DK167138B1 - PHARMACEUTICAL PREPARATIONS CONTAINING ERGOTAL KALOIDS - Google Patents

Description

DK 167138 Bl

The present invention relates to pharmaceutical compositions containing 9,10-dihydro-ergot alkaloids.

9,10-Dihydro-ergot alkaloids comprise the 9,10-dihydro derivatives of natural ergot alkaloids as well as ergot alkaloids which can be formed by fermentation or by chemical synthesis. They may, for example, have substituents, for example, as usually known in the field of ergot alkaloid chemistry, and may be in the form of isomers, e.g., as 8R and 8S isomers, for example as described in "Ergot alkaloids and related compounds", edited by B. Berde and HD Shield, 10 Springer Verlag, Berlin. Heidelberg. New York. 1978, hereafter called "Berde and Schild".

From EP 95 123 and US 3,147,187, respectively, sustained-release oral formulations are known, which formulations as active substances contain diethylpropion-HCl and 15 amphetamine and amobarbital, respectively.

According to EP 95 123, release of tartaric acid as stabilizer is achieved over a period of 8 hours.

The system described in US 3,147,187 also operates for 8 hours (see Tables 1, 2 and 3 of this publication), the use of maize starch being an uncertain factor in the rate of release of the active substance and the corn starch being co-processed. when making tablets instead of capsules.

However, according to the present invention, with a similar preparation, but without the use of tartaric acid, release over 24 hours of the active substances in question, especially hydergin, can be obtained (see the tables below).

The most preferred compounds are dihydroergocornin, dihydroergocristine, dihydroergocryptin, dihydro / S-ergocryptin and co-dergocrine and dihydroergotamine.

DK 167138 B1 2

Co-dergocrin is the generic name for a molar 3: 3: 2 mixture of dihydroergocomin, dihydroergocristine, dihydro-α-ergocryptin and dihydro- / 3-ergocryptin (cf. Berde and Schild, p. 58).

For pharmaceutical use, codergocrine can be used in the form of an acid addition salt, for example as the ethane sulfonate, maleate, fumarate, tartrate, hydrochloride or preferably mesylate. They exhibit the same degree of activity as the free base form and are prepared in a manner known per se.

The methanesulfonate salt is listed in the Merck Index. 1983, under the trade name HYDERGIN, cf. reference 3596 on pages 525-527.

This compound is also known as ergolide mesylate.

The pharmacological and clinical properties have been extensively described in Berde and Schild.

Co-dergocrin modifies cerebral neurotransmission and improves learned cerebral metabolic function. It has a further stabilizing effect on the tone of the skull blood vessels and has antihypertensive effect.

Co-dergocrine is therefore indicated for the treatment of cerebral insufficiency in the elderly and for the treatment of cerebrovascular disorders, especially when associated with hypertension, and for the prevention of migraine.

Usual oral daily doses are 3-6 mg. A recommended oral daily dose is 4.5 mg, preferably divided into smaller doses of 1.5 mg three times daily.

Dihydroergocomine, dihydroergocristine, dihydro-α-ergocryptin and dihydro-β-ergocryptine can be used individually for the same indications at the same dose.

The pharmacological and clinical properties of dihydroergotamine 30 are also described in Berde and Schild.

DK 167138 B1 3

The compound can be administered in the form of the free base or as a pharmaceutically tolerable acid addition salt. Such acid addition salts are known. A typical acid addition salt form is the methanesulfonate salt (mesylate), described in Merck 5 Index 1983, reference 3151, and marketed under the trade name DIHYDERGOT.

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

Dihydroergotamine is also indicated to be active in the treatment of Herpes Zoster.

The drug is usually administered orally at daily doses of about 15%. 1-10 mg.

The present invention relates to a controlled release composition for oral administration containing a 9,10-dihydro-ergot alkaloid a pharmaceutically tolerable hydrophilic swelling substance and a pharmaceutically tolerable inert fat.

In particular, the invention relates to a controlled release composition in which the 9,10-dihydroergothalkaloid preparation is a peptide alkaloid.

Preferred hydrophilic swelling agents include one or more natural, fully or partially synthetic, anionic or preferably non-ionic hydrophilic gums, modified cellulosic and proteinaceous substances such as acacia gum, tragacanth gum, carob gum, guar gum, kara gum, carrageenin, soluble and insoluble alginates, methyl cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxypolymethylene and gelatin.

Preferred are cellulose hydrocolloids which include methyl cellulose, hydroxypropyl cellulose and especially hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose.

Suitable pharmaceutically tolerable inert fats include beeswax; fatty acids? long chain fatty alcohols such as ethyl alcohol, myristyl alcohol and stearyl alcohol, esters such as glycerides, e.g., glyceryl esters of fatty acids or hydrogenated aliphatic acids such as glyceryl monostearate, glyceryl di-stearate, glyceryl esters of hydrogenated castor oil, etc .; and oils such as mineral oil, etc. Fats are preferably those having melting points of between 30 and 90 ° C.

Particularly preferred fats have a melting point of between 45 and 65 ° C and include glycerides such as glyceryl palmitate and stearate and fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.

The composition preferably contains both hydroxypropyl methyl cellulose as swelling agent and cetyl palmitate as fat.

It is also convenient in the composition to incorporate at least one additional soluble or insoluble pharmaceutical excipient such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silica and magnesium stearate. A soluble excipient, especially lactose, is preferred. The ratio of hydrocolloid to additional excipient may be, for example, between 1: 0.5 and 1: 2.

The composition may be prepared in the usual manner by mixing the ingredients together, preferably by melting the fat.

The resulting mixture is in powder form. The powder can be pressed into a tablet, but preferably filled into a capsule.

DK 167138 B1 5

If the fat is melted, the drug and additional excipients such as lactose, silica, calcium sulfate or calcium phosphate can be taken up in the molten fat. The mixture is then allowed to solidify and then divided into small particles (granules).

The resulting granule may be mixed with a, preferably particulate, hydrophilic swelling substance and additional excipients, e.g., magnesium stearate, and the mixture may be compressed into a tablet or preferably filled into a capsule.

Thus, in a preferred aspect of the present invention, there is provided a composition containing a 9,10-dihydro-ergot alkaloid in a matrix granule of a fat which granulate particles is in contact with a hydrophilic swelling substance.

Preferably, the swelling substance occurs in particulate form.

Surprisingly, it has been found that the preparation has excellent stability despite the fact that the alkaloids are sensitive to many chemical reagents. In addition, the preparations have satisfactory pharmacodynamic and pharmacokinetic profile.

The resulting delayed release compositions generally have comparable bioavailability in standardized clinical trials compared to usual non-retarded preparations containing the same alkaloid amounts. The compositions of the invention, although administered once daily, can produce a therapeutic effect for at least 24 hours and even as long as 35 hours. Thus, the compositions can be administered only once daily by known indications for 30 alkaloids in approximately the same daily dosage amounts used in usual non-retarded forms.

DK 167138 Pg 6

9.10- The dihydro-ergot alkaloids in particular comprise 9,10-dihydro-peptide gut alkaloids of general formula I

(XjsC1 o> - "n ^ JLo j.

CH3 K * R2

Hi-5 where the symbols% and R2 can have the same or different meaning, e.g.

R 1 = CX-4 alkyl and R 2 = C 1-4 alkyl or benzyl and X = CH 2 or S.

9.10- Dihydro-ergot alkaloids comprise 9,10-dihydro-peptide - 10 ergot alkaloids of general formula I wherein the carbon atom in the 9 'position is replaced by a sulfur atom, as described in British Patent Specification No. 2,109,795 B. The compounds may be preferably used in pharmaceutical form as acid addition salts.

The preferred compound of general formula I wherein X = S is 9'-thia-9,10-dihydroergotamine. This compound is preferably used in the form of the hydrogen malonate. The preferred indication is for the prevention and treatment of vascu-learning headaches and for the treatment of orthostatic syndrome.

There is no publication on the clinical use of this active substance and no specific forms of this extended release agent have been described.

Epicryptin is the generic name for a compound of the general formula I wherein Rx = isopropyl, R2 = 2R-butyl and X = DK 167138 B1 7 CH2, which is disclosed in British Patent Specification No. 2,114,980 B. The chemical name of the compound are: (5R, 8R, 10R) -N- [(2R, 5S, 11S, 12S) -5- (2R-butyl) octahydro-12-hydroxy-2-isopropyl -3,6-dioxo-8H-oxazolo [ 3,2-a] pyrrolo [2,1-c] pyrazinyl] -6-5 methylergoline-8-carboxylic acid amide. Epicryptin is also known as epicriptine.

The compound can be administered in the form of a pharmaceutically tolerable acid addition salt. Preferably, the free base is used.

The compound is indicated for use in the treatment of lactation, galactorrhoea, hyperprolactinemic hypergonadism, acromegallia or prolactinoma.

Epicryptin is also indicated for use in the treatment of cerebral insufficiency, for example for senile dementia, especially in its earlier forms, and for increased vigilance.

Epicryptin is also useful for the treatment of hypertension, especially in geriatrics, and in stroke. The preferred indication is hypertension. The compound is administered at a daily dose of between ca. 0.1 and 15 mg, preferably 2-5 mg.

The administration of the ergo talc oids may occasionally be accompanied by adverse side effects, e.g., effects on the heart, vascular effects, effects on the central nervous system, on the autonomic and peripheral nervous system, and endocrine effects. See. Berde and Schild, pp. 815-820.

The concentration of the ergot alkaloids is preferably maintained at a therapeutically active level, but within narrow limits, and the drug "storm" is avoided, which can occur just after administration of unregulated preparations. This leads to temporarily high blood levels and 30 relatively severe side effects.

DK 167138 B1 8

The compositions of the present invention are well tolerated.

The present compositions further provide similar activity profile in food interaction studies, e.g., before and 5 after administration of breakfast to fasting patients.

In particular, the present invention relates to controlled release formulations for oral administration containing codergocrine, dihydroergotamine or epicryptin as active agents in unit dosage forms.

The pharmaceutical compositions of the invention preferably contain 1-15 mg of 9,10-dihydro-ergot alkaloid.

Preferred ratios of 9,10-dihydro-ergot alkaloid to swelling are in the range of approx. 1: 4 and 1:50, for example, at 1: 4-1: 25.

Preferred ratios of 9,10-dihydro-ergot alkaloid to fat are between 1: 0.5 and 1:10.

Preferred units of unit dose codergocrine are in the range of 2 to 10 mg, especially of 3-6, e.g., 4.5 or 3 mg. Codergocrine is preferably in mesylate form.

Preferably, the ratio of co-dergocrine to swelling is between 1:50 and 1:10, especially between 1:10 and 1:30, e.g., 1: 15-1: 25.

The ratio of co-dergocrine to fat is preferably between 1: 1 and 1:10, especially between 1: 1 and 1: 5.

If other excipients such as lactose or magnesium stearate are present, the weight ratio of co-dergocrine to the other excipients is preferably conveniently between 1: 5 and 1:40, especially at 1: 15-1: 40.

DK 167138 B1 9

Preferred unit doses of dihydroergotamine are in the range of 4 to 15 mg, eg 5 mg, especially 8-12 mg, eg 10 or 7.5 mg. The dihydroergotamine is preferably also in mesylate form.

The ratio of dihydroergotamine to swelling is preferably between 1: 4 and 1:20, e.g., 1: 5-1: 20, especially between 1: 4 and 1:12, e.g., 1: 5-1: 12.

The ratio of dihydroergotamine to fat is preferably between 1: 0.5 and 1: 2, especially between 1: 0.5 and 10 1: 1.5, e.g., 1: 0.8-1: 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 preferably conveniently 1: 3-1: 20, especially 1: 4-1: 15.

Epicryptin may also appear as an acid addition salt, but this compound is preferably used in the controlled release formulations as the free base.

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

According to the present invention, for the first time, an oral pharmaceutical composition containing 9'-thia-9,10-dihydroergocryptin or epicryptin is provided for once daily administration.

Compositions for once-daily administration may be formulated in the usual manner, for example as a capsule or tablet, and may contain 1-15 mg of active agent. They preferably have the same release profile as determined by in vivo or in vitro solubility tests as for the compositions of the present invention, e.g. 50-90, eg 50-60, 30 70-80 or 80-90% over 7 hours at 0.1N HCl, for example as in the experimental conditions described in Example 2.

DK 167138 B1 10

The invention is further illustrated in the examples below in which all temperature indications are uncorrected.

Further information on the properties, etc. of the pharmaceutical excipients listed below can be obtained from the manufacturers listed below, from manufacturers' brochures or other sources, especially H.P. Fiedler Lexikon der Hilfstoffe fur Pharmazie, Cosmetics and adjoining areas, 2nd edition, 1981, Edito Cantor, Aulendorf, West Germany.

For example, silica (silica) is the brand Aerosil® 200 from Deut-10 sche-Gold und Silberscheideanstalt, Frankfurt, West Germany.

For example, glycerol-ditripalmitostearate is labeled Precirol Ato 5 from ETS Gattefossé 929100 Boulogne-Brillancourt, France.

For example, hydroxypropyl methyl cellulose 15000 cps and 4000 cps are the Methocel® K15M and Methocel® 4EM brands of the Dow Chemical 15 Company, Michigan 48640, USA.

For example, cetyl palmitate is labeled Cutina® CPA from Henkel 4000, Dusseldorf, West Germany, or from Gattefossé or from A / S Johan C. Martens and Company, Bergen, Norway.

EXAMPLE 1 20 Composition of each capsule

Ingredient mg a) Codergocrine (in mesylate form) 4.5 b) Lactose (200 mesh) 124.265 25 c) Silica 10 d) Glycerol-ditripalmitostearate 40 e) Hydroxypropyl methylcellulose 4000 cps 110

Capsule (hard gelatin) 78 DK 167138 B1 11

Preparation (batch of 6000 capsules)

The ingredients a), b) and c) are sieved and mixed. Component d) is melted by heating to 56 ° C (melting point 54 ° C) and added to the mixture which is heated to 55 ° C. The mass is stirred for 2 minutes or until a homogeneous mixture is formed and cooled overnight. The cooled mass is broken up and sieved (through openings of 250 μαi). Ingredient (e) is sieved (through 360 μαι openings) and mixed over 10 minutes. Then the mixture is encapsulated.

EXAMPLES 2-5

Composition of each capsule

Ex. 2 Ex. 3 Ex. 4 Ex. Ingredient mg mg mg mg a) Codergocrine (in mesylate form) 4.5 4.5 3.0 3.0 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) Hydroxypropylmethyl cellulose (4000 cps) 90.0 e) Magnesium stearate 1.0 1.0

Capsule (hard gelatin, 78 mg)

manufacturing

The ingredients are mixed by analogy with that described in Example 1, except that component d) is replaced by an equivalent amount of cetyl palmitate, silica c) is omitted, and hydroxypropyl methylcellulose d) is mixed with magnesium stearate.

In vitro release DK 167138 B1 12

In vitro experiments (USP XXI, pp. 1243-1244, apparatus 1, 1000 ml 0.1N HCl, 100 rpm), the following release results were obtained: 5 Time Release of co-Time (hours) Release of co - (hours) dergocrin dergocrin

Ex. 2 Ex. 3 Ex. 4 Ex. 5 1 15% 16% 1 19% 20% 10 3 32% 37% 2 32% 37% 5 50% 52% 4 48% 49% 7 66% 64% 7 67% 73% 24 99% 86% 24 100% EXAMPLE 6

Composition of each capsule

Ingredient mg a) Dihydroergotamine (in mesylate form) 10.0 b) Lactose (200 mesh) 88.0 c) Silicon dioxide 1.0 d) Glycerol-dithripalmitostearate 10.0 e) Hydroxypropyl methylcellulose (4000 cps) 90.0 f) Magnesium stearate 1.0 Capsule (hard gelatin) 62.0

Preparation (batch of 6000 capsules)

The ingredients a), b) and c) are sieved and mixed. Component d) is melted by heating to 56 ° C (melting point 54 ° C) and added to the mixture which is heated to 55 ° C. The mixture is stirred for 2 minutes or until a homogeneous mixture is formed, and DK 167138 B1 13 is cooled overnight. The cooled mass is broken up and sieved (through openings of 800 / mi). The ingredients (e) and (f) are sieved (through openings of 500 µm) and mixed over 10 minutes. Then the mixture is encapsulated.

5 In vitro release (experimental conditions: see example 2)

Time (hours) Release of dihydroergotamine 1 9% 2 17% 10 4 29% 6 41% 24 96% EXAMPLE 7 15 Composition of each capsule

Component mg a) Dihydroergotamine (in mesylate form) 10.0 b) Lactose (200 mesh) 107.0 c) Cetyl palmitate 10.0 d) Hydroxypropyl methylcellulose (15000 cps) 70.0 e) Silicon dioxide 1.0 f) Magnesium stearate 2, 0

Capsule (Hard Gelatin) 62.0

manufacturing

The ingredients are mixed by analogy with that described in Example 6 except that component d) is replaced by an equivalent amount of cetyl palmitate.

In vitro release (experimental conditions: cf. example 2) DK 167138 B1 14

Time (hours) Release of dihydroergotamine 1 24% 5 2 41% 4 65% 6 80% 8 100% 10 EXAMPLES 8-10

Composition of each capsule

Ex. 8 Ex. 9 Ex. 10

Ingredient mg mg mg 15 a) Dihydroergotamine (in mesylate form) 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 (4000 cps) 80.0 40.0 80.0

All ingredients are mixed by analogy with that described in Example 6:

Components a), b) and c) are incorporated into component d), the solidified mixture is granulated and mixed with component e).

In vitro release (experimental conditions: cf. example 2) DK 167138 B1 15

Time (hours) Release of dihydroergotamine

Ex. 8 Ex. 9 Ex. 10 5 1 10% 14% 10% 2 19% 26% 22% 4 33% 49% 41% 6 46% 67% 56% 24 96% 99% 101% 10 ______

Comparative clinical trial

Objective: To investigate the bioavailability (in healthy volunteers) of co-dergocrin in a controlled release oral capsule A (according to Example 2) compared to co-dergocrin in a conventional tablet B.

Usual composition in tablet form

Ingredient mg 1. Co-dergocrine (in mesylate form) 1.0 20 2. Stearic acid 2.0 3. Talc 4.0 4.0 Polyvinylpyrrolidone 4.0 5. Starch 8.0 6. Lactose 141.0 25

The ingredients 1-6 are mixed, granulated with a mixture of alcohol and water, dried and pressed into a tablet.

One dose of two 4.5 mg co-dergocrine mesylate-containing capsules A (= 9 mg) was compared to one dose of 4 usual 30 tablets B containing 1 mg of co-dergocrine mesylate (= 4 mg).

The lower dose for the tablet was chosen to avoid any expected side effects due to the high peak levels of the usual tablets without controlled release.

The study model was an open label, 2-period model for each subject randomly assigned to one of two treatment sequences, followed by a third treatment period during which all subjects received the identical third treatment.

Ten healthy male subjects received fasting on both stomachs during the first hour period followed by one 10 dose retard capsule A along with food for period three.

Blood samples were collected from the 10 subjects from a inserted cannula at specific times up to 24 hours after administration of the capsules.

The co-dergocrine concentrations measured after administration of Capsule A and Tablet B were plotted graphically as shown in FIG. 1 as corresponding mean curves A.l (without food), A.2 (with food) and B (without food) in picogram / ml, time T (in hours).

From the measured co-dergocrine concentrations, the following parameters (as arithmetic averages) were obtained.

20 Retard hood - Retard hood - Oral tablet

cell A cell B B

with food without food without food

AUC

25 (Area under the curve, 0-24 hours) 2066 2066 2242 *

Tip (in picograms / ml) 172 162 511 *

Time (in hours) 5.9 3.9 0.9 30 * Extrapolated from 4 mg to 9 mg DK 167138 B1 17

This is justified since co-dergocrine mesylate shows linear dose proportionality for AUC in the dose range of 0-9 mg.

The retinal capsule A showed an AUC similar to that of the usual tablet B (corrected for dose) administered on an empty stomach 5 or with a meal. Compared to tablet B, the retard capsule A showed a statistically significantly lower peak level and prolonged peak time (from less than 1 hour to 3.9 hours on a fasting stomach after 5.9 hours when administered with a meal). In general, however, the profile of compound 10A after administration on a fasting stomach was similar to that obtained after administration after a meal, except for the delay in absorption of the full-stomach drug (probably caused by a delay in gastric emptying).

The retinal capsule A administered on a fasting stomach or in combination with a meal provides prolonged release of drug without dose dumping and, what is particularly noteworthy, without significant loss of bioavailability, compared to oral reference tablet B.

Side effects such as headache and gastrointestinal discomfort were 20 transient and mild to moderate in degree.

Single dose of retard capsule A administered as 2 x 4.5 mg retard capsules A is safe and well tolerated.

EXAMPLE 11

The co-dergocrin and dihydroergotamine in the above examples can be replaced by an equivalent amount of epicryptin or 9'-thia-9,10-dihydroergotamine.

Claims (14)

A composition for oral administration and controlled release containing a 9,10-dihydro-ergot alkaloid as a medicament, a pharmaceutically tolerable hydrophilic swelling substance and a pharmaceutically tolerable inert fat. Composition according to claim 1, characterized in that the medicament is a peptide alkaloid. Composition according to claim 1 or 2, characterized in that the swelling substance is hydroxypropylmethyl cellulose. Composition according to any one of claims 1-3, characterized in that the fat is a fatty acid ester. Composition according to any one of claims 1-4, characterized in that it contains 1-15 mg of ergot alkaloid per day. unit dosage form. Composition according to any one of claims 1-5, 20, characterized in that it contains 2-10 mg of codergocrine. Composition according to any one of claims 1-6, characterized in that it contains 4-15 mg of dihydrogen gutamine. Composition according to any one of claims 1-6, characterized in that the weight ratio of co-dergo-crin to the swelling substance is from 1:10 to 1:50. 19 DK 167138 B1 Composition according to any one of claims 1-5 and 7, characterized in that the weight ratio of dihydro-ergotamine to the swelling substance is between 1: 4 and 1:20. Composition according to any one of claims 1-6 and 8, characterized in that the weight ratio of co-dergocrine to fat is between 1: 1 and 1:10. Composition according to any one of claims 1-5 and 7 and 9, 10, characterized in that the weight ratio of dihydro-ergotamine to fat is between 1: 0.5 and 1: 2. Composition according to any one of claims 1 to 11, characterized in that it contains the 9,10-dihydro-ergot alkaloid in a matrix granule of a fat, which 15 granulate particles contact with a hydrophilic swelling substance. Composition according to any one of claims 1-5, characterized in that it contains epicryptin. Composition according to any one of claims 1-5, 20, characterized in that it contains 9'-thia-9,10-dihydroergotamine.