LU86289A1 - SUSTAINED RELEASE FORMULATION CONTAINING Rye ergot alkaloids - Google Patents

Description

* 1 - 1 -

The present invention relates to new pharmaceutical compositions containing alkaloids of ergot 9,10-dihydrogenated rye.

The 9,10-dihydrogenated ergot alkaloids com-5 take the 9,10-dihydrogenated derivatives of the natural ergot alkaloids as well as the ergot alkaloids h obtainable by fermentation or by chemical synthesis. They can for example include substituents such as those. generally known in the chemistry of ergot alkaloids, and may exist as isomers, for example 8R and 8S isomers, (see for example "Ergot alkaloids and related compounds", Editors B. Berde and HD Schild, Springer Verlag, Berlin, Heidelberg, New York 1978).

Particularly preferred compounds are dihydro-ergocornine, dihydroergocristine, dihydro-a-ergocryptine, dihydro-ß-ergocryptine, as well as co-dergocrine and dihydroergotamine.

Co-dergocrine is the common name of a mixture of 3: 3: 2: 1 moles of dihydroergocornine, dihydroergocristine, dihydro-a-ergocryptine and dihydro-ß-ergocryptine (see the already cited book by Berde and Schild, page 58).

For pharmaceutical use, co-dergocrine can be used in the form of an acid addition salt, such as ethane sulfonate, maleate, fumarate, tartrate, chlor-, hydrate or, preferably mesylate (methanesulfonate). These salts have the same order of activity as the free base and can be prepared according to known methods.

Methanesulfonate is listed in the Merck Index, 1983, under the brand name Hydergine, see reference 3596 pages 526-527. This salt is also known as ergoloid mesylates.

The pharmacological and clinical properties of these substances have been extensively discussed in the work of Berde and Schild.

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Co-dergocrine modifies the cerebral neurotransmission and corrects the cerebral metabolic deficit. In addition, co-dergocrine has a stabilizing effect on the tone of the cranial vessels and an anti-hypertensive activity.

Thanks to these properties, co-dergocrine is indicated for the treatment of cerebral insufficiency in senescence and cerebrovascular disorders, in particular associated with hypertension, as well as for the prophylaxis of migraine.

The normal daily oral dose is between 3 and 6 mg. A daily dose recommended by oral route is 4.5 mg, preferably distributed throughout the day in three doses of 1.5 mg each.

Dihydroergocornine, dihydroergocristine, dihydro-a-ergocryptine and dihydro-ergocryptine can be used individually for the same indications and at the same doses.

The pharmacological and clinical properties of dihydro-ergotamine were also treated in the work of Berde and Schild.

The compound can be administered as a free base or as a pharmaceutically acceptable acid addition salt. These acid addition salts are known. Methane sulfonate (mesylate) is a typical acid addition salt. It appears in the Merck Index 1983, reference 3151, and is marketed under the brand Dihydergot.

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

Dihydroergotamine is normally administered orally in daily doses between 1 and 10 mg.

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The subject of the present invention is a sustained-release formulation for oral administration, said formulation comprising a 9,10-dihydro-ergot rye alkaloid, a pharmaceutically acceptable hydrophilic swelling substance and a material pharmaceutically acceptable inert fat.

The invention relates in particular to a sustained release formulation in which the 9,10-dihydrogenated alkaloid is a peptide alkaloid.

Preferred hydrophilic bulking substances include natural hydrophilic partially or fully synthetic, anionic or, preferably, nonionic gums, modified cellulosic substances and protein substances such as acacia, tragacanth, locust bean, guar gum, Karaya gum, agar, peptine, carrageenan-15, soluble and insoluble alginates, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,

Hydroxyethylcellulose, sodium carboxymethylcellulose, carboxypolymethylene and gelatin.

Preferably cellulosic hydrocolloids such as methylcellulose, hydroxypropylcellulose and in particular hydroxypropylmethylcellulose and sodium carboxymethylcellulose are used.

Suitable inert fats include beeswax, fatty acids, long chain fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, esters, for example glycerides such as glyceryl esters of hydrogenated fatty acids or aliphatic acids such as glyceryl monostearate, glyceryl distearate, glycerol esters of hydrogenated castor oil, etc., oils such as mineral oils, etc. Preferably, fats whose melting point is between 30 and 90 ° C. will be used.

* τ - 4 -

We will especially choose fats whose melting point is between 45 and 65 ° C such as glycé-wrinkles like palmitates and glyceryl stearates, fatty acids like hydrogenated castor oil, and esters 5 d fatty acids like cetyl palmitate.

The formulations preferably contain hydroxypropylmethylcellulose as the blowing agent and cetyl palmitate as the fat.

It is also advantageous to incorporate into the formulations at least one other soluble or insoluble pharmaceutical excipient such as calcium sulphate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silica, tartaric acid and magnesium stearate. Preferably, a soluble excipient will be chosen, in particular lactose. The ratio of the hydrocolloid to the other excipient can for example be between 1: 0.5 and 1: 2 by weight.

The formulations can be prepared according to conventional methods by mixing the ingredients, preferably by melting the fat. The resulting mixture is in powder form. This powder can be pressed into tablets, but is preferably put in capsules.

If the fat is melted, the active ingredient and additional excipients such as lactose, silica, calcium sulfate or calcium phosphate, can be incorporated into the melted fat. The mixture is then allowed to solidify and it is transformed into small particles, hereinafter referred to as granules.

These granules can be mixed with a hydrophilic, preferably porous, swelling substance and other excipients, for example magnesium stearate, and the mixture is pressed to form tablets or, preferably, put in capsules.

According to a preferred aspect, the subject of the present invention is therefore a formulation containing a 9,10-dihydrogenated ergot alkaloid incorporated in a fat matrix in the form of granules, the granules being in contact with a swelling substance. hydrophilic.

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The swelling substance is preferably in a porous form.

It has surprisingly been found that the formulations have excellent stability, despite the sensitivity of the alkaloids to many chemical agents. The formulations also have a satisfactory pharmacodynamic and pharmacokinetic profile.

In clinical trials, the resulting sustained release formulations generally exhibit bioavailability comparable to conventional sustained release formulations containing the same amount of alkaloids. Even when administered once daily, the formulations of the invention can produce a therapeutic effect for at least 24 hours, or even up to 35 hours. These formulations can therefore be administered only once a day for the known indications of the active ingredients and at approximately the same daily doses as those usually administered for the forms without prolonged action.

The 9,10-dihydrogenated ergot alkaloids include in particular the 9,10-dihydrogenated ergot peptide alkaloids of formula I

n 25 30 \; - 6 -

The substituents Ri and R2 can be identical or different, for example

R1 represents a C1-C4 alkyl group, and R2 represents a C1-C4 alkyl group or a benzyl group, and X represents CH2 or S.

The 9,10-dihydrogenated ergot alkaloids of formula I in which the carbon atom in position 9 ′ is replaced by a sulfur atom, are described in British Patent No. 2,109,795 B For their use in therapy, the compounds will preferably be used in the form of an acid addition salt.

The preferred compound of formula I in which X = S is 9'-thia-9,10-dihydroergotamine. It is preferably used in the form of hydrogen malalonate. The preferred indication is prophylaxis and treatment of vascular headache and treatment of orthostatic syndrome. There is no publication on the clinical use of this active ingredient, and no specific sustained release form of this same active ingredient has been described.

Epicryptin is the common name of the compound of formula I in which Ri = an isopropyl group, R2 = a group * 2R-butyl and X = CH2, i.e. (5R, 8R, 10R) -N - [(2R, 5S, $ 11, 12S) -5- (2R-butyl) -octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-8H-25 oxazolo [3,2-a] pyrroloC2, lc] pyrazinyl] -6-methyl-ergoline-8-carboxamide. This compound is described in British Patent No. 2,114,980 B. Epicryptin is also known as epicriptine.

The compound can be administered as a pharmaceutically acceptable acid addition salt. The free base is preferably used.

This compound can be used in the treatment of lactation, galactorrhea, hyperprolactinemic hypogonadism, acromegaly or prolactinoma.

- 7 - Epicryptin is also indicated for the treatment of cerebral insufficiency, for example senile dementia, in particular in its early forms, and to increase alertness.

Epicryptin is further indicated for the treatment of hypertension, particularly in geriatrics, and stroke. The preferred indication is hypertension.

The compound is administered in daily doses of between about 0.1 and 15 mg, preferably between 2 and 5 mg.

The administration of such ergot alkaloids 10 may occasionally be accompanied by undesirable effects, in particular on the heart, on the vascular system, on the central nervous system, on the autonomic and peripheral system and on the endocrine system ( See Berde and Schild, pages 815-820). This is the reason why, while remaining at an active therapeutic level, the concentration of these ergot alkaloids is preferably kept within narrow limits in order to avoid the high plasma peak which can suddenly occur. produced immediately after administration of conventional preparations without sustained release action, leading to elevated blood levels and proportionately pronounced adverse effects. The formulations of the invention are on the other hand well tolerated and also exhibit activity profiles similar in interaction studies with food, for example before or during breakfast.

The present invention relates in particular to sustained-release formulations for oral administration which contain co-dergocrine, dihydroergotamine or epicryptine as active ingredients, in unit dosage form.

The pharmaceutical formulations according to the invention contain preferably between 1 and 15 mg of rye ergot 9,10-dihydrogenated alkaloid.

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The preferred ratios of the alkaloid to the swelling substance are between about 1: 4 and 1:50, for example between 1: 4 and 1:25 by weight.

Preferred ratios of the alkaloid to fat 5 are between 1: 0.5 and 1:10 by weight.

The preferred amounts of co-dergocrihe in the unit doses are between 2 and 10 mg, in particular between 3 and 6 mg, for example 4.5 or 3 mg. Co-dergocrine is preferably used in the form of a mesylate.

The ratio of co-dergocrine to the swelling substance is preferably between 1:50 and 1:10, in particular between 1:10 and 1:30, for example between 1:15 and 1:25 by weight.

The ratio of co-dergocrine to fat is preferably between 1: 1 and 1:10, in particular between 1: 1 and 1: 5 by weight.

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

The preferred amounts of dihydroergotamine in the unit doses are between 4 and 15 mg, for example 5 mg, in particular between 8 and 12 mg, for example 10 or 7.5 mg. Dihydroergotamine is also preferably used in the form of a mesylate.

The preferred ratios of the dihydroergotamine to the swelling substance are preferably between 1: 4 and 1:20, for example between 1: 5 and 1:20, in particular between 1: 4 and 1:12, for example between 1 : 5 and 1:12 by weight.

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

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If other excipients are used such as lactose, silica, magnesium stearate or tartaric acid, the weight ratio of dihydroergotamine to the other excipients is preferably between 1: 3 and 1:20, especially between 1: 4 and 5 1:15.

Epicryptin can also be used in the form of an acid addition salt, but in sustained release formulations it is preferably in the form of the free base.

The unit doses preferably contain an amount of active substance of between 2 and 7 mg, in particular 5 mg.

The invention further relates to a pharmaceutical composition for oral administration containing 9'-thia-9,10-dihydroergocryptine or epicryptine in a form suitable for once-daily administration.

j5 The formulations to be administered once a day may be in a conventional form, that is to say in the form of tablets or capsules, which may contain between 1 and 15 mg of active principle and all have the same release profile as determined during in vitro or in vivo dissolution tests, namely 2o a release of between 50 and 90%, for example from 50 to 60%, from 70 to 80% or from 80 to 90% over 7 hours in HCl 0, 1 N, for example under the test conditions of Example 2.

The following examples illustrate the present invention without in any way limiting its scope. In these examples, all temperatures are given in degrees Celsius and are not corrected.

Further information on the properties, etc. pharmaceutical excipients mentioned below can be obtained from the manufacturers listed below, as well as in brochures published by these manufacturers or by other sources, in particular in the book by HP Fiedler "Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und.angrenzende Gebiete ", 2nd edition 1981, Edito Cantor, Aulendorf, FRG.

Silica is for example marketed under the brand Aerosil 200 by the company Deutsche-Gold und Silberscheideanstalt, 35 Frankfurt, RFA. Glycerol ditripalmitostearate is for example marketed under the brand name Precirol Ato 5 by establishments * 3 - 10 -

Gattefossé, 92100 Boulogne-Billancourt, France. Hydroxypropyl methylcellulose 15,000 cps and 4000 cps are, for example, sold under the brands Methocel K15M and Methocel 4EM by the company Dow Chemical Company, Michigan 48640, United States. Cetyl palmitate is for example sold under the brand name Cutina CPA by the company Henkel 4000, Düsseldorf, RFA, or can be obtained from Etablissements Gattefossé or from A / S Johan C. Martens and Company, Bergen, Norway.

EXAMPLE 1 Çomposition_de_çhaguejéIuie 10 Ingredients mg a) Co-dergocrine mesylate 4.5 b) Lactose (200 mesh) 124.265 c) Silica 10 15 d) Ditripalmitostearate of glycerol 40 e) Hydroxypropylmethylcellulose 4000 cps 110 Capsule 78

Preparation (load of 6000 capsules) The ingredients a), b) and c) are sieved and mixed. The ingredient d) is melted by heating it to 56 ° (F = 54e) and it is added to the mixture heated to 55 °. The mass is stirred for 2 minutes or until a homogeneous mixture is obtained and allowed to cool overnight. The cooled mass is broken up and sieved (mesh of 250 microns). The ingredient e) is sieved (360 micron mesh) and mixed with the rest for 10 minutes. The mixture obtained is then put into capsules.

»Î - 11 - EXAMPLES 2 TO 5:

Composition of each capsule Ex. 2 Ex. 3 Ex. 4 Ex. 5

Ingredients mg mg mg mg 5 a) Co-dergocrine mesylate 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) Hydroxypropylmethylcellulose 90.0 70.0 70.0 (15,000 cps) 10 d2) Hydroxypropylmethylcellulose 90.0 (4,000 cps) e) Magnesium stearate 1.0 1.0 Capsule (78 mg) 15 Preparation

The ingredients are mixed in a similar manner to that described in Example 1, except that the ingredient d) is replaced by an equivalent amount of cetyl palmitate, that the silica c) is removed and that 1 hydroxypropylmethylcellulose e) with magnesium stearate.

In vitro release

In the tests carried out in vitro (USP XXI, pages 1243-1244, Apparatus 1, 1000 ml 0.1N HCl, 100 rotations per minute), the following release results were obtained: 25

Time in Release of the Time in Release of the co-dergocrine hours in% co-dergocrine hours in%

Ex. 2 Ex. 3 Ex. 4 Ex. 5 30 1 15 16 1 19 20 • 3 32 37 2 32 37 5 50 52 4 48 49 7 66 64 7 67 73 24 99 86 24 100 101

* J

- 12 - EXAMPLE 6: Çomgosition_de_chague_ ^ él_ul_e_

Ingredients mg_ a) Dihydroergotamine mesylate 10.0 b) Lactose (200 mesh) 88.0 5 c) Silica 1 »0 d) Ditripalmitostearate glycerol 10.0 e) Hydroxypropyl methylcellulose 4000 cps 90.0 f) Magnesium stearate 1, 0 Capsule 62.0 10 Preparation (load of 6000 capsules)

The ingredients a), b) and c) are sieved and mixed. Ingredient d) is melted by heating it to 56 ° (F = 54 °) and it is added to the mixture heated to 55 °. The mass is stirred for 2 minutes or until a homogeneous mixture is obtained and allowed to cool overnight. The cooled mass is broken and sieved (800 micron mesh). We pass the ingredients e) and f) (500 micron mesh) and mix everything for 10 minutes. The mixture is then put into capsules. In_vitro release (test conditions: see example 2) 20 Time in hours Release of dihydroergotamine in l 1 9 2 17 i.

4 29 6 41 25 24 96 EXAMPLE 7: Composition_de_chague_3éJ_u] _e

Ingredients a) Dihydroergotamine mesylate 10.0 30 b) Lactose (200 mesh) 107.0 c) Cetyl palmitate 10.0 d) Hydroxypropyl methylcellulose (1500 cps) 70.0 e) Silica 1.0 * - - 13 -

Ingredients mg_ f) Magnesium stearate 2.0 Capsule 62.0

Preparation 5 The ingredients are mixed in a similar manner to that described in Example 6, except that the ingredient d) is replaced by an equivalent amount of cetyl palmitate.

In vitro release (test conditions: see example 2)

Time in hours Release of dihydroergotamine in% 10. 1 24 2 41 4 65 6 80 8 100 15 EXAMPLES 8 to 10

Co! Ïigosition_de each çjéjule_. Ex. 8 Ex. J3 Ex1_10

Ingredients mg mg mg a) Dihydroergotamine mesyTate 7.5 7.5 7.5 b) Tartaric acid 0.18 0.2 0.18 20 c) Lactose 81.32 144.3 81.32 d) Cetyl palmitate 8 .0 5.0 8.0 ^ e) Hydroxypropyl methylcellulose 80.0 40.0 80.0 (4000 cps)

The ingredients are mixed in a similar manner to that described in Example 6.

The constituents a), b) and c) are incorporated into the constituent d), the solidified mixture is granulated, then mixed with the constituent e).

In vitro release (test conditions see example 2) 30 Time in hours Release of dihydroergotamine in%

Exi_8_ Ex._9 Εχλ_10 1 10 14 10 2 19 26 22 • * - 14 -

Time in hours Release of dihydroergotamine in &

Ex.8 Ex.9 _Ex.lO

4 33 49 41 6 46 67 56 5 24 96 99 101

Comparative Clinical Trial The bioavailability of a codergocrine A prolonged-release capsule according to Example 2 administered orally compared to that of a conventional co-dergocrine tablet was studied in healthy volunteers. administered orally and having the following composition:

Ingredients mg_ 1. Co-dergocrine mesylate 1.0 2. Stearic acid 2.0 15 3. Talc 4.0 4. Polyvinylpyrrolidone 4.0 5. Starch 8.0 6. Lactose 141.0

Ingredients 1 to 6 are mixed together and the mixture is granulated with a mixture of alcohol and water, dried and pressed into tablets.

^ A dose of two capsules A each containing 4.5 mg of co-dergocrine mesylate (i.e. 9 mg) was compared with a dose of 4 conventional tablets B each containing 1 mg of co-dergocrine mesylate (i.e. 4 mg) . The lower dose for the tablet was chosen in order to avoid the undesirable effects that might be expected due to the high plasma peaks of conventional tablets without prolonged action.

The trial was carried out in an open study on two treatment sequences, each patient being randomized to one of the two treatment sequences, followed by a third treatment sequence during which all the subjects were subjected to identical treatment. .

10 healthy male volunteers were fasted on both treatments in the first two sequences and then were given a capsule A with food in the third sequence.

Blood samples were taken from the 10 - volunteers using a cannula at specified time intervals, up to 24 hours after administration of the capsules.

Co-dergocrine concentrations (in picograms / ml) measured after administration of the capsules. A and tablets B were plotted as a function of time (in hours). In the attached FIG. 1, the average curves are shown. corresponding A.l (without food), A.2 (with food) and B (without food).

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

Gélu] es_A G§lules_A Comprimés_B

with food without food- without food ture 20 AUC (Area under 2066 2066 2242 curve 0-24 hours) k

Peak (in picograms / ml) 172 162 511

Time (in hours) 5.9 3.9 0.9 OC *

Extrapolated from 4 mg to 9 mg

This is justified by the fact that co-dergocrine mesylate has a linearity of AUC as a function of the dose in the dose range of 0 to 9 mg.

30 Administered on an empty stomach or with food, capsule A has an AUC similar to that of conventional tablet B (dose-adjusted). Compared to tablet B, capsule A has a statistically significantly lower plasma peak * * - 16 - and a delay in the onset of the peak (3.9 hours fasting or 5.9 hours with a meal, compared to less than 'one hour). In general, the profile of composition A administered on an empty stomach was however similar to the profile obtained after a meal, except as regards the delay in assimilation of the drug with a full stomach (delay probably due to the delay in gastric emptying).

Capsule A, administered on an empty stomach or with a meal, allows a sustained release of the drug without the appearance of an undesirable peak, which is particularly appreciable, and without significant loss of bioavailability compared to the reference tablet B.

Side effects, such as headache and gastrointestinal upset, were mild to moderate and only 15 passengers.

The administration of two capsules A each containing 4.5 mg of active substance is safe and well tolerated.

EXAMPLE 11

In the previous examples, the co-dergocrine and the dihydroergotamine can be replaced by an equivalent amount of epicryptine or of O'-thia-g.lO-dihydroergotamine.

Claims (13)

1. A sustained release formulation for oral administration, characterized in that it comprises a 9,10-dihydrogenated ergot alkaloid, a pharmaceutically acceptable hydrophilic swelling substance and a pharmaceutically acceptable inert fat. 2. A formulation according to claim 1, characterized in that the alkaloid of ergot 9,10-dihydrogenated rye is a peptide alkaloid. 3. A formulation according to claim 2, characterized in that the peptide alkaloid is co-dergocrine, dihydroergotamine, epicryptine or 9'-thia-9,10-dihydro-ergotamine. 4. A formulation according to any one of claims 1 to 3, characterized in that the hydrophilic swelling substance is a partially or fully synthetic hydrophilic natural gum, anionic or nonionic, a modified cellulosic substance or a proteinaceous substance . 5. A formulation according to claim 4, characterized in that the hydrophilic swelling substance is a cellulosic hydro-colloid. 6. A formulation according to claim 5, characterized in that the hydrophilic swelling substance is hydroxypropyl-methylcellulose. 7. A formulation according to any one of claims 1 to 6, characterized in that the fat is a glyceride, a fatty acid or a fatty acid ester. 8. A formulation according to claim 7, characterized in that the fat is cetyl palmitate. 9. A formulation according to any one of claims 1 to 8, characterized in that it is in the form of a unit dose containing from 1 to 15 mg of rye ergot alkaloid. "* · - 18 - 10, - A formulation according to any one of claims 1 to 9, characterized in that it contains from 2 to 10 mg of co-dergocrine. 11. A formulation according to any one of claims 1 to 9, characterized in that it contains from 4 to 15 mg of dihydroergotamine. 12, - A formulation according to any one of claims 1 to 10, characterized in that the ratio of co-dergocrine to the swelling substance is between 1:10 and 10 1:50 by weight. 13. A formulation according to any one of claims 1 to 9 and 11, characterized in that the ratio of dihydroergotamine to the swelling substance is between 1: 4 and 1:20 by weight. 14. A formulation according to any one of claims 1 to 10 and 12, characterized in that the ratio of co-dergocrine to fat is between 1: 1 and 1:10 by weight. 15. A formulation according to any one of claims 1 to 9, 11 and 13, characterized in that the ratio of dihydroergotamine to fat is between 1: 0.5 and 1: 2 by weight. 16. A formulation according to any one of claims 1 to 15, characterized in that it contains a 9,10-dihydrogenated ergot alkaloid incorporated in a fat matrix in the form of granules, the granules being in contact with a hydrophilic swelling substance. 17. A pharmaceutical composition to be administered orally and containing epicryptin, characterized in that it is in a form suitable for administration once a day. 18. A pharmaceutical composition to be administered orally and containing 9'-thia-9,10-dihydroergotamine, - 19 - ß * * ί% τ characterized in that it is in a form suitable for the administration a times a day. 19.- Products and processes in substance as above described with reference to the examples cited.