CH667592A5 - PHARMACEUTICAL COMPOSITIONS CONTAINING 9,10-DIHYDROGENATED ERGOTAL CALOIDS. - Google Patents

Description

DESCRIPTION

The invention relates to pharmaceutical compositions. which contain 9,10-dihydroergotalkaloids. The group of 9,10-dihydroergotalkaloids includes not only 9,10-dihydro derivatives of natural ergot alkaloids, but also ergot alkaloids which can be produced by fermentation or by 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 contained in "Ergot alkaloids and related compounds", edited by B. Berde and H.D. Sign, Springer-Verlag, Berlin, Heidelberg, New York 1978, included. This book is referred to below as a mountain and shield.

The most preferred compounds are dihydroergocornin. Dihydroergocristin, Dihydro-a-ergocryptin, Dihy-dro-ß-ergogryptin, Co-dergocrin and Dihydroergotamine.

Co-Dergocrine is the generic name of a mixture of dihydroergocornin, 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. be used as ethanesulfonate, maleate, fumarate, tartrate, hydrochloride or preferably as mesylate. These salts have approximately the same activity as the free base form and can be prepared in a known manner.

The methane sulfonate is mentioned in The Merck Index, 1983 under the brand name HYDERGIN. Reference is made to reference 3596 on pages 526-527. The pharmacological and clinical properties have been extensively discussed in the book by Berde and Schild. Co-dergocrin alters cerebral neurotransmission and improves reduced cerebral metabolic function. It has a stabilizing effect on the tension of the brain vessels and has an antihypertensive activity.

Co-dergocrin is therefore used for the treatment of cerebral insufficiency in the elderly and for cerebrovascular disorders, especially if it is associated with high blood pressure. The product is also used to prevent migraines.

The daily oral doses are usually 3-6 mg, with 4.5 mg specifically recommended. This amount is preferably distributed in smaller doses of 1.5 mg, which are taken three times a day.

Dihydroergocornin, dihydroergocristin, dihydro-a-ergocryptin 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 pharmaceutically acceptable acid addition salt. A typical addition salt is methanesulfonate (the mesylate), described in "The Merck Index" 1983, reference 3151, and is sold under the brand name DIHYDERGOT. Dihydroergotamine is used for the treatment of hypotension and orthostatic circulation disorders and for the treatment of acute migraine attacks and related vascular headaches, as well as for their interval treatment. Dihydroergotamine is also mentioned to be effective in the treatment of herpes zoster. The drug is usually taken orally in daily dosages of around 1-10 mg.

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

The invention particularly relates to a controlled release composition in which the 9,10-dihydroergotaloid is a peptide alkaloid.

As hydrophilic swellable substances such. B. one or more natural, partially or completely synthetic, preferably nonionic hydrophilic resins, modified cellulose-like substances or proteinaceous substances, such as acacia, tragacanth resin, acacia bean resin, guar resin, karaya resin, agar, pectin, carrageen,

soluble and insoluble alginates, methyl cellulose,

Hydroxypropylmethyl cellulose, hydroxypropyl cellulose,

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Hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxypolymethylene and gelatin are suitable.

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

Useful pharmaceutically acceptable inert fatty materials are e.g. Beeswax, fatty acids, long-chain fatty alcohols, e.g. Cetyl alcohol, myristyl alcohol, stearyl alcohol, esters, e.g. Glycerides such as glyceryl esters of fatty acids or of hydrogenated aliphatic carboxylic acids, e.g. Glyceryl monostearate, glyceryl distearate, glyceryl ester of hydrogenated castor oil, or oils such as mineral oil. Preferred fatty materials are those with a melting point between 30 and 90 C.

Particularly preferred fatty materials are those with a melting point between 45 and 65 ° C, e.g. Glycerides such as glyceril palmitates and stearates; Fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.

The composition preferably contains both hydroxypropyl methyl cellulose as a swellable substance and cetyl palmitate as a fatty material.

The formulation can also contain other soluble or insoluble pharmaceutical auxiliaries, such as calcium sulphate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silicon dioxide or magnesium stearate. A soluble auxiliary, in particular lactose, is preferably present. The weight ratio of hydrocolloid to these other auxiliaries can then be between 1: 0.5 and 1: 2.

The composition can be prepared in a conventional manner by mixing the components, preferably the fatty material being melted. The resulting mixture is in powder form. The powder can be pressed into a tablet, but is preferably filled into capsules.

If the fatty material is melted, the active ingredient and other excipients such as lactose, silicon dioxide, calcium sulphate or calcium phosphate can be incorporated into the melted fatty material. The mixture is then cooled until solidification and distributed into small particles (granules).

The resulting granulate can be mixed with a preferably porous, hydrophilic swellable substance and with other auxiliaries, e.g. Magnesium stearate, are mixed and the mixture can be pressed into a tablet or, preferably, filled into capsules.

The invention preferably relates to a composition of a 9,10-dihydroergotalkaloid in a fatty matrix granulate, in which the granulate is in contact with a hydrophilic swellable substance.

The swellable substance is preferably present in a porous form. The composition has been found to have excellent stability, although the alkaloids are sensitive to many chemical reagents. In addition, the compositions have an excellent pharmacodynamic and pharmacokinetic profile.

In standard clinical trials, the resulting delayed-release compositions have a bioavailability which is comparable to that of conventional non-delayed-release formulations with the same amounts of alkaloids. The compositions according to the invention, even when taken once a day, can cause a therapeutic effect for at least 24 hours or even up to 35 hours. For the known indications of the alkaloids in question, the composition therefore only needs to be taken once a day in approximately the same daily dosage as the conventional non-retarded forms.

The 9,10-dihydroergotalkaloids particularly include the 9,10-dihydropeptidergotalkaloids of formula I.

.CO-NH

The groups Ri and R2 can be the same or different, e.g. B.

Ri = (Ci_4) alkyl, and

R2 = (Ci_4) alkyl, or benzyl, and

X = CH: or S.

9,10-Dihydroergotalkaloids include 9,10-Dihydropepididergotalkaloids of formula I, in which the carbon atom in position 9 'is replaced by a sulfur atom, as described in British Patent 2 109 795 B. The compounds are preferably in pharmaceutical form as an acid addition salt used.

The preferred compound of formula I, wherein X = S, is 9'-thia-9,10-dihydroergotamine, which is preferably used as the malonate. The preferred indication is for the prevention and treatment of vascular headaches and for the treatment of orthostatic syndrome. No publications on the clinical use of these drugs have been published and no specific forms for the delayed release of these drugs have been described.

Epicryptin is the general name of a compound of formula I, wherein Ri = isopropyl, R2 = 2R-butyl and X = CH2, and is described in British Patent 2,114,980. The chemical name is:

(5R, 8R, 10R) -N - [(2R, 5S, IIS, 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-carbon acid amide.

Epicryptin is also called epicriptin.

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

It is used for the treatment of lactation, galactor rhoea, hyperprolactinaemic hypogonadism, acromegaly or prolactinoma.

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

The administration of ergot alkaloids can occasionally be associated with undesirable side effects, and z. B. affect the heart, the vessels, the central nervous system or the autonomic and peripheral nervous system and the glands. See mountain and shield. Pages 815-820. The concentration of the ergot alkaloids is preferably

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at a therapeutically effective level, but kept between narrow limits and thereby avoiding an active substance release explosion which occurs just after the intake of compositions which are not controlled in the release, which causes high plasma levels and correspondingly strong side effects. In this regard, the compositions according to the invention are well tolerated. They also have similar activity profiles in experiments in which the influence on food is examined. e.g. B. before and after taking a breakfast 10 in fasting subjects.

Within the scope of the invention there is in particular a composition with delayed release of the active ingredient, for oral administration, which co-dergocrin, dill}. contains droergotamine or epicryptin as active ingredients in uniform dosage forms. The pharmaceutical compositions according to the invention preferably contain 1 to 15 mg of 9,10-dihydroergotalkaloid. Preferred weight ratios of 9,10-dihydroergotalkaloid to swellable substance are about 1: 4 to 1:50. E.g. 1: 4 20 to 1:25.

Preferred weight ratios of 9,10-dihydoergot-alkaloid to fatty material are from about 1: 0.5 to 1:10. Preferred amounts of co-dergocrine in a uniform dosage form are from 2 to 10 mg. especially 3 to 6, e.g. 4.5 25 or 3 mg. The co-dergocrin is preferably present as a mesylate.

Preferably the weight ratio of co-dergo-crin to swellable substance is from 1:50 to 1:10, especially from 1:10 to 1:30. E.g. from 1:15 to 1:25. The weight-30 ratio of co-dergocrin to fatty material is preferably from 1: 1 to 1:10, particularly from 1: 1 to 1: 5.

If other auxiliary substances such as lactose or magnesium stearate are present, the most favorable weight ratio of co-dergocrin to the other weight auxiliary substances is from 35 1: 5 to 1:40. Especially from 1:15 to 1:40.

Preferred amounts of dihydroergotamine in the unitary dosage form are from 4-15 mg, e.g. B. 5 or a)

7.5 mg. especially 8-12, e.g. 10 mg. Preferably b) the dihydroergotamine is also present as mesylate. The weight ratio of dihydroergotamine to swellable substance is preferably from 1: 4 to 1:20, e.g. 1: 5 to 1:20, e) especially from 1: 4 to 1: 12. B. 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 excipients. e.g. Lactose, silicon dioxide, magnesium stearate or tartaric acid are present, the weight ratio of dihydroergotamine to the other auxiliaries is expediently from 1: 3 to 1:20, preferably from 1: 4 to 1:15.

Epicryptin can also be used as an acid addition salt. In the controlled release composition, it is preferably present as a free base. The unitary dosage form preferably contains 2-7 mg. especially of 5 mg of active ingredient.

For the first time, an oral pharmaceutical dosage form can be offered, which 9'-thia-9,10-dihy-

contains droergocryptin or epicryptin for once daily use. The once-daily compositions can be prepared in a conventional manner as capsules or tablets and contain 1 to 15 mg of active ingredient. They have a similar release profile as can be determined by in vivo or vitro dissolution rate experiments, e.g. a release of 50 to 90, e.g. B. from 50 to 60, 70 to 80 or 80 to 90%, distributed over 7 hours, in 0.1 N HCl, e.g. described in the experimental results in the examples. In the following examples, all temperatures are in degrees Celsius and uncorrected.

Further information on the properties of the pharmaceutical auxiliaries, which are mentioned below, can be obtained from the manufacturer mentioned or from its brochures or other sources, in particular H.P. Fiedler Lexicon of auxiliaries for pharmacy, cosmetics and related areas, 2nd edition 1981, Edito Cantor, Aulendorf, FRG.

Silicon dioxide is e.g. the branded product Aerosil 200, available from Deutsche-Gold und Silberscheideanstalt, Frankfurt. FRG. Glycerol titripalmitostearate is e.g. the branded product Precirol Ato 5, available from ETS Gattefos-se 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. B. the branded product Cutina CPA, available from HENKEL 4000, Düsseldorf, FRG, or is available from Gattefosse or from A / S Johan C. Martens and Company, Bergen. Norway.

EXAMPLE 1

Capsule composition component mg

Co-dergocrin as mesylate 4.5

Lactose 124,265 silica 10

Glycerol titripalmitostearate 40

Hydroxypropylmethylcellulose 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 to 56 ° C. (melting point 54 ° C.) by heating and melted and added to the mixture heated to 55 ° C. The mass was stirred for 2 minutes until a homogeneous mixture formed and cooled overnight. The cooled mass was sieved crushed (through 250 micron openings). Component e) was also sieved (through 360 micron openings) and mixed for 10 minutes. The mixture was encapsulated.

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Capsule compositions:

Ex. 2

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Ex. 5

Component mg mg mg mg a) Co-dergocrin as mesylate

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b) lactose

165.5

c) cetyl palmitate

10.0

8.0

8.0

8.0

d 1) 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)

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Manufacturing

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

Release in vitro In vitro experiments (USP XXI, pages 1243-1244, apparatus 1.1000 ml 0.1 N HCl, 100 circulations per minute) gave the following release results:

Time (hours) of co-dergocrin release Time (hours) of co-dergocrin release

Ex. 2

Ex. 3

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Ex. 5

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37%

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52%

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48%

49%

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'66%

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73%

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99%

86%

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100%

101%

EXAMPLE 6

Capsule composition

Component mg

a)

Dihydroergotamine as mesylate

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Lactose

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Silicon dioxide

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Glycerol titripalmitostearate

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Hydroxypropylmethylcellulose 4000 CPS

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Magnesium stearate

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Capsule (hard gelatin)

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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 cooled overnight. The cooled mass was comminuted by sieving (by opening 800 micrometers). Ingredients e) and 0 were sieved (through 500 micron openings) 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 the dihydroergotamine (%)

a)

Dihydroergotamine (as mesylate)

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Lactose

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Cetyl palmitate

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Silicon dioxide

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Magnesium stearate

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EXAMPLE 7

Capsule composition

Component mg

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

Release in vitro

Time (hours)

Release of the dihydroergotamine (%)

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Capsule composition Ex. 8 Ex. 9 Ex. 10

Components mg mg mg a) Dihydroergotamine (as mesylate)

b) tartaric acid c) lactose d) cetyl palmitate e) hydroxypropylmethyl cellulose (4000 CPS)

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7.5 0.2 144.3 5.0

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7.5 0.18 81.32 8.0

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

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

Release in vitro (experimental conditions as in example 2)

Time (hours)

Release of the dihydroergotamine

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Ex. 9

Ex. 10

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Comparative clinical trial of a capsule A taken orally by healthy volunteers according to Example 2, which contains the co-dergocrin in

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released in a controlled manner, the bioavailability was compared to that of a conventional tablet B, also taken orally, of the following composition:

Conventional composition of tablet B

Component mg

1. Co-dergocrin (mesylate) 1.0 io

2. Stearic acid 2.0

3. Talk 4.0

4. Polyvinylpyrrolidone 4.0

5. Strength 8.0

6. Lactose 141.0 is

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

A dosage of two capsules A (= 9 mg) containing 4.5 mg co-dergocrin mesylate 20 was given with a dosage of 4 conventional tablets B, which contain 1 mg Co-

dergocrin mesylate in (= 4 mg) were compared. The low dose of the tablet was chosen to avoid expected side effects from the high plasma concentration explosions of the uncontrolled release from the conventional tablets. The trial consisted of three randomized treatments and had a marked distribution pattern. Capsules A and tablets B were administered to ten healthy male subjects in a fasting state in two different treatments, followed by a third treatment with capsule type A which was taken with breakfast. Blood samples were taken from the subjects at certain intervals up to 24 hours after taking the doses. The co-dergocrin concentrations, measured after taking capsules A and tablets B, were graphically represented as corresponding average curves A 1 (without food), A 2 (with food) and B (without food) (in picograms / ml, time / in hours) ) shown in Figure 1.

The following parameters were calculated as arithmetic averages from the measured codocrin concentrations.

Prolonged-release capsule A prolonged-release capsule A oral tablet B with food without food without food

AUC (Area under the curve, 0-24 hrs.) 2066 2066 2042 *

Peak value (in picogram / ml) 172 162 511 *

Time (in hours) 5.9 3.9 0.9

* Extrapolated from 4 mg to 9 mg

Extrapolation is permissible because co-dergocrin mesylate has a linear dependence of the plasma concentration in the dose range of 0 to 9 mg.

The prolonged-release capsule A has approximately the same bioavailability (AUC) as tablet B at the same dosage, both when fasted and taken with breakfast. Compared to tablet B, prolonged-release capsule A has a statistically significantly lower peak value. The capsule A peak is also reached later (a delay of less than 1 hour after ingestion to up to 3.9 hours when fasting or up to 5.9 hours with a meal). In general, however, the profile with capsule A when fasted is about the same as that associated with capsule A with a meal, except for the delay in absorption of the active ingredient in a filled stomach (presumably by delaying gastric emptying).

Capsule A shows whether, when the subject is fasting, whether there is a delayed release of the active ingredient at mealtime, and, this is particularly noteworthy, no significant loss of bioavailability can be found compared to the oral reference tablets B.

Side effects such as headache and gastrointestinal disorder were transient and mild to moderate in their effects. Single doses of prolonged-release capsules A taken as 2 x 4.5 mg prolonged-release capsules A are safe and are well tolerated.

EXAMPLE 11

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

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Claims (12)

667 592 PATENT CLAIMS 1. A composition for oral administration with controlled release of the active ingredient, characterized by - A 9,10-dihydroergotalkaloid as an active ingredient - a pharmaceutically acceptable hydrophilic swellable substance - a pharmaceutically acceptable inert fatty material. 2. The composition according to claim 1, wherein the active ingredient is a peptide alkaloid. 3. Composition according to one of the preceding claims, wherein the swellable substance is hydroxypropyl methyl cellulose. 4. Composition according to one of the preceding claims, wherein the fatty material is a fatty acid ester. 5. Composition according to one of the preceding claims, which contains 1-15 mg ergot alkaloid per unit dosage form. 6. A composition according to any one of the preceding claims, which contains 2 to 10 mg co-dergocrin. 7. Composition according to one of the preceding claims 1 to 5, which contains 4 to 15 mg of dihydroergotamine. 8. Composition according to one of the preceding claims 1 to 6, wherein the weight ratio of co-dergocrine to the swellable substance is from 1:10 to 1:50. 9. Composition according to one of the preceding claims 1 to 5 and 7, wherein the weight ratio of dihydroergotamine to swellable substance from 1: 4 to 1:20. 10. The composition according to any one of the preceding claims 1 to 6 and 8, wherein the weight ratio of co-dergocrin to the fatty material is from 1: 1 to 1:10. 11. The composition according to any one of the preceding claims 1 to 5, 7 and 9, wherein the weight ratio of dihydroergotamine to the fatty material is from 1: 0.5 to 1: 2. 12. Composition according to one of the preceding claims, which contains the 9,10-dihydroergotalkaloid enclosed in a fatty matrix granulate and the granulate particles are coated with the hydrophilic swellable substance.