and to treat orthostatic syndrome. There are no publications on the clinical use of this active agent, and no specific sustained release forms of the active material of this compound have been described.

Epicryptine is the general name of a compound of formula 1, wherein an isopropyl group, the 2R-butyl group and X represent the CH 2 group, which compound is described in British Pat. No. 2,114,980 B. Its chemical name is: 15 (5R 8R, 1QR) -N- / ~ 2R, 5S, 11S, 12S) -5-2R-butyl) -octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-8H-oxazolo / 3,2- α / pyrrolo / 2,1-pyrazinyl-7-6-methyl-ergoline-8-carboxylic acid amide. Epicryptine is also known as epicriptine.

The compound can be administered in the form of a pharmaceutically acceptable acid addition salt. The free base is preferably used.

It is indicated for use in the treatment of lactation, galactorrhoea, hyperprolactinemic hypogonadism, acromegaly or prolactinomy.

Epicryptine is also indicated for use in the treatment of cerebral insufficiency, for example for senile dementia, in particular its premature forms and for an increasing degree of insomnia.

In addition, epicryptine is useful in the treatment of hypertonia, especially in geriatric patients and cerebral haemorrhage. The recommended indication is hypertension.

The compound is administered in a daily dose of about 0.1 to 15 mg, preferably 2 to 5 mg.

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Administration of the ergot alkaloids used according to the invention can sometimes be associated with adverse side effects, for example effects on the heart, vascular effects, effects on the central nervous system, autonomic and peripheral nervous system and endocrine effects. See Berde and Schild, pp. 815-820.

Preferably, the concentration of the ergot alkaloids is kept at a therapeutically active level, but within narrow limits, and avoids the drug explosion that may occur immediately after administration of uncontrolled sustained-release preparations. This leads temporarily to high blood levels and relatively powerful adverse effects.

The preparations according to the invention are well tolerated.

In addition, the compositions of the present invention provide corresponding activity profiles in food interaction studies, for example before and after breakfast, and in patients who have fasted.

In particular, the present invention provides sustained-release preparations for oral administration containing co-dienocrine, dihydroergotamine or epicryptine as active ingredients, in unit dosage form.

The pharmaceutical preparations according to the invention preferably contain 1 to 15 mg of 9,10-dihydroergotalkaloid.

Recommended ratios of the 9,10-dihydroergot alkaloid to swelling material are between about 1: 4 and 1:50, for example, between 1: 4 and 1:25.

Preferred ratios of 9,10-dihydroergotalkaloid to fat material are between 1: 0.5 and 1:10.

Recommended amounts of co-dienocrine in unit dosage form are between 2 to 10 mg, especially 3-6 mg, and are, for example, 4/5 or 3 mg. Preferably, the co-dienocrine is in the mesylate form.

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It is recommended that the ratio of co-dienocrine to swelling material be between 1:50 and 1:10, in particular between 1:10 and 1:30, for example, between 1:15 and 1:25.

It is recommended that the ratio of cerdocrine to fat material is between 1: 1 and 1:10, in particular between 1: 1 and 1: 5.

When other excipients, such as lactose or magnesium stearate, are present, the weight ratio of co-dieno-crinine to other excipients is suitably between 1: 5 and 1:40, in particular between 1:15 and 1:40.

Recommended amounts of dihydroergotamine in unit dosage form are between 4 and 15 mg, for example 5 mg, especially between 8 and 12 mg, and are, for example, 10 or 7.5 mg. Preferably, dihydroergotamine is also in the mesylate form.

It is recommended that the ratio of dihydroergotamine to swelling material be between 1:41 and 1:20, for example between 1: 5 and 1:20, in particular between 1: 4 and 1:12, 20 for example between 1: 5 and 1: 12.

The ratio of dihydroergotamine to the fat material is preferably between 1: 0.5 to 1: 2, in particular from 1: 0.5 to 1: 1.5, for example between 1: 0.8 and 1: 1.5 .

If other excipients, such as lactose, silicon dioxide, magnesium stearate or tartaric acid, are present, the weight ratio of dihydroergotamine to the other excipients is suitably between 1: 3 and 1:20, in particular between 1: 4 and 1:15 .

Epicryptine may also be present as an acid addition salt, but the recommended form in the sustained-release preparations is the free base.

The unit dosage form preferably contains an amount of 2-7 mg, especially 5 mg, of drug.

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The present invention for the first time provides an oral pharmaceutical composition containing 9'-thia-9,10-dihydroergocryptine or epicryptine for once daily administration.

Once-a-day preparations may be prepared or prepared in a conventional manner, for example, into a capsule or tablet, and may contain 1-15 mg of active agent. Preferably they exhibit the same release profile, determined according to in vivo or in vitro dissolution tests, as the compositions of the present invention, for example a release of about 50 to 90, e.g. 50 to 60, 70 to 80 or 80 to 90% for 7 hours in 0.1 NHCl, such as, for example, according to the test conditions set forth in Example II.

In the following examples, all temperatures are expressed in ° C and uncorrected.

Further information regarding the properties etc. of the pharmaceutical excipients listed below may be obtained from the manufacturer listed below, manufacturer's brochures and other sources, in particular H.P. Fiedler 20 Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und an boundende Gebiete, 2nd edition 1981, Edito Cantor, Aulendorf, West Germany.

Silicon dioxide (silica) is, for example, Aerosil 200 from Deutsche-Gold und Silberscheideanstalt, Frankfurt, West _

Germany.

Glycerol ditripalmitostearate is, for example

Precirol Ato 5 of ETS Gattefossé 929100 Boulogne-Brillancourt, France.

Hydroxypropylmethylcellulose 15000 cps and 4000 cps are, for example, Methocel K15M and Methocel 4EM from Dow Chemical 30 Company, Michigan 48640, United States of America.

Cetyl palmitate is, for example, Cutina CPA from Henkel 4000, Düsseldorf, West Germany or can be obtained from Gattefossé or from A / S Johan C. Martens and Company, Bergen,. : 5 1 t * - 10 -

Norway.

Example I: the composition of each capsule.

5 components: mg a) Co-dienocrine (in mesylate form) 4.5 b) lactose (200 mesh) 124.265 c) silicon dioxide 10 10 d) glycerol ditripalmitostearate 40 e) hydroxypropylmethylcellulose 4000 cps 110 capsule (hard gelatin) 78 15 Preparation (6000 fill capsules).

Components a), b) and c) are sieved and mixed. Component d) is melted and heated to 56 ° C (melting point 54 ° C) and is added to the mixture heated to 55 ° C. The mass is stirred for 2 minutes or until a homogeneous mixture is quenched and it is left to cool overnight. The cooled mass becomes s.

broken and sieved (through a sieve with 250 micEon openings). Component e) is sieved (through a 360 micron aperture sieve) and taken up by mixing for 10 minutes.

The mixture is then placed in capsules.

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Examples II-V

the composition of each capsule vb II vb III vb IV vb V

component mg mg mg mg a) Mesodylate co-dienocrine 4.5 4.5 3.0 3.0 5 b) lactose (200 mesh) 165.5 c) cetyl palmitate 10.0 8.0 8.0 8.0 dl) hydroxypropylmethyl cellulose (15000 cps) 90.0 70.0 70.0 d2) hydroxypropyl methyl cellulose (4000 cps) 90.0 e) magnesium stearate 1.0 1.0 capsule (harcf gelatin; 78 mg) 15 Preparation .

The ingredients are mixed in an analogous manner as described in Example I, except that component d) is replaced by an equivalent amount of cetyl palmitate, the silicon dioxide c) is omitted and the hydroxypropyl methyl cellulose d) is mixed with magnesium stearate.

In vitro release.

In In Vitro Trials (USP XXI, pp. 1243-1244,

Device 1, 1000 ml 0.1 N HCl, 100 revolutions per minute), the following release values were obtained.

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Time (hours) release of time (hours) release of co-gregocrine co-gregocrine

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1 15% 16% 1 19% 20% 5 3 32 37 2 32 37 5 50 52 4 48 49 7 66 64 7 67 73 24 99 86 24 100 101 10

Example VI: composition Y ^ ^ each ^ capsule components: mg a) dihydroergotamine (in mesylate form) 10.0 b) lactose (200 mesh) 88.0 15 c) silicon dioxide 1.0 d) glycerol ditripalmitostearate 10.0 e) hydroxypropyl methyl cellulose 4000 cps 90.0 f) magnesium stearate 1.0 20 capsule (hard gelatin) 62.0

Preparation (filling of 6000 capsules).

The components a), b) and c) are sieved and mixed. Component d) is melted by heating at 56 ° C (melting point: 54 ° C) and added to the mixture heated at 55 ° C. The mass is cooled overnight for 2 minutes or until a homogeneous mixture is many-rose. The cooled mass is crushed and sieved (through a 800 micron opening sieve). The components e) and f) are sieved (through a sieve with 500 micron openings) and taken up by mixing for 10 minutes. Finally, the mixture is placed in capsules.

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In vitro release (test conditions; see Example II) time (hours of dihydroergotamine release (%) 1.9 9 2 17 5 4 29 6 41 24 96

Example VII: Composition of each capsule 10 Components mg a) dihydroergotamine in mesylate form 10.0 b) lactose (200 mesh) 107.0 c) cetyl palmitate 10.0 d) hydroxypropylmethylcellulose (15000 cps) 70.0 15 e) silicon dioxide 1.0 f) magnesium stearate 2.0 capsule (hard gelatin) 62.0

Preparation.

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The ingredients are mixed in an analogous manner as described in Example VI, except that ingredient d) is replaced by an equivalent amount of cetyl palmitate.

25 In vitro release (conditions of the experiment; see example II) time (hours) dihydroergotamine release (%) 1 24 2 41 4 65 30 6 80 8 100 ...- - j. ; ; i r v

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Examples VIII-X

Composition of each capsule Vb VIII Vb IX Vb X

ingredients: mg mg mg a) dihydroergotamine in mesylate form 7.5 7.5 7.5 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) hydroxypropylmethylcellulose 80.0 40.0 80.0 (4000 cps) 10

The ingredients are mixed in an analogous manner as described in Example VI.

The components a), b) and c) are included in component b), the solidified mixture is granulated and mixed with component e).

In vitro release (conditions of the test: see Example II):

Time (hours) of release of - - dihydroergotamine

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1 10% 14% 10% 2 19 26 22 4 33 49 e 41 6 46 67 56 25 24 96 99 101

Clinical comparison test v

Objective: To study the bioavailability of co-dienocrine in a controlled release oral capsule A according to Example 2 in healthy volunteers, compared to co-dienocrine in a conventional tablet. B.

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Usual preparation in tablet form components mg 1. Co-dienocrine in mesylate form 1.0 2. stearic acid 2.0 5 3. talc 4.0 4. polyvinylpyrrolidan 4.0 5. starch 8.0 6. lactose 141.0 X0 The components 1-6 were mixed together, granulated with a mixture of alcohol and water, dried and compressed into a tablet.

A dose of two capsules A containing 4.5 mg of co-dienocrine mesylate (9 mg) was compared with one dose of four conventional tablets B containing 1 mg of co-dienocrine mesylate (4 mg). The lower dose of the tablet was chosen to avoid expected side effects due to the high peak values of the conventional non-controlled release tablets.

The design of the study was an open label, two-period study {in which each subject was randomly assigned to one of the two treatments, followed by a third treatment period, with all subjects undergoing equal third treatment.

Ten healthy male volunteers underwent treatment in the first 4-hour periods on an empty stomach, followed by one dose of the sustained-release capsules A, with food administered in the third period.

Of the ten volunteers, blood samples were taken through an internal cannula at certain times to 24 hours after the capsules were administered.

The concentrations of co-dienocrine, measured after administration of capsules A and tablet B, were plotted as shown. - Λ Λ ï: rv, ju * - 16 - give in the enclosed figure 1 as corresponding mean curves A1 (without food), A.2 (with food) and B (without food) in picograms ml, time T plotted in hours .

The following parameters (as arithmetic means) were obtained from the measured coderocrine concentrations.

capsule A with capsule A with oral tablet delayed delayed, af- B without delivery with delivery without food food „food 10

AUC

(area below 2066 2066 2242 * the curve, 0-24 hours) peak (in picograms / ml) 172 162 511 * 15 time (in hours) 5.9 3.9 0.9 * extrapolated from 4 mg to 9 mg

This is justified, since the co-dienocrine mesylate exhibits a linear dose proportion for the AUC in the range of a dose of 0-9 mg.

The sustained-release capsule A has an AUC analogous to that of conventional tablet B (dose corrected) when administered on an empty stomach or with a meal. Compared to tablet B, sustained-release capsule A exhibits a statistically significantly lower peak height and longer time to peak (from less than 1 hour to 3.9 hours on an empty stomach or 5.9 hours when taken with a meal. administered). Generally, the compound A profile when given on an empty stomach was analogous to that administered after a meal, except for the delay in absorption of the drug on a full stomach (probably due to a delay in emptying the stomach).

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The delayed-release capsule A, given on an empty stomach or with a meal, gives a slow release of the medicine without a large dose being released quickly and, most notably, without a noticeable loss of bioavailability, compared to the oral tablet of standard B.

Side effects, such as headaches and upset of the gastrointestinal tract, are temporary and mild to moderate in severity.

Single doses of the sustained release capsules A, when administered as 2 x 4.5 mg sustained release capsules A, are safe and well tolerated.

Example 11:

The co-dienocrine and dihydroergotamine used in the previous examples can be replaced by an equivalent amount of epicryptine or 91-thia-9,1O-dihydroergotamine.

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Claims (26)

A slow-release preparation for oral administration of the active material, characterized in that it comprises one or more 9,10-dihydroergotalkaloids as medicaments, one or more pharmaceutically acceptable hydrophilic swelling materials, and one or more number of pharmaceutically acceptable, inert fat materials. 2. A composition according to claim 1, characterized in that the medicament is a peptide alkaloid. Preparation according to claim 2, characterized in that the peptide alkaloid is co-dienocrine, dihydroergotamine, epicryptine or 9'-thia-9,10-dihydroergotamine. 4. A composition according to any one of the preceding claims, characterized in that the swelling agent is a cellulose hydrocolloid. Preparation according to any one of the preceding claims, characterized in that the swelling agent is hydroxypropylmethylcellulose. is. Preparation according to any one of the preceding claims, characterized in that the fat material is a hydrophobic material with a melting point between 30 and 90 ° C. Preparation according to any one of the preceding claims, characterized in that the fat material is an ester of a fatty acid. 8. A composition according to any one of the preceding claims, characterized in that the fat material is a cetyl palmitate. Preparation according to any one of the preceding claims, characterized in that it contains 1-15 mg ergot alkaloid per unit dosage form. 10. A composition according to any one of the preceding claims, characterized in that it contains 4-10mg of co-dienocrine. Preparation according to any one of the preceding claims, characterized in that it contains 4-15 mg of dihydroergotamine. Z) Λ Λ .3 - - V5 V v! * r - 19 - 12. Preparation according to any one of the preceding claims 1-10, characterized in that the weight ratio of co-gedocrine to the swelling material is between 1:10 and 1:50. Preparation according to any one of claims 5 to 9 and 11, characterized in that the weight ratio of dihydroergotamine to the swelling material is between 1: 4 and 1:20. Preparation according to any one of claims 1 to 10 and 12, characterized in that the weight ratio of cerdocrine to the fat material is between 1: 1 and 1:10. Preparation according to any one of claims 1 to 9, 11 and 13, characterized in that the weight ratio of dihydroergotamine to the fat material is between 1: 0.5 to 1: 2. 16. A composition according to any one of the preceding claims, characterized in that it contains hydroxypropylmethylcellulose as a swelling agent and cetyl palmitate as a fat material. Preparation according to claim 1, substantially as described by one of the preceding examples. 18. A composition according to any one of the preceding claims, characterized in that it contains the 9,10-dihydroergotalkaloid in a granular matrix of a fat material, the granular particles in contact with a hydrophilic swelling agent. 19. A method of treating cerebral insufficiency and disorders, hypertension, or migraine, characterized in that a patient in need of such treatment is given a therapeutically effective amount of a composition according to any one of the preceding claims. contains. 20. Compositions according to any one of the preceding claims, related to co-dienocrine, for use in the treatment or prevention in the method according to claim 19, characterized in that a unit dosage form containing 2-10 mg of co-dienocrine is used . Λ b - 20 - a 21. A method of treating hypotension, orthostatic circulatory disorders or migraine, characterized in that a therapeutically effective amount of a composition according to any preceding claim containing dihydroergotamine is administered to a patient in need of such treatment. 22. A composition according to any one of the preceding claims related to dihydroergotamine for use in the treatment or prevention of the process according to claim 10, characterized in that a unit dosage form containing 5-15 mg of dihydroergotamine is used. 23. A method of preparing or manufacturing a preparation for oral administration which slowly releases the active material, characterized in that a?, 10-dihydroergot alkaloid drug, a hydrophilic swelling material and a fat material are mixed. 24. A method according to claim 13, characterized in that the medicament is mixed with the melted fat material, the mixture is allowed to solidify and granulate and the granular particles are mixed with the porous swelling material. 25. An oral pharmaceutical preparation containing epicriptine, characterized in that this preparation is for administration once a day. 26. An oral pharmaceutical composition containing 9'-thia-9,10-dihydroergotamine, characterized in that it is for once daily administration.