CA1139222A

CA1139222A - Galenical compositions

Info

Publication number: CA1139222A
Application number: CA000342212A
Authority: CA
Inventors: Joachim Franz; Ludwig Patt
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1978-12-21
Filing date: 1979-12-19
Publication date: 1983-01-11
Also published as: AU5403179A; NL7909105A; GB2038181A; MY8500129A; PH25178A; CY1330A; FI793888A; FR2444463A1; DK529879A; DK154607B; ATA803679A; FR2444463B1; DE2950154C2; SE7910227L; DK154607C; GB2038181B; WO1980001242A1; IE49323B1; IE792471L; AU534051B2

Abstract

GALENICAL COMPOSITIONS
Abstract of the disclosure The invention provides solid enteric-coated composi-tions in unit dose form for oral application, the core of the composition containing an ergot alkaloid and a poly-alkoxyalkylene sterol ether. The compositions are characterised by a prolonged effect and a good bioavail-ability of the active agent. The core may be in solid solution form. The enteric-coating may also be surrounded by an outer medicament layer.

Description

1~39Z22 Case lCO-5129 ( GALENICAL CO.~POSITIONS

The invention provides galenieal eompositions for oral application of ergot alkaloidswhie}l are characterised by a prolonged effeet and a good bioavailability of the active agent~
It is undisputed amongst medieinal speeialists, that under many eireumstanees it is preferred to apply a drug onee a day instead of more times a day. This mav be aehieved in so-ealled "retard systems" by sustaining and delaying the release of the active agent, with the aim of produeing a longer duration of therapeutie effect. In the field of the ergot therapy, a retarclation ~Jith elassieal systems, e.g.with a ~atrix system or with the aid of miero-eneapsulation, induees eaeh time an important deerease of the total bioavailability.
It is also known, that ergot alkaloids are stable in the presenee of aeids, ~7hieh means that they do not disintegrate in the gastrie juices, and that the resorp-tion of ergot alkaloids takes place mainly in the intestinal traet. Enteric coated drugs containins an ergot alka]oid are therefore not expected to provide an improved bioavailability.
It is therefore surprising tha-t with the ai.d of an enteric coating one observes that the duration of action of an ercJot alkaloid is not only significantly proloncJed but that, moxeover, the total bioavailability is not signifi-cantly reduced when the coated core contains, in addition to the 1~39ZZZ

ergot alkaloid, a polyalkoxyalkene sterol ether.
The invention therefore provides, more specifically, a solid enteric-coated composition for oral application, the core of the composition containing an ergot alkaloid and a polyalkoxyalkylene sterol ether.
The invention also provides a process for the produc-tion of compositions according to the invention, by enteric coating a core comprising an ergot alkaloid and a poly-alkoxyalkylene sterol ether (hereinafter designated sterol ether).

The term "core" comprises any mixture of an ergot alkaloid and a sterol ether, if desired in admixture with further physiologically acceptable material, that can be surrounded by a enteric-coating. The term "core" com-prises, in a wide sense, not only tablets, pellets or granules but also capsules, e.g. soft or hard gelatinecapsules filled with a liquid or waxy mixture of an ergot alkaloid, a sterol ether and optionally pharmaceutically acceptable material. Such capsules may then be enteric-coated, e.g. in conventional manner. When tablet cores are used they have preferably a hardness of from ca 10 toca 70N.
The pellets or granules may, after application of the enteric-coating, be used as such or to fill capsules, e.g.
hard gelatine capsules. Suitable applications of the ~39222 - 2a -compositions according to the invention are therefore tablets, pellets, granules or capsules.
The term "solid compositions" means compositions which are of a definite shape, i.e. not wholly liquid. Hence the term solid composition covers capsules partially filled with pellets, enteric coated granules and pellets and soft gelatine capsules containing liquids.
The term "ergot alkaloids" comprises natural ergot ~ t il39Z2Z
- 3 - 100-51~9 alkaloids such as ergotamine, ergocri,stine, a-ergocryptine, ~-ergocryptine and ergoco~ ine, synthetic or semi-synthetic derivatives thereof such as ergovaline, dihydroergotoxine (also kno~m as co-dergocrine) and dihydroergotamine in free base form or in the form of an acid addition salt with pharmaceutically acceptable organlc or inorganic acids such as methanesulphonic, maleic, tartaric or hydrochloric acid.
The active agents which are of special interest for use in the invention, are compounds of formula I

; - NH ~

Ç[~ R2 HN~LRl wherein Rl is hydrogen or halogen, R2 is hydrogen or Cl 4alkyl, R3 is isopropyl, sec.-butyl, isobutyl or benzyl, R4 is methyl, ethyl or isopropyl, and either R5 is hydrogen and R6 is hydrogen or methoxy or R5 and R6 together are an additional bond, or mixtures thereof.
When Rl is halogen, it is preferably bromine.
Especially preferred compositions of the invention ~3922Z

contain dihydroergotoxine, bromocryptine or dihydroergot-amine in free base form or, preferably, in acid addition salt form as active agent.
Preferred sterol ethers Eor use in the compositions of the invention have a hydrophilic-lipophilic balance value (HLB group number) of from about 10 to about 20, especially from 12 to 16. They preferably are ethers of lanosterol, dihydrocholesterine and, particularly, of cholesterine or mixtures of such ethers. Especially suitable sterol ethers are sterols etherified with an average of 8 to 75, prefer-ably 9 to 30 alkylene oxide units. The hydroxy group in the end alkylene unit of such sterol ethers may be par-tially or completely acylated, e.g. by acyl radicals of aliphatic carboxylic acids, such as acetyl. Especially preferred are sterol ethers etherified with ethylene oxide and/or propylene oxide units. These sterol ethers are also known in the literature as polyoxyalkylene sterol ethers, e.g. polyoxyethylene sterol ethers, and polyalkylene glycol sterol ethers, e.g. polyethylene glycol sterol ethers.
The sterol ethers may be obtained by conventional manner by etherifying the sterol with the corresponding amount of epoxide and optionally acylating the so obtained alcohols. They are in general available on the market and are e.g. offered for sale by the firm Amerchol under the trade name Solulan~. Examples of Solulan~ types which 1~39ZZZ

- 4a -are available on the market and are suitable for use in the compositions according to the invention are such obtainable by alkoxylation of e.g.
a) 1 mol cholesterin with about 24 mol ethylene oxide (Solulan~ C-24) ~1392Z2 5 ~ 100-512~

b) 1 equi'valent of lanolinalcohols with about 16 equival.ents ethylene o~lde (Solulan~ 16) c) 1 equivaient of lanolir.a,~cohols wlth about 25 equivaler.ts ethylene oxide ( Solulan~ 25) d) 1 equivalent of lanolin alcohols ~7ith about 75 equivalents ethylene oxide (Solulan~ 16) e) 1 equivalent of lanolin alcohols with about 10 equivalents propylene oxide (Solulan~ PB-10) and also the f) partially acetylated derivative of 1 equivalent of lanolin alcohols ethoxylated ~lith aboutlO equivalents ethylene oxide (Solulan~ 98) and the g) completely acetylated deri~ative of 1 equivalent or lanolin alcohols ethoxylated with about 9 equiva].ents ethylene o~ide (Solulan~ 97) The term "about" ln the above paragraphs a) to g) indicates that the given number of ethylene oxide or propylene oxide equivalents involved is a mean value, i.e.
that some sterol ethers bear more and others less ethylene-oxy- or propyleneoxy-groups.
Lanolin alcohols are also kno~n as wool fat alcohols (Handbuch der Kosmetika,und Riechstoffe, 2. Ed. 19~0, Vol. I, page 1101 (Janistyn)) and are a mixture of i.e.
cholesterin , dihydrocholesterin and lanosterol.
The term "enteric coating"comprises any pharmaceutically acceptable coating preventing the release of the act_ve agent in the stomach and sufficiently disintegratirlg in thé
intestinal tract (by contact with approximately nelltral '~ !

1~392~Z

- 6 - 100-512g or alkaline intestine juices) to al]o~J the resorpti~n of the active agent through the ~7alls of the intestinal tract.
Various in vitro tests for determining ~7hether or not a coating is classified as an enteric coating have been published in the pharmacopoeia Gf various countries.
More speci~ically, the term "enteric coating" accord-ing to the invention refers to a coating ~7hich remains intact for at least 1 hour, e.g. 2 hours, in contac-t ~7ith artificial gastric juices such as HCl of pH 1.2 at 36 to 38C and thereafter disintegrates with 30 minutes in artificial intestinal juices such as a KH2P04 buffered solution of pH 6.8.
The thickness of the coating ma~ vary and depends inter alia on its permeability in water and acids and the desired retard effect. In general satisfactory results are obtained with a coating of 5 - 100 ~m, preferably 20 - 80 ~m,thickness. The coatinc3 is suitably selected from macromGlecular polymers. Suitable polymers are listed in e.g. HageYs Handbuch der pharmazeutischer Praxis, 4th Ed. Vol. 7a, pages 739 to 742 and 776 to 778, (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th Ed., pages 1689 to 1691 (Mack Publ. Co., 1970) and comprise e.g. cellulose ester derivatives, cellulose ethers, acrylic resins, such as methylacrylate copolymers and copolymers. of m~leic acid and phthalic acid derivatives.
The preferred films are made from cellulose acetate li39Z2~
~ 7 - 100--5129 phthalate; copolymers derived from me~hylacrylic acid and es-ters thereof, containing at least 40% methylacr~lic acid;
and especially hydroxypropyl methylcellulose phthalate.
~n example of an appropriate cellul.ose acetate phthalate is the marketed product C~P (E~stman Kodak, P~ochester N.Y., USA). Example.s of suitable hydroxypropyl methyl cellulose phthalates are the rnarketed products IIP 50 and HP 55 (Shinetsu, Tokyo, Japan).
- Since a coating consisting essentially of CAP
disintegrates at a higher pH as e.g. a coating consisting essentially of HP 50 the release of the active agent from compositions provided with the former coating will be morc delayed than from compositions provided with the latter coating. In such a way, one can,by suitable selection of the coating, obtain a retard effect that takes into account the properties of the active agent involved in an optimal way.

The process according to the invention may be carried ou-t in a manner analogous to methods known for the application of an enteric-coating.
20 For the preparation of coated tablets, pellets or granules one proceeds e.g. by spraying the corcs ~ith a solution of the enteric-coating.
Suitable solvents for the enteric-coating are .~or example organic solvents, e.g. an alcohol such as e~hanc)l, a ketone such as acetone, halogenated hydrocarbons such as CH2C12 or mixtures of ~uch so].vents, e.g. ethanal/acet:one 1:1. Conveni.er~tly a softener such as di-n-butylphthalate :1139222 ( is added to such a solution.
Con~eniently the cores are warmed up at 25 up to 40C
e.g. by means of warm air of 40 up to 70C, before spraying. To avoid sticking of the cG.res the spray procedure is prefera~ly interrupted at certain time intervals and the cores 'chen waxmed up again. The spray pressu~e ma;~ vary ,7ithin ~ide rangest in general sati.sfactory results are obtained with a spr~y pressure of from about 1 to about 1.5 bar. It is, ho~ever, also possible to proceed ~ithout interru~tion o the spray procedure, e.g. by automatic regulation of the spray amount in function of the tem~erature cf exhaust air and/or co~es.
The enteric-coated compositions of the invention have the ad~antageous property that, after p.o. a-dmir.istration to man the maxim~n concentration of the active agent in the blood plasma n~y be obtained after about 4 - 6 hours, whereas the initial pea~ after administration of a ncrmal com osition e.g. a tablet, is already reached after 0.5 - 1 hour.
The sust.ained reiease effect of the compositions of the invention is also illustrated by clete~mination of the concentra ior of active agent (and metabolites) in the secreted urine: the maxln;um ccncentl-ation in the ~ine may be found apprcximately G hours after aclministration ~herecls this ma~imum is obtained af-ter about 2 hours when a normal 25 composition is ad~inistered.
ln acldition, the plasma level after ad~ istration of the co~lpositions according to the in~ention n~y be bet~een 1~39~

6 and 24 hours after application, higher than after administration of a normal composition e.g. a tablet. This is illustrated by the area under the plasma concentration level (AUC) and is a measure of the excellent bioavailability of the compositions of the invention.
Accordingly, the compositions of the invention show a therapeutically desirable retard e~fect together with an excellent bioavailability and allow consequently treat-ment with one unit dGsage a day.
The compositions of the invention, especially the tablets may in addition be covered by an outer medicament layer. This outer layer may contain in addition to an active agent, such as an ergot alkaloid, carriers and/or fillers which are soluble or dispersible in the gastric juices such as talc, microcrvstalline cellulose, magnesiurn stearate, mannitol, polyvinylpyrrolidone etc..Such composi-tions may for example be used when a rapid onset of the activity is required. The high initial concentration of the ergot alkaloid in the blood is then maintained by its sustained release out of the core in the intestinal tract.
The optimal weight ratio in the core of ergot alkaloid:
sterol ether depends to a great extent on the physical properties of the sterol ether involved, the adjuvants used and the type and the size of the composition, e.g.
the amount oE the abovementioned sterol ethers of the type Solulan~ 16, Solulan ~ 25 and Solulan~ C-24is limited in view oE their waxy nature.

~39222 - 10 -- 10~-51~9 However, in general satisfactory results are obtained when a weight ratio ergot alkaloid : sterol ether rrom 1:1 to 1:25, preferably from 1:2 to 1:8,especially 1:4,is used. The range 1:2 to 1:8 is especially preferred ~hen the cores are present in solid soluti.on form of the ergot a].kaloid and especailly when polyvinylpyrrolidone is used as solid solvent.
The cores may be compounded with conventional excipients for example binding agents, lubricants, fillers and disintegrants. Suitable fillers for the prepara'ion of tablet cores are e.g. silicagel,calcium carbonate, sodium carbonate, lactose, starch, talc; suitable granula-ting and disintegrating agents are e.g. starch and alginic acid; suitable binding agents are e.g. starch and gelatine and suitable lubricants,stearic acid and talc.
The use of cores in solid solution form is a special embodiment of the invention. Such cores may be prepared as follows.
An ergot alkaloid, a sterol ether and a pharmaceuti-cally acceptable polymer which .is at least partly solublein an aqueous medium, especially a polyalkylene ~31ycol, polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate or a mixture of these are mixed tocJether.
Suitable polyalkylene glycols include polyethylene 25 glycol and polypropylene glycol and their copolymers having a molecular weight of 200 to 20,000, preferably 4000 to 15,000, more preferably 6000 to 13,000. Ry "polyvinyl-~1392~

pyrrolidone" is meant uncrosslillked poly (~-vinyl)pyrrGli~
done-2, suitably of molecular weight between 10,000 and 100,000, preferably 11,500 to 40,000, more pre~erably 20,000 to 30,000. The copolymer of vinylpyrrolidone and vinyJ
acetate preferably contains 60% by weight vinylpyrrolidone and 40% by weight vinyl acetate and preferably has a molecular weiyht of 30,000 to 100,000, more pre~erably 40,000 to 90,000.
When desired stabilizers such as acids, preferclbly methanesulphonic acid, maleic acid or tartaric acid are'added to adjust the pH of the composition. The preferred pH range fo~ the composition is pH 4-6, preferably pH 4 5.
The weight ratio ergot alkaloid : sterol ether :
- pharmaceutically acceptable polymer may vary between wide ranges; however, iIl general, satisfactory results are obtained with ratios varying in the range 1 : 1 - 10: 0.1-10, especially 1 : 2 - 8: 0.1 - 10 and more preferably 1 : 2 - 5: 0.1 - 5.
For the preparation of the solid solutions according to the invention the polymers are employed in solid form.
In case one of the polymers uscd is liquid at roorr, temperature, e.g. a polyalkylene glycol havinc~ a molccular weight of about 200, then it is obvious that such a polymer is not used alone, but in conjunction with a polyMer which is solid at room ternperature.
The abovementioned constituents are dissolved by stirring in a suitab,e solvent, for example in a lower 1~392;i~2 - 12 - 100-512~

alcohol such as etllanol or methanol, or in chloroform, at a tempexature of from 30 to 70~C, preferably 40 to 60C, and the solvent may be rernoved by evaporation under vacuum at the same temperature. In the preparation of the solution it is also possible to add on]y a part of the polymer and the additional ingredients, if any, and to add the remainder during the evaporation of the solvent. The resulting clear solution is left to solidify at room ternperature (15 to 25C) and the solid solution or dispersiGn may then he ground to a fine powder and dried, suitably under vacuum at 30C, to remove all traces of the solvent.
The solid solution (core of the composition) obtained accordin~ to the above process is then compounded in known manner with pharmaceutically acceptable diluents or carriers, 15 optionally with an additional amount of a sterol ether and the total content of sterol ether in the core should preferahly lie in the above given ranges.
The following examples illustrate the in-vention.
A11 temperatures are in degrees Celsius.

~39Z2:i~
- 13 - 10~-51~9 ( EX~`1PLE

rJablet cores cGnsisting of 3 g ciihydroergotamine 75 g cholesterin which is ethoxylated with about 24 ml ethylene oxide (Solulan~(C-24))and 22 g highly dispersed silicagel are heated to 30 during 10 minutes ~Jith the aid of warm air of 50 in a coating pan which is repeatedly rotated. The tablet cores are then sprayed, with the aid of a spray pistol, with a solution of 5.4 g hydroxypropyl methylcel-lulose r~hthalate (HP50) and 1.35 g di-n-butylp~thalate in a 1:1 ethanol/acetone mixture at a spray pressure of 1 - 1.5 bar using conventional inte~val spray coating procedures, and the so obtained coated tablets are then dried.

EXA~PLE 2 One proceeds analogous to Example 1 using however - 75 g lanolin alcohols ethoxylated ~ith about 25 equivalents ethylene oxide (Solulan~ 25) instead o~ 75 g cholesterin ethoxylated with about 2 4 mol ethylene oxide.

_~MPLE 3 - Coated tahlets wich core~ in solid solu~ion form 15 g Dihydroeryotoxine methanesulphonate l.OS g 20 (Solulan~ C-24) 33.95 y po7yvinylpyrrolidone (average molecular ~eight 25,000) and 250 ml methanol are charged into a 1 litre rowld-bottomed flask. rhe flas}; is attaclled to a rotary evaporator and rotated at a bath temperature of 60 until the flas}; contents reach 60, by which time a clear sollltion is obtained.

, . , - 1~3~2:~2 - i4 - 100-5129 The bath temperature is maintained at 60 and the sol~7ent evaporateîd under reduced pressure until the residue has a syrupy consistency. The residue is decanted into an evaporating basin and left to solidify for 2 hours at room temperature.
The solid residue is dried in a vacuum oven at 30, ca. 1 Torr for ca. 12 hours, yround to a fine powder and dried again.
26.8 g of the so obtained solid solutior. are then mixed with the following adjuvants:

silicon dioxide1.0 g (Aerosil~ 200, Deyùssa) polyvinylpyrrolidone 8.0 g (crosslinked) corn starch 20.0 g Talc 30.0 g Solular~ C-24 30.0 g cellulose granules42.0 g (Elcema~G 250) lactose 122.0 g until an homogenous mixture is obtained and then pressed, in conventional manner, to tablet cores of 140.0 mg (hardness 10-32N).
The so obtainecl cores are thell, analo~ous to Example 1, sprayed with a solu-tion of - 15 - 100-51~9 cellulose acetate phthalate (C~P) 90.0 g di-n-butylphthalate 22.5 g acetone 240.0 g ethanol 21.0 g dichloromethane 526.5 ~
900.0 g until the cores are coated with ca. 10 mg of the cellulose acetate phthalate/di-n-butylphthalate mixture per core.
The so obtained coated tablets are resistant against 10 the gastric juices since the cores remain intact after a treatrnent of 1 hour with artificial gastric juices of pH = 1.2. The disintegration time in artificial intestine juices is at pH 5.5 longer than 1 hour, and lies at pH 6.0 between 23-28 minutes and at pH 6.8 bet~een 12 and 16 minutes.
EXA~LE 4 One proceeds analogous to Example 3, sprayiny, however, the tablet cores of 140 mg with a solution of 140.0 g hydroxypropyl methylcellulose phthalate (HP 50) and 28 g di-n-butylphthalate in a mixture of 616 g ethanol and 616 g acetone, until the cores are coated with ca. 9 mg of the 20 hydroxyplopyl methylcellulose phthalate/di-n-butylphthalate mixture (ratio 10:2) per core.
E~IPL~ 5 Analogous to Example 3 is obtained a solid solution of 4 g dihydroergotoxine methanesulpholIate, 0.3 g Solulan 16 and 9.1 g polyvinylpyrrolidone (averaye mol ~eight 2000).
This solid solution is then mixed ~llth ( - .
silicon dioxide G.5 g polyvinylpyrrolidone 4.0 g (average mol weight 2000) corn starch 10.0 g t~lc 15.0 g Solulan~ 16 15.0 g cellulose granules 21.0 g (~lcema G 250) lactose 61.1 y and this mixture pressed to tablets of 140.0 mg.
The so obtained tab].et cores are then sprayed, analogous to Example 4, until each core is coated either with ca 10 mg or with ca 15 mg of the mixture:hyaroxy-propyl methylcellulose phthalate/di-n-butylphthalate.
Analogous to the procedure described in the above Examples are obtained the tablets as listed below in Table I.
In case Ib and Ic (see table) are used, the tablet cores are in solid solution form.

~ 17 ~ 100-5;29 (' TABLE
¦E`~.~IPL~ 6 ¦ 7 ¦ 8 ~ ~ ~ J 13 Ia Dihydroergot- 4-0 4.0 4,0 4.0 4~04.0l _ oxinemesylate Dihydroergot-oxinemes~late 6.0 6,0 Ib Solulan~ C24 0,3 0.3 0,3 0.3 0,3 0.4 Ic Po]yvinyl-pyrrolidone9.1 9.1 9.1 9.1 9,1 13.5 II Solulan~ C24 15.0 15.0 31.7 7.323.7 15.3 22,9 22.5 Sil;cion 2.4 2.4 0! 5 0~5 0,50,5 3.6 3,6 dioxide corn starch24.0 24.0 10.0 10 0 10.010.0 35.0 36.0 Cellulose 72.0 72.0 21.0 21.0 21.021.0 108,C 108.0 .
.
lactose 110.8 110.8~4.4 68.8 52.461,1 '~'-o.4 lG6.4 ~a~nesium 2.4 2.4 3.6 3.6 Kollidon~ 4 0 4.0 4~0 4.0 Polyvinyloyr- 9.1 13,5 rolidone(25) talc 15.0 15.015. l ~3P~CP* 26.0 7,07.2 9.0 9.0 9.0 7,2 7.2 Di-n-butyl-phthalate 1.8 _ _ _ 1,~ 1.8 . _._ . .. . , , ~ 1 ) total ~7ei~ht ?66.0 247.0 149.0 .l49 0 149.0 149.0 36~.0l369.
(rng) *IIPMCP = Hydrox.ypropyl nlethylcellulose phthalate (1) the cores of these tablets ~7ere pressed to possess a hardness of 50-60N

, , q; . .

113922;~

. - i8 - 100-51~9 ( ~ .
r X~ ~LE 14 : Tabl~-~t wlth an outer m.edic~.rent ~aver ~lântle table~) a) The cores are p.repared analogous to Example 3 by mi:-ing 26.8 g of a soli.d solution (consisting of 8.0 g dihydroergotamiJIe Jn~sylate, 0.6 g So3ulan~)C-2~ and 18.2 g polyvinylpyrroli.done) together with 1.0 g highly disperse silicagel, 8.0 g crosslinked polyvinylpyrrolidorle, 20 g corn starch, 47.4 g Solulan~ C-24, 42.0 g ce]lulose granules, 104.8 g lactose and 30.0 g talc until the mi~ture is homogenous. The mixture is then pressed to cores of 140.0 mg.
b) The so obtained cores are sprayed ~J.ith a solution or 140.0 g hydroYypropyl methylcellulose phthalate and 28.0 g di-n-butylphthalate in a mixture of 616 g ethanol and 15 616 g acetone, until the cores are coated with ca. 1.0 mg per tablet.
c) The outer medicament layer is prepared ky mixing 4.0 g dihydroergotamine mesylate with 4.0 g highlv dis~ersed silica-gel, 6.0 g magnesiwn stearate, 166.8 g cellulose powder, 20 40.0 g tâlc~ 191. 2 g corn starch and 348.0 g calcium hydro(3en phosphate until the mixture is homogenous. Thi.s mix~ture is then pressed ~ith the coa-tecl tablets (according to Example 14 b) to prepare tablets with an outer medic~nent layer, having a total weight of 530.0 mg per tablet.
E"~:~LE 15 One proceeds ana].ogous to any one ol Lxarl~lcs 1 to 14, using 4 mg bromocryptine, 4 mg dihydroergovaline or4mcc~ ydro ~13922~

( - 19 - lC0-5129 , er~onine instead of dihydxoeraoto~ine or dihydroerso-tar.line, and oht~ins tablets containin~ the corresponding er~ot alkaloid as active agen~.

EXAilPLE 16 : Clinical trial _ _ _ _ _ _ _ _ _ . _ _ _ The composition according to EY.ample 4 ~7as com~ar~d ~ith a solid solution of dihydroergotoxine mesylate (composition A) and a conventional composition of dihydroergotoxine mesylate (composition B).
Each person treatecl obtained 4 mg dihydroergotoxine mesylate.
The result is lis-ted in the follo~7ing table.
. _ ..... ..
Composition Example 4 B I A
. _ .. ...
Concentration in Plasma alter 20' 0.0~7~0.012 o,,76fo,07& 0~2-~+0.064 40' 0.092+0.039 0,~72+0,070 0.50~ .0~9 Max. conc. in 0.615-0.077 0.507-0.071 0~538-0.037 plasma (ng.ml~l) Time (in hours) 3.33-0,4~ 0.64-0.06 0.78-0,12 after ~hich max.
20 is reached Bioavailability AUC (0-24 hours) 4.77~-0.415 3.~75-0.279 3.754-0.171 (n~. ml % eliminated by 1.010-0.154 U.737-0.121 0.740-0 . O o l 25 ~rine (0-96 hours) _ _ ~ __ ~139Z22 - 20 - 100-~129 The good retarding effect and the excellent bioavail-ability of the composilion according to the i.nven~ion is clearly illustrated by tne figures in the above table. On the other hand, we found a clearly inferior b.ioavail-abi.lity (60-7~% of composition B) when testing a marketed composition of dihydroergotoxin retarded according to conventional manner.
Analogous tests with other compositions accordiny to the invention give similar good results. Additionally, a marketed composition of dihydroergotamine retarded according to conventional manner, showed a bioavailability that was about 30 to 40~ inferior to that found with the corresponding unretarded reference composition and inferior to compositions according to the invention.

Claims

WHAT WE CLAIM IS:

1. A solid enteric-coated composition for oral application, the core of the composition containing an ergot alkaloid and a polyalkoxyalkylene sterol ether, wherein the weight ratio ergot alkaloid:
polyalkoxyalkylene sterol ether is between 1 : 1 and 1 : 25.

2. A composition according to Claim 1 wherein the ergot alkaloid is a compound of formula I, I

wherein R1 is hydrogen or halogen, R2 is hydrogen or C1-4alkyl, R3 is isopropyl, sec.-butyl, isobutyl or benzyl, R4 is methyl, ethyl or isopropyl, and either R5 is hydrogen and R6 is hydrogen or methoxy or R5 and R6 together are an additional bond, or mixtures thereof.

3. A composition according to Claim 1 or 2 wherein the ergot alkaloid is dihydroergotamine.

4. A composition according to Claim 1 or 2 wherein the ergot alkaloid is dihydroergotoxine.

5. A composition according to Claim 1 or 2 wherein the ergot alkaloid is bromoergocryptine.

6. A composition according to Claim 1 wherein the polyalkoxyalkylene sterol ether has an hydro-philic-lipophilic balance of from 10 to 20.

7. A composition according to Claim 6 wherein the polyalkoxyalkylene sterol ether has a hydro-philic-lipophilic balance of from 12 to 16.

8. A composition according to Claim 1 wherein the sterol part of the polyalkoxyalkylene sterol ether is lanosterol, dihydrocholesterin and/or cholesterin.

9. A composition according to Claim 1 wherein the polyalkoxyalkylene sterol ether is a sterol etherified with about 8 to about 75 alkylene oxide units.

10. A composition according to Claim 9 wherein the sterol is etherified with from about 9 to about 30 alkylene units.

11. A composition according to Claim 1 wherein the polyalkoxyalkylene sterol ether is a sterol etherified with ethylene oxide or propylene oxide.

12. A composition according to Claim 1 wherein the enteric-coating is selected from a cellulose ester derivative, a cellulose ether, an acrylic resin or a copolymer of maleic acid and phthalic acid derivatives.

13. A composition according to Claim 12 wherein the enteric-coating is of cellulose acetate phthalate.

14. A composition according to Claim 12 wherein the enteric-coating is of hydroxypropyl methyl-cellulose phthalate.

15. A composition according to Claim 12 wherein the enteric-coating is of methylacrylic acid and esters thereof, containing at least 40 % methyl-acrylic acid.

16. A composition according to Claim 1 wherein the enteric-coating contains a softener.

17. A composition according to Claim 16 wherein the softener is di-n-butylphthalate.

18. A composition according to Claim 1 in form of a tablet.

19. A composition according to Claim 1 in the form of pellets.

20. A composition according to Claim 1 wherein the enteric-coating is on a capsule.

21. A composition according to Claim 18 wherein the tablet additionally has an outer medicament layer surrounding the enteric-coating.

22. A composition according to Claim 1 wherein the weight ratio ergot alkaloid : polyalkoxyalkylene sterol ether is from 1 : 2 to 1 : 8.

23. A composition according to Claim 1 wherein the core is in solid solution form.

24. A composition according to Claim 23 wherein the core contains a polyalkylene glycol, polyvinyl-pyrrolidone and/or a copolymer of vinylpyrrolidone and vinyl acetate as solid solvent.

25. A composition according to Claim 24 wherein the weight ratio within the core of ergot alkaloid :
polyalkoxyalkylene sterol ether : solid solvent lies in the range 1 : 1 - 10 : 0.1 - 10.

26. A composition according to Claim 25 wherein the weight ratio lies in the range 1 : 2 - 8 :
0.1 - 10.

27. A composition according to Claim 26 wherein the weight ratio lies in the range 1 : 2 - 5 :
0.1 - 5.

28. A composition according to Claim 23 wherein the core contains a stabilizer.

29. A composition according to Claim 28 wherein the core is stabilised by adjusting its pH, with an acid, at pH 4 - 6.

30. Process for the production of a composition as defined in Claim 1 characterised by enteric-coating a core comprising an ergot alkaloid and a polyalkoxyalkylene sterol ether.

31. Process according to Claim 30 for enteric-coating tablets, pellets or granules wherein the cores are sprayed with a solution of the enteric-coating.

32. Process according to Claim 31 characterised in that the cores, before spraying, are warmed up from 25 ° C to 40 ° C.

33. An enteric coated composition for oral application comprising a core of an ergot alkaloid chosen from dihydroergotamine, dihydroergotoxine and bromocryptine in a solid solution of polyvinyl-pyrrolidone, and a sterol etherified by from 8 to 75 moles of ethylene oxide per mole of sterol, the ratio of ergot alkaloid to sterol ether being from 1 : 2 to 1 : 8, the core being enteric-coated by hydroxypropyl methyl cellulose phthalate.

34. A composition as claimed in Claim 33 wherein the ergot alkaloid is dihydroergotoxine.

35. A composition as claimed in Claim 33 wherein the ergot alkaloid is dihydroergotamine.