CA1263087A - Pharmaceutical 9,10-dihydrogenated ergot alkaloid containing compositions - Google Patents
Pharmaceutical 9,10-dihydrogenated ergot alkaloid containing compositionsInfo
- Publication number
- CA1263087A CA1263087A CA000501011A CA501011A CA1263087A CA 1263087 A CA1263087 A CA 1263087A CA 000501011 A CA000501011 A CA 000501011A CA 501011 A CA501011 A CA 501011A CA 1263087 A CA1263087 A CA 1263087A
- Authority
- CA
- Canada
- Prior art keywords
- formulation according
- fatty material
- dergocrine
- dihydroergotamine
- swelling substance
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
PHARMACEUTICAL 9,10-DIHYDROGENATED ERGOT ALKALOID CON-TAINING COMPOSITIONS
Abstract of the Disclosure A controlled release formulation for oral administration comprising - a 9,10-dihydro ergot alkaloid, - a pharmaceutically acceptable hydrophilic swelling substance and - a pharmaceutically acceptable inert fatty material.
Abstract of the Disclosure A controlled release formulation for oral administration comprising - a 9,10-dihydro ergot alkaloid, - a pharmaceutically acceptable hydrophilic swelling substance and - a pharmaceutically acceptable inert fatty material.
Description
~2~i3~137 PHARMACEUTIC~L 9,10-DIHYDRO ERGOT ALKALOID CONTAINING
COMPOSITIONS
This invention relates to pharmaceut;cal compositions con taining 9,10-dihydro ergot alkaloids, 9,10-dihydro ergot alkaloids encompass the 9910-dihydro-derivatives of natural ergot alkaloids as well as ergo~ alkaloids obtainable by fermenta~ion or by chemical synthesis. They may e.g. have substituents, e.g. usually known in the chemistry of ergot alkaloids and may exist in the form of isomers, e.g. as 8R- and 8S-isomers, e.g.
as descri.bed in "Ergot alkaloids and related compounds, Editors B.Berde and H.D.Schild, Springer Verlag, Berlin, Heidelberg, New York 1978, herein~fter referred to as Berde and .~ .
The mos~ preferred compounds are dihydroergocornine, di-hydroergocristine, dihydro-a-ergocryptine, dihydro-~-ergo-cryptine, and co-dergocrine and dihydroergotamine.
Co^dergocrine is the generic name of a molar 3:3:2:1 ~ix-ture of dihydroergocornine, dihydroergocristine, dihydro-a-ergocryptine and dihydro ~-ergocryptine,(see Berde and Schild, page 58).
For pharmaceutical use co~dergocrine may be used in the form 3n of an acid addition salt, e.g. the e~hane-sulphonate, the maleate~ fu~arate, tar~rate, hydrochloride or preferably ~: . the mesulate. They exhibit the same order of activity
COMPOSITIONS
This invention relates to pharmaceut;cal compositions con taining 9,10-dihydro ergot alkaloids, 9,10-dihydro ergot alkaloids encompass the 9910-dihydro-derivatives of natural ergot alkaloids as well as ergo~ alkaloids obtainable by fermenta~ion or by chemical synthesis. They may e.g. have substituents, e.g. usually known in the chemistry of ergot alkaloids and may exist in the form of isomers, e.g. as 8R- and 8S-isomers, e.g.
as descri.bed in "Ergot alkaloids and related compounds, Editors B.Berde and H.D.Schild, Springer Verlag, Berlin, Heidelberg, New York 1978, herein~fter referred to as Berde and .~ .
The mos~ preferred compounds are dihydroergocornine, di-hydroergocristine, dihydro-a-ergocryptine, dihydro-~-ergo-cryptine, and co-dergocrine and dihydroergotamine.
Co^dergocrine is the generic name of a molar 3:3:2:1 ~ix-ture of dihydroergocornine, dihydroergocristine, dihydro-a-ergocryptine and dihydro ~-ergocryptine,(see Berde and Schild, page 58).
For pharmaceutical use co~dergocrine may be used in the form 3n of an acid addition salt, e.g. the e~hane-sulphonate, the maleate~ fu~arate, tar~rate, hydrochloride or preferably ~: . the mesulate. They exhibit the same order of activity
-2- ~63~7 100-6572 as ~he free base form and are prepared in manner known per se.
The methanesulphonate salt is listçd in the Merck Index, 1983, under the brand name HYDERGI~ see the reference 3596 on pages 526-527. This is also known as ergoloid mesylates.
The pharmacological and clinical properties have been ex-tensively reviewed in the book of Berde and Schild.
lo Co-dergocrine modifies cerebral neurotransmission and im-proves impaired cerebral metabolic function. Furthermore, it has a stabilizing effect on ~he tonus of cranial vessels and has anti-hypertensive activity.
Co-dergocrine is therefore indicated for the treatment of cerebral insufficienty in the elderly and of cerebrovascu-lar disorders, especially when associated with hyperten-sion, as well as for the prevention of migraine.
Usual oral daily dosages are 3 to 6 mg. A recommended oral daily dosage is 4.5 mg~ preferably divided into smaller dosages of 1.5 mg three times a day.
Dihydroergocornine, dihydroergocristine, dihydro-~-ergo-cryp~ine and dihydro-~-ergocryptine may be used individually for the same indications in thc same dosa9e order.
The pharmacological and clinical properties of dihydro-er~otamine haYe been reviewed as well in Berde and Schild.
.
: :~
:~ ' :
~263~
The methanesulphonate salt is listçd in the Merck Index, 1983, under the brand name HYDERGI~ see the reference 3596 on pages 526-527. This is also known as ergoloid mesylates.
The pharmacological and clinical properties have been ex-tensively reviewed in the book of Berde and Schild.
lo Co-dergocrine modifies cerebral neurotransmission and im-proves impaired cerebral metabolic function. Furthermore, it has a stabilizing effect on ~he tonus of cranial vessels and has anti-hypertensive activity.
Co-dergocrine is therefore indicated for the treatment of cerebral insufficienty in the elderly and of cerebrovascu-lar disorders, especially when associated with hyperten-sion, as well as for the prevention of migraine.
Usual oral daily dosages are 3 to 6 mg. A recommended oral daily dosage is 4.5 mg~ preferably divided into smaller dosages of 1.5 mg three times a day.
Dihydroergocornine, dihydroergocristine, dihydro-~-ergo-cryp~ine and dihydro-~-ergocryptine may be used individually for the same indications in thc same dosa9e order.
The pharmacological and clinical properties of dihydro-er~otamine haYe been reviewed as well in Berde and Schild.
.
: :~
:~ ' :
~263~
-3- 100-6572 The compound may be administered ln the form of the free base or of a pharmaceu~ically acceptable ac1d addi-tion ~alt. Such acid addition salts are known.
A typical acid addition salt form is the methanesulphonate salt (the mesylate), d scribed in The Merck Index 1983, reference 3151, ant sold under the brand name DIHYDERGOT.
Dihydroergota~ine is indicated for use in the treatment o of hypotens~on and orthostatic circulation disturbances, in the trea~ment of acute migraine attacks and related vascular headaches as well as in the interval treatment of migraine and other v.ascular headaches.
Further dihydroergotamine is indicated.to be active in the treatment of Herpes Zoster.
The drug is usually orally administered in daily closages of about 1 - 10 mg.
The pre~ent inventlon provides a con~rolled release formu-latlon for oral administration comprising a 9,10-dihydro ergot alkaloid a pharmaceutically acceptable hydrophilic swelling substance and a pharmaceutically acceptable inert fatty material.
: , .
~2 ~3 ~
-~- 100-6572 The invention specially provides such a controlled release formulation in which the 9,10-dihydro ergot alkaloid is a pepti`de alkaloid.
Hydrophilic s~elling substances that are preferred include one or more natural, partially or totally synthetic,anionic or, preferably, nonionic hydrophilic gums, modi~ied cellu-lose substances or pro~ein aceous substances such as, for example~ acacia, gum tragacanth, locust bean gum~ guar gum, karaya gum9 agar, peptin, carrageen, soluble and insoluble alginates9 methylcellulose, hydroxypropylmethylcellulose3 hydroxypropylcellulose, hydroxyethylcellulose, sodiumcar-boxymethylcellulose, carboxypolymethylene, gelatin.
Preferred are cellulose hydrocolloids which include methyl cellulose, hydroxypropylcellulose and especially hydroxy-propylmethylcellulose and sodium carboxymethylcellulose.
Suitable pharmaceutically acceptablP inert fatty materials include bees~ax; fatty acids; long chain fatty alcohols, such as, for example, cetyl alcohol, myristyl alcohol, stearyl alcohol, esters, e.5. glycerides such as glyceryl esters of fatty acids or hydrogenated aliphatic acids such as, for example, glyceryl mono-stearate, glyceryl distea-r~ate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oil and the like. Fatty materials are preferably such with melting points between 30 and 90C.
Most preferahly fatty ma~erials have a melting point from 45C to 65C and include glyceride~ such as glyceryl pal-mitates and stearates and fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.
., ~3 ~7 The formulation contains preferably both hydroxypropyl-methylcellulose as a swell;ng agent and cetyl palmitate as a fatty material.
It is also convenient to incorporate in the formulation at least one of other soluble or insoluble pharmaceutical ex-cipients such as calcium sulfate~ calciuro phosphate,lactose, mannitol,sucrose,sorbitol~colloidal silica,and magnesium stearateOPreferably a soluble excipient,especially lactose is present. Tha ratio of hydrocolloid to other excipient, 10 - may be e.~.from l 0.5 to 1:2.
The formulat1on may be produced in conventional manner by mixing the ingredients together, preferably ~elting the fatty materialO The resultant mixture is in powder form.
The po~der can be pressed to Form a tablet, but is pre-ferably filled into a capsule.
IF the fatty material is melted, the drug and addltional excipients such as lactose~ silica, calcium sulphate or calcium phosphate may be taken up in the mGlten fatty ma~erial.
2Q The mlxture is then allowed to solidify and is then divi-ded into small particles (granules).
The resultant granulate may be mixed with a~preferably porous, hydrophilic swelling substance and further exci-pients, e.g. ~agnesium stearate/and the mixture may be pressed to form a tablet or may be preferably filled into a capsul 2 o In a preferred aspect the present inYention accordingly ~3Q provides a formulation containing a 9,10-dihydro ergot alkaloid in a fatty material matrix granulate~ the granu-late particles being in contact with a hydrophilic s~elling substance.
: - , ~3 ~7 Preferably the s~elling substance is present in a porous formO
We have surprisingly found that the formulation posse~s an excellent stability, despite the fact that the alkaloids are sensitive to many chemical reagents. Moreover, the formulations have a satisfactory pharmac.odynamic and pharmacokinetic profileO
The resultant retarded formulations in general have com-parable bioavailability in standard clinical trials to conventional non-retarded formul ati ons oontai ni ng the same amounts of alkaloidsO The formulations of the invention, even if administered once a day, may produce a therapeutic effect for at least 24 hours and even as much as 35 hours.
The formulation may thus be administered only once a day in the known indica~ions of the alkaloids at approx;mately the same daily doses as employed in the conventional non-retarded forms.
The 9,10-dihydro ergot alkaloids especially encompass ~ 9,10-dihydro peptide ergot alkaloids of formula I
H ~ CO~U.
~ ~CH~ H R2 .
3~ ~7 The groups Rl and R2 may be the same of different, e.g.
Rl = (Cl_4)alkyl, and R2 = (Cl-~)alkyl~ or benzyl, and X - CH2 or S.
9,10-dihydro eryot alkaloids encompass 9,lO-dihydro peptide ergot alkaloids of formula I in which the carbon atom in position 9' is replaced by a sul~ur atom~ as disclosed in the British patent 2,109,795 B. The compounds ~ay pre ferably be used in pharmaceutical form as acid addition s~ltsO
The preferred compound of formula I wherein X = S is 9'-thia-9,10 dihydroergotamine. This is preferably used in the form oF the hydrogen malonate. The preferred indication is for the prevention and treatment of vascular headaches and for the treatment of orthostatic syndrome. No publications on the clln~ca~ use of this active agent have been made and no specific sustained release forms o~ this agent ; have been described.
~ Epicryptine is the generic name of a compound o~ the 25~ formula I in which Rl ~ ~sopropyl, R2 = 2R-butyl and X =
CH2, and is disclosed in the British patent 2,114,980 B.
Its chemical name is: (SR,8R,lOR)-N-[(2R,55~11S,12$)-5 (2R-butyl)-octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-8H-oxazolo[3,2-a]pyrrolo~291-c~pyrazinyl~-6-methyl-ergoline-8-carboxylic acid amide~ Epicryptire is also known as 30 ~ epicript~ne- -~ ~6 3~
The compound may be administered in the form of a pharma-ceutically acceptable acid additîon salt. Preferably the free base is used.
It is indicated for use in the treatment of lactation, galactorrhoea, hyperprolactinaemic hypogonadism, acrome-galy or prolactinoma.
Epicryptine is also indicated for use in the treatment of cerebral insufficiency, e.g. for senile dementia, particu larly the early forms thereof, and for increasing vigi-lance.
Additionally epicryptine is useful in the treatment of hypertonia, especially ~or geriatrics, and of stroke. The preferred indication is hypertension.
The compound is administered at a daily dosage of from about 0~1 to 15 mg, preFerably 2 to 5 mg.
The administra~ion of the ergot alkaloids used according to the inven~ion can orcasionally be associated with adverse side effectsg e.g. effects on the heart, vascular effects, central nervous system effects, autonomic and peripheral nervous syste~
and endocrine effects. See Berde and Schild, pages 815-820.
We pre~erably keep the concentration of the ergot alkaloids on a therapeutically active level but between narrow limits and avoid the drug burst which may occur just after admini-stration of non-controlled release preparations. This leads to ~emporary high blood leYels and to proportionately strong adverse effects.
The formulations of the present invention are well tolera-ted.
MoreoYer, the present formulations provide similar profiles of activity in food interaction studies, e.g. before and af~er administration of breakfast, with fasted subjects.
,,.
The present invention especially provides controllPd release formu-lations for oral administration con~aining co-dergocrine,dihydroergo-tamine or epicryptine as active agents in unit dosage forms.
The pharmaceutical formula~ions according to the inven~ion,contain preferably 1 to 15 mg of 9,lO~dihydro ergot alkaloi~.
Preferred ratios of 9,10-dihydro ergot alkaloid to swelling substance are from about 1:4 to 1:50,e.9O 1:4 to 1:25.
Preferred ratios of 9,10-dihydro ergot alkaloid to fatty material are from 1:0.5 to 1:10.
lo Preferred amounts of co-dergocrine in unit dosage form are from 2 to10 mg,especially 3-6,e.g.4.5 or 3 mg.Preferably co-dergocrine is in mesylate form.
Preferably the ratio of co-dergocrine to swelling substance is from 1:50 to l:lO,especially from 1:10 to 1:30,e.g. from 1:15 to 1:25.
The ratio of co-dergocrine to the fatty material is preferably from 1:1 to l:lO,especially from 1:1 to 1:5.
If other excipients like lactose or magnesium stearate are present,then preferably the weight ratio of co-dergocrine to the other excipients is conveniently from 1:5 ~o 1:40,especially 1:15 to 1:40.
Preferred amounts of dihydroergo~amine in unit dosage form are from 4 15 mg, ~.9.5 mg,especially 8-12,e.s.10 or 7.5 mg. Preferably dihydro-ergotamine is in mesylate form as well.
Preferably the ratio of dihydroergotamine to swelling substance is from 1:4 to 1:20je~g.1:5 to 1:20,especially from 1:4 to 1:12 e.g. from 1:5 to 1:12.
The ratio of dihydroergotamine to the fatty material is preferably from 1:0.5 to 1:2,especially from 1:0.5 to 1:1.5 e.g. from 1:0.8 to 1:1.5.
If other excipients like lactose~silicon dioXide,magnesium s~earate or tartaric acid3are present,then preferably the weight ratio of dihydro-ergotamine to the other excipients is convenien~ly from 1:3 to 1:20, especially from 1:4 to 1:15.
% ~3~ 7 -lo- 100-6572 Epicryptine may also be present as an acid addition salt,but the pre-ferred form in the controlled release formulation is the free base.
The unit dosage form contains preferably an amount of 2 to 7 mg, especially 5 mg of drug.
The present invention provides for the first time an oral pharmaceutical formulation containing 9'-thia-9,10-dihydroergocryptine or epicryptine for once-a-day administration.
Once-a-day formulations may be formulated in conventional mannerJe.g.
lo to be a capsule or tablet and may contain from 1 to 15 mg of active agent. Preferably they have the same release profile as detenmined by in vi~o or in vitro dissolution tests as for the formulations of the present invention,e g. a release of about 50 to 90,e.g. 50 to 60, 70 to 80 or 80 to 90 per cent over 7 hours at 0.1 N~Cl,e.g. as in the ex-perimental conditions in Example 2.
In the following examples all temperatures are in dPgrees Centigrade and are uncorrected.
Further information on the proporties etc.of the pharmaceutical exci-pients named hereinafter may be obtained from the manufacturer, listed hereinafter, manufacturer's brochures or other sources,especially H.P.
Fiedler Lexikon der Hilfss~offe fUr Pharmazie,Kosmetik und angrenzende Gebiete,2nd Edition 1981, Edito Cantor,Aulendorf, W.Germany.
Silicon diox;de (silica) is e.g. brand Aerosil 200 aYailable from Deutsche-Gold und Silberscheideanstalt, Frankfurt, W.Germany.
Glycerol ditripalmi~ostearat is e.g. brand Preciro~ Ato 5 aYailable from ETS Gattefossé 929100 Boulogne-Brillancourt, France.
Hydroxypropylmethylcellulose 15000 cps and 4000 cps are e.g.brands Methocel KlSM and Methocel 4EM available from Dow Chemical Company, Michigan 48640 USA.
Cetyl palmitate is e.g. brand Cutina CPA available from Henkel 4000, DUsseldorf,W~Germany,or is available from Gattefossé or from A/S
Johan C.Martens and Company,Bergen, Norway.
,. ~
~.
3 ~7 ~ 100-6572 EXAMPLE 1: Comeosltlon Of-each-caesule Ingredient mg a) Co-dergocrine (in mesylate form) 4.5 b) Lactose (200 mesh~ 1241265 c) Si1icon dioxide 10 d) Glycerol ditripalmitosbearate40 e) Hydroxypropylmethylcellulose 4000 cps 110 Capsule (Hard gelatine) 78 Preparation (Charge of 6000 capsules) -Ingredients a), b) and c) are sieved and mixed. Ingre-dient d) is melted by heating to 56C tm.p.54C) and is added to the mixture which is heated to 55C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The cooled macs is broken up and sieved ~through 250 micron openings). In~redient e) is sieved (through 360 micron openings) and mixed in over 10 minutes. The mixture is then encapsulated.
EXAMPLE 2 T0 5:
Composition of each capsuleEx.2 Ex~3 Ex.4 Ex.5 Ingredient mg mg mg mg a) Co-dergocrine 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-cellullose (15000 cps) 90.0 70.0 70.0 d2~ Hydroxypropylmethyl :30 cellulose (4000 cps) 90.0 e) Magnesium stearate 1.0 1.0 :: Capsule (Hard gelatine; 78 mg) :,,, 3~ ~
Preparation The ingredients are mixed in analogous manner to that dis-closed in Example l,except that constituent d) is re-placed by an equivalent amount of cetyl palmitate, the silicon dioxide c) is omitted and the hydroxypropylmethyl-cellulose d) is mixed with magnesium stearate.
In vîtro release In in vitro experimen~s (USP XXI, pages 1243~1244, Appa-lo ratus 1, 1000 ml 0.1 n HCl, 100 rotations per min.) the following release results were obtained:
Time (hours) Release of Time (hours) Release of co-dergocrine co-dergocrine Ex.2 Ex.3 Ex.4 Ex.5 1 15~ 16% 1 l9~o 20%
S 50 52 4 48 ~9 24 99 86 24 100 10~
_ . _ _ _ :~.
~2~3~
-l3 l00-6573 EXAMPLE 6: Com~osition of each caesul e I ngredi ent mg a) Dihydroergotamine (in mesylate ~orm) lO.0 b) Lactose (200 mesh) 88.0 c) Silicon dioxide l.0 d) Glycerol ditripalmitostearate lO.0 e) Hydroxypropylmethylcellulose 4000 cps 90.0 f) Magnesium stearate l.0 Capsule (Hard gelatine) 62.0 Preparation (Charge of 6000 capsules) Ingredients a), b) and c) are sieved and mixed. Ingreclient d) is melted by heating to 56C ~m.p. 54C) and is added to the mixture which is heated to 55C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The cooled mass is broken up and sieved (through 800 micron openings). Ingredients e) and f) are sieved (through 500 micron openings) and mixed in over lO
minutes. The mixture is then encapsulated.
In vitro release (Experimental condit;ons: see Example 2) _, .
Time (hours) Release of dihydroergotamine (%~
z 17
A typical acid addition salt form is the methanesulphonate salt (the mesylate), d scribed in The Merck Index 1983, reference 3151, ant sold under the brand name DIHYDERGOT.
Dihydroergota~ine is indicated for use in the treatment o of hypotens~on and orthostatic circulation disturbances, in the trea~ment of acute migraine attacks and related vascular headaches as well as in the interval treatment of migraine and other v.ascular headaches.
Further dihydroergotamine is indicated.to be active in the treatment of Herpes Zoster.
The drug is usually orally administered in daily closages of about 1 - 10 mg.
The pre~ent inventlon provides a con~rolled release formu-latlon for oral administration comprising a 9,10-dihydro ergot alkaloid a pharmaceutically acceptable hydrophilic swelling substance and a pharmaceutically acceptable inert fatty material.
: , .
~2 ~3 ~
-~- 100-6572 The invention specially provides such a controlled release formulation in which the 9,10-dihydro ergot alkaloid is a pepti`de alkaloid.
Hydrophilic s~elling substances that are preferred include one or more natural, partially or totally synthetic,anionic or, preferably, nonionic hydrophilic gums, modi~ied cellu-lose substances or pro~ein aceous substances such as, for example~ acacia, gum tragacanth, locust bean gum~ guar gum, karaya gum9 agar, peptin, carrageen, soluble and insoluble alginates9 methylcellulose, hydroxypropylmethylcellulose3 hydroxypropylcellulose, hydroxyethylcellulose, sodiumcar-boxymethylcellulose, carboxypolymethylene, gelatin.
Preferred are cellulose hydrocolloids which include methyl cellulose, hydroxypropylcellulose and especially hydroxy-propylmethylcellulose and sodium carboxymethylcellulose.
Suitable pharmaceutically acceptablP inert fatty materials include bees~ax; fatty acids; long chain fatty alcohols, such as, for example, cetyl alcohol, myristyl alcohol, stearyl alcohol, esters, e.5. glycerides such as glyceryl esters of fatty acids or hydrogenated aliphatic acids such as, for example, glyceryl mono-stearate, glyceryl distea-r~ate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oil and the like. Fatty materials are preferably such with melting points between 30 and 90C.
Most preferahly fatty ma~erials have a melting point from 45C to 65C and include glyceride~ such as glyceryl pal-mitates and stearates and fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.
., ~3 ~7 The formulation contains preferably both hydroxypropyl-methylcellulose as a swell;ng agent and cetyl palmitate as a fatty material.
It is also convenient to incorporate in the formulation at least one of other soluble or insoluble pharmaceutical ex-cipients such as calcium sulfate~ calciuro phosphate,lactose, mannitol,sucrose,sorbitol~colloidal silica,and magnesium stearateOPreferably a soluble excipient,especially lactose is present. Tha ratio of hydrocolloid to other excipient, 10 - may be e.~.from l 0.5 to 1:2.
The formulat1on may be produced in conventional manner by mixing the ingredients together, preferably ~elting the fatty materialO The resultant mixture is in powder form.
The po~der can be pressed to Form a tablet, but is pre-ferably filled into a capsule.
IF the fatty material is melted, the drug and addltional excipients such as lactose~ silica, calcium sulphate or calcium phosphate may be taken up in the mGlten fatty ma~erial.
2Q The mlxture is then allowed to solidify and is then divi-ded into small particles (granules).
The resultant granulate may be mixed with a~preferably porous, hydrophilic swelling substance and further exci-pients, e.g. ~agnesium stearate/and the mixture may be pressed to form a tablet or may be preferably filled into a capsul 2 o In a preferred aspect the present inYention accordingly ~3Q provides a formulation containing a 9,10-dihydro ergot alkaloid in a fatty material matrix granulate~ the granu-late particles being in contact with a hydrophilic s~elling substance.
: - , ~3 ~7 Preferably the s~elling substance is present in a porous formO
We have surprisingly found that the formulation posse~s an excellent stability, despite the fact that the alkaloids are sensitive to many chemical reagents. Moreover, the formulations have a satisfactory pharmac.odynamic and pharmacokinetic profileO
The resultant retarded formulations in general have com-parable bioavailability in standard clinical trials to conventional non-retarded formul ati ons oontai ni ng the same amounts of alkaloidsO The formulations of the invention, even if administered once a day, may produce a therapeutic effect for at least 24 hours and even as much as 35 hours.
The formulation may thus be administered only once a day in the known indica~ions of the alkaloids at approx;mately the same daily doses as employed in the conventional non-retarded forms.
The 9,10-dihydro ergot alkaloids especially encompass ~ 9,10-dihydro peptide ergot alkaloids of formula I
H ~ CO~U.
~ ~CH~ H R2 .
3~ ~7 The groups Rl and R2 may be the same of different, e.g.
Rl = (Cl_4)alkyl, and R2 = (Cl-~)alkyl~ or benzyl, and X - CH2 or S.
9,10-dihydro eryot alkaloids encompass 9,lO-dihydro peptide ergot alkaloids of formula I in which the carbon atom in position 9' is replaced by a sul~ur atom~ as disclosed in the British patent 2,109,795 B. The compounds ~ay pre ferably be used in pharmaceutical form as acid addition s~ltsO
The preferred compound of formula I wherein X = S is 9'-thia-9,10 dihydroergotamine. This is preferably used in the form oF the hydrogen malonate. The preferred indication is for the prevention and treatment of vascular headaches and for the treatment of orthostatic syndrome. No publications on the clln~ca~ use of this active agent have been made and no specific sustained release forms o~ this agent ; have been described.
~ Epicryptine is the generic name of a compound o~ the 25~ formula I in which Rl ~ ~sopropyl, R2 = 2R-butyl and X =
CH2, and is disclosed in the British patent 2,114,980 B.
Its chemical name is: (SR,8R,lOR)-N-[(2R,55~11S,12$)-5 (2R-butyl)-octahydro-12-hydroxy-2-isopropyl-3,6-dioxo-8H-oxazolo[3,2-a]pyrrolo~291-c~pyrazinyl~-6-methyl-ergoline-8-carboxylic acid amide~ Epicryptire is also known as 30 ~ epicript~ne- -~ ~6 3~
The compound may be administered in the form of a pharma-ceutically acceptable acid additîon salt. Preferably the free base is used.
It is indicated for use in the treatment of lactation, galactorrhoea, hyperprolactinaemic hypogonadism, acrome-galy or prolactinoma.
Epicryptine is also indicated for use in the treatment of cerebral insufficiency, e.g. for senile dementia, particu larly the early forms thereof, and for increasing vigi-lance.
Additionally epicryptine is useful in the treatment of hypertonia, especially ~or geriatrics, and of stroke. The preferred indication is hypertension.
The compound is administered at a daily dosage of from about 0~1 to 15 mg, preFerably 2 to 5 mg.
The administra~ion of the ergot alkaloids used according to the inven~ion can orcasionally be associated with adverse side effectsg e.g. effects on the heart, vascular effects, central nervous system effects, autonomic and peripheral nervous syste~
and endocrine effects. See Berde and Schild, pages 815-820.
We pre~erably keep the concentration of the ergot alkaloids on a therapeutically active level but between narrow limits and avoid the drug burst which may occur just after admini-stration of non-controlled release preparations. This leads to ~emporary high blood leYels and to proportionately strong adverse effects.
The formulations of the present invention are well tolera-ted.
MoreoYer, the present formulations provide similar profiles of activity in food interaction studies, e.g. before and af~er administration of breakfast, with fasted subjects.
,,.
The present invention especially provides controllPd release formu-lations for oral administration con~aining co-dergocrine,dihydroergo-tamine or epicryptine as active agents in unit dosage forms.
The pharmaceutical formula~ions according to the inven~ion,contain preferably 1 to 15 mg of 9,lO~dihydro ergot alkaloi~.
Preferred ratios of 9,10-dihydro ergot alkaloid to swelling substance are from about 1:4 to 1:50,e.9O 1:4 to 1:25.
Preferred ratios of 9,10-dihydro ergot alkaloid to fatty material are from 1:0.5 to 1:10.
lo Preferred amounts of co-dergocrine in unit dosage form are from 2 to10 mg,especially 3-6,e.g.4.5 or 3 mg.Preferably co-dergocrine is in mesylate form.
Preferably the ratio of co-dergocrine to swelling substance is from 1:50 to l:lO,especially from 1:10 to 1:30,e.g. from 1:15 to 1:25.
The ratio of co-dergocrine to the fatty material is preferably from 1:1 to l:lO,especially from 1:1 to 1:5.
If other excipients like lactose or magnesium stearate are present,then preferably the weight ratio of co-dergocrine to the other excipients is conveniently from 1:5 ~o 1:40,especially 1:15 to 1:40.
Preferred amounts of dihydroergo~amine in unit dosage form are from 4 15 mg, ~.9.5 mg,especially 8-12,e.s.10 or 7.5 mg. Preferably dihydro-ergotamine is in mesylate form as well.
Preferably the ratio of dihydroergotamine to swelling substance is from 1:4 to 1:20je~g.1:5 to 1:20,especially from 1:4 to 1:12 e.g. from 1:5 to 1:12.
The ratio of dihydroergotamine to the fatty material is preferably from 1:0.5 to 1:2,especially from 1:0.5 to 1:1.5 e.g. from 1:0.8 to 1:1.5.
If other excipients like lactose~silicon dioXide,magnesium s~earate or tartaric acid3are present,then preferably the weight ratio of dihydro-ergotamine to the other excipients is convenien~ly from 1:3 to 1:20, especially from 1:4 to 1:15.
% ~3~ 7 -lo- 100-6572 Epicryptine may also be present as an acid addition salt,but the pre-ferred form in the controlled release formulation is the free base.
The unit dosage form contains preferably an amount of 2 to 7 mg, especially 5 mg of drug.
The present invention provides for the first time an oral pharmaceutical formulation containing 9'-thia-9,10-dihydroergocryptine or epicryptine for once-a-day administration.
Once-a-day formulations may be formulated in conventional mannerJe.g.
lo to be a capsule or tablet and may contain from 1 to 15 mg of active agent. Preferably they have the same release profile as detenmined by in vi~o or in vitro dissolution tests as for the formulations of the present invention,e g. a release of about 50 to 90,e.g. 50 to 60, 70 to 80 or 80 to 90 per cent over 7 hours at 0.1 N~Cl,e.g. as in the ex-perimental conditions in Example 2.
In the following examples all temperatures are in dPgrees Centigrade and are uncorrected.
Further information on the proporties etc.of the pharmaceutical exci-pients named hereinafter may be obtained from the manufacturer, listed hereinafter, manufacturer's brochures or other sources,especially H.P.
Fiedler Lexikon der Hilfss~offe fUr Pharmazie,Kosmetik und angrenzende Gebiete,2nd Edition 1981, Edito Cantor,Aulendorf, W.Germany.
Silicon diox;de (silica) is e.g. brand Aerosil 200 aYailable from Deutsche-Gold und Silberscheideanstalt, Frankfurt, W.Germany.
Glycerol ditripalmi~ostearat is e.g. brand Preciro~ Ato 5 aYailable from ETS Gattefossé 929100 Boulogne-Brillancourt, France.
Hydroxypropylmethylcellulose 15000 cps and 4000 cps are e.g.brands Methocel KlSM and Methocel 4EM available from Dow Chemical Company, Michigan 48640 USA.
Cetyl palmitate is e.g. brand Cutina CPA available from Henkel 4000, DUsseldorf,W~Germany,or is available from Gattefossé or from A/S
Johan C.Martens and Company,Bergen, Norway.
,. ~
~.
3 ~7 ~ 100-6572 EXAMPLE 1: Comeosltlon Of-each-caesule Ingredient mg a) Co-dergocrine (in mesylate form) 4.5 b) Lactose (200 mesh~ 1241265 c) Si1icon dioxide 10 d) Glycerol ditripalmitosbearate40 e) Hydroxypropylmethylcellulose 4000 cps 110 Capsule (Hard gelatine) 78 Preparation (Charge of 6000 capsules) -Ingredients a), b) and c) are sieved and mixed. Ingre-dient d) is melted by heating to 56C tm.p.54C) and is added to the mixture which is heated to 55C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The cooled macs is broken up and sieved ~through 250 micron openings). In~redient e) is sieved (through 360 micron openings) and mixed in over 10 minutes. The mixture is then encapsulated.
EXAMPLE 2 T0 5:
Composition of each capsuleEx.2 Ex~3 Ex.4 Ex.5 Ingredient mg mg mg mg a) Co-dergocrine 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-cellullose (15000 cps) 90.0 70.0 70.0 d2~ Hydroxypropylmethyl :30 cellulose (4000 cps) 90.0 e) Magnesium stearate 1.0 1.0 :: Capsule (Hard gelatine; 78 mg) :,,, 3~ ~
Preparation The ingredients are mixed in analogous manner to that dis-closed in Example l,except that constituent d) is re-placed by an equivalent amount of cetyl palmitate, the silicon dioxide c) is omitted and the hydroxypropylmethyl-cellulose d) is mixed with magnesium stearate.
In vîtro release In in vitro experimen~s (USP XXI, pages 1243~1244, Appa-lo ratus 1, 1000 ml 0.1 n HCl, 100 rotations per min.) the following release results were obtained:
Time (hours) Release of Time (hours) Release of co-dergocrine co-dergocrine Ex.2 Ex.3 Ex.4 Ex.5 1 15~ 16% 1 l9~o 20%
S 50 52 4 48 ~9 24 99 86 24 100 10~
_ . _ _ _ :~.
~2~3~
-l3 l00-6573 EXAMPLE 6: Com~osition of each caesul e I ngredi ent mg a) Dihydroergotamine (in mesylate ~orm) lO.0 b) Lactose (200 mesh) 88.0 c) Silicon dioxide l.0 d) Glycerol ditripalmitostearate lO.0 e) Hydroxypropylmethylcellulose 4000 cps 90.0 f) Magnesium stearate l.0 Capsule (Hard gelatine) 62.0 Preparation (Charge of 6000 capsules) Ingredients a), b) and c) are sieved and mixed. Ingreclient d) is melted by heating to 56C ~m.p. 54C) and is added to the mixture which is heated to 55C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The cooled mass is broken up and sieved (through 800 micron openings). Ingredients e) and f) are sieved (through 500 micron openings) and mixed in over lO
minutes. The mixture is then encapsulated.
In vitro release (Experimental condit;ons: see Example 2) _, .
Time (hours) Release of dihydroergotamine (%~
z 17
4 29 3~
EXAMPL 7: Com~osition of each caesule Ingredient mg a) Dihydroergo~amine in mesylate form10~0 b) Lactose ~200 mesh) 107~0 c) Cetyl pal~itate lO~0 d) ~ydroxypropylmethylcellulose (1500.0 cps~ 70.0 e) Sili.con dioxide 1.0 f) Magnesi.um stearate 2,0 Capsule (Hard gelatine) 62.0 Pre_aration_ The ;ngredients are mixed in analogous manner to that dis-closed in Example 6, except ~hat constituent d) is replaced by an equivalent amount of cetyl palmitate.
In vi.tro_release (Exper;mentalcond;tions: see Example 2) Time (hours) Release of dihydroergotamine (%) zo 8 lOo EXAMPLE 8 T0 10:
___~_ 5Omposition of each capsuleEx.8 Ex.9 Ex.10 ___ _ _ ~
Ingredi.ent mg mg mg 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.~ 8.0 e) Hydroxypropylmethylcellulose8040 4040 8000 (4000 cps) . - -~2 ~3~7 The ingredient~ are mixed in analogous manner to that disclosed in Example 6:
Consti:tuents a), b) and c) are occluded in constituent d), the solidi~ied mixture is gran~lated and is mixed with constituent e).
In vitro release (Experi~ental conditions: see Example 2) Time (hours) Release of dihydroergotamine Ex.8 Ex.9 Ex.10 1 10% 14% 10%
C ompa rative clinical_ test Objective : To study in healthy volunteers the bioavaila-bility of co-dergocrine in an oral controlled release capsule A according to Example 2 in comparison to co-der-gocrine in a conventional tablet B-Conventional composition in tablet form Ingredient mg 1. Co-dergocrine in mesylate form 1~0 2. Stearic acid 2.0 3. Talc 4.0 4. Polyvinylpyrrolidone 4~0
EXAMPL 7: Com~osition of each caesule Ingredient mg a) Dihydroergo~amine in mesylate form10~0 b) Lactose ~200 mesh) 107~0 c) Cetyl pal~itate lO~0 d) ~ydroxypropylmethylcellulose (1500.0 cps~ 70.0 e) Sili.con dioxide 1.0 f) Magnesi.um stearate 2,0 Capsule (Hard gelatine) 62.0 Pre_aration_ The ;ngredients are mixed in analogous manner to that dis-closed in Example 6, except ~hat constituent d) is replaced by an equivalent amount of cetyl palmitate.
In vi.tro_release (Exper;mentalcond;tions: see Example 2) Time (hours) Release of dihydroergotamine (%) zo 8 lOo EXAMPLE 8 T0 10:
___~_ 5Omposition of each capsuleEx.8 Ex.9 Ex.10 ___ _ _ ~
Ingredi.ent mg mg mg 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.~ 8.0 e) Hydroxypropylmethylcellulose8040 4040 8000 (4000 cps) . - -~2 ~3~7 The ingredient~ are mixed in analogous manner to that disclosed in Example 6:
Consti:tuents a), b) and c) are occluded in constituent d), the solidi~ied mixture is gran~lated and is mixed with constituent e).
In vitro release (Experi~ental conditions: see Example 2) Time (hours) Release of dihydroergotamine Ex.8 Ex.9 Ex.10 1 10% 14% 10%
C ompa rative clinical_ test Objective : To study in healthy volunteers the bioavaila-bility of co-dergocrine in an oral controlled release capsule A according to Example 2 in comparison to co-der-gocrine in a conventional tablet B-Conventional composition in tablet form Ingredient mg 1. Co-dergocrine in mesylate form 1~0 2. Stearic acid 2.0 3. Talc 4.0 4. Polyvinylpyrrolidone 4~0
5. Starch. 8~0
6. Lactose 141.0 The ingredients 1 to 6 were mixed together, granulated with a mix~ure of alcohol and water, dried and.compressed to a tablet.
3~
One dosage of t~o 4.5 mg co-dergocrine mesylate containing capsules A (= 9 mg) was compared ~ith on~ dosage of 4 con-ventional ta~lets B containing 1 mg co-dergocrine mesylate (= 4 mg), The lower dose for the tablet was chosen to avoid expeoted - ~ _ side effects due to the high peak levels of the conventional non-controlled release tablets.
The study design was an open label~ 2 period design with each subject randomly assigned to one of two treatment sequences, follo~ed by a third treatment period in which all subjects received the identical third treatment.
10 healthy male volunteers received on a fasted stomach both treatments in the first hour periods, followed by one closage of retard capsules A with food in period three.
Blood samples were obtained from the 10 volunteers by an ind~elling cannula, at specific time points up to 24 hours after administration of the capsules.
The co-dergocrine concent8r~ ions, measured after the admini-stration of capsules A and~B, were plotted graphically as shown in aocompanying in figure 1 as corresponding mean curves A.l (without food), A.2 (with food) and B (without food) in picograms ml, time T in hours).
From the measured co-dergocrine concentrations, the following parameters were obtained (as arithmetic means).
~ Retard Caps.A Retard Caps.A Oral tablet g with food without food without food ~UC
(Area under the2066 2066 2242*
curve90-24 hours) Peak (in pico-9r3m/ml) 172 162 511*
Time (in hours)5.9 3.9 0.9 *Ex~rapolated from 4 mg to 9 mg This is justified since co-dergocrine mesylate shows linear dose propor-tionality for the AUC in the O - 9 mg dose range.
~i3Ni8~
~17- 100-6572 The retard capsule A showed an AUC, similar to that of the conventi`onal tablet B (corrected for the dose) when given on an empty stomach or with a meal. Compared to the tablet B the retard capsule A showed a statistically significant lower peak level and a delayed time to peak (from less than 1 hour to 3.9 h on a Fasted stomach or 5.9 h when given with a meal). In generals however, the profile of compound A when given on a fasted stomach was similar to that when given after a meal, except for the delay in the absorption of drug with a full stomach (presumably due to a delay in stomach emptying).
- The retard capsule A, given on a fasted stomach or with a meal, provides sustained release of drug without dose dum-1S ping and7 which is especially ~oteworthy, without signifi-cant loss of bioavailability, compared to the oral tablet reference Standard B.
Side effects such as headache and gastrointestinal upset were transitory and ~ere mild to mod~rate in severity.
Single dose of retard capsules Ag administered as 2 x 4.5 mg retard capsules A are safe and well tolerated.
EXAMPLE 11:
2s The co-dergocrine and dihydroergotamine in the above examples ~ay be replaced by an equ~valent amount of epi-cryptine or 9'-thia-9,10-dihydrcergotamine.
.
3~
One dosage of t~o 4.5 mg co-dergocrine mesylate containing capsules A (= 9 mg) was compared ~ith on~ dosage of 4 con-ventional ta~lets B containing 1 mg co-dergocrine mesylate (= 4 mg), The lower dose for the tablet was chosen to avoid expeoted - ~ _ side effects due to the high peak levels of the conventional non-controlled release tablets.
The study design was an open label~ 2 period design with each subject randomly assigned to one of two treatment sequences, follo~ed by a third treatment period in which all subjects received the identical third treatment.
10 healthy male volunteers received on a fasted stomach both treatments in the first hour periods, followed by one closage of retard capsules A with food in period three.
Blood samples were obtained from the 10 volunteers by an ind~elling cannula, at specific time points up to 24 hours after administration of the capsules.
The co-dergocrine concent8r~ ions, measured after the admini-stration of capsules A and~B, were plotted graphically as shown in aocompanying in figure 1 as corresponding mean curves A.l (without food), A.2 (with food) and B (without food) in picograms ml, time T in hours).
From the measured co-dergocrine concentrations, the following parameters were obtained (as arithmetic means).
~ Retard Caps.A Retard Caps.A Oral tablet g with food without food without food ~UC
(Area under the2066 2066 2242*
curve90-24 hours) Peak (in pico-9r3m/ml) 172 162 511*
Time (in hours)5.9 3.9 0.9 *Ex~rapolated from 4 mg to 9 mg This is justified since co-dergocrine mesylate shows linear dose propor-tionality for the AUC in the O - 9 mg dose range.
~i3Ni8~
~17- 100-6572 The retard capsule A showed an AUC, similar to that of the conventi`onal tablet B (corrected for the dose) when given on an empty stomach or with a meal. Compared to the tablet B the retard capsule A showed a statistically significant lower peak level and a delayed time to peak (from less than 1 hour to 3.9 h on a Fasted stomach or 5.9 h when given with a meal). In generals however, the profile of compound A when given on a fasted stomach was similar to that when given after a meal, except for the delay in the absorption of drug with a full stomach (presumably due to a delay in stomach emptying).
- The retard capsule A, given on a fasted stomach or with a meal, provides sustained release of drug without dose dum-1S ping and7 which is especially ~oteworthy, without signifi-cant loss of bioavailability, compared to the oral tablet reference Standard B.
Side effects such as headache and gastrointestinal upset were transitory and ~ere mild to mod~rate in severity.
Single dose of retard capsules Ag administered as 2 x 4.5 mg retard capsules A are safe and well tolerated.
EXAMPLE 11:
2s The co-dergocrine and dihydroergotamine in the above examples ~ay be replaced by an equ~valent amount of epi-cryptine or 9'-thia-9,10-dihydrcergotamine.
.
Claims (19)
1. A controlled release formulation for oral administration comprising -a 9,10-dihydro ergot alkaloid as a drug -a pharmaceutically acceptable hydrophilic swelling substance -a pharmaceutically acceptable inert fatty material.
2. A formulation according to claim 1, wherein the drug is a peptide alkaloid.
3. A formulation according to claim 2, wherein the peptide alkaloid is co-dergocrine, dihydroergotamine, epicryptine or 9'-thia-9,10-dihydroergotamine.
4. A formulation according to claim 1, 2 or 3 wherein the swelling substance is a cellulose hydrocolloid.
5. A formulation according to claim 1, 2 or 3 wherein the swelling substance is hydroxypropylmethylcellulose.
6. A formulation according to claim 1, 2 or 3 wherein the fatty material is a hydrophobic material with a melting point between 30 and 90°C.
7. A formulation according to claim 1, 2 or 3 wherein the fatty material is fatty acid ester.
8. A formulation according to claim 1, 2 or 3 wherein the fatty material is a cetyl palmitate.
9. A formulation according to claim 1, 2 or 3 containing 1 to 15 my of ergot alkaloid per unit dosage form.
10. A formulation according to claim 1, 2 or 3 containing of from 2 to 10 mg of co-dergocrine.
11. A formulation according to claim 1, 2 or 3 containing of from 4 to 15 mg of dihydroergotamine.
12. A formulation according to claim 1, 2 or 3 wherein the weight ratio of co-dergocrine to the swelling substance is from 1:10 to 1:50.
13. A formulation according to claim 1, 2 or 3 wherein the weight ratio of dihydroergotamine to the swelling substance is from 1:4 to 1:10.
14. A formulation according to claim 1, 2 or 3 wherein the weight ratio of co-dergocrine to the fatty material is from 1:1 to 1:10.
15. A formulation according to claim 1, 2 or 3 wherein the weight ratio of dihydroergotamine to the fatty material is from 1:0.5 to 1:2.
16. A formulation according to claim 1, 2 or 3 containing hydroxypropylmethylcellulose as a swelling agent and cetyl palmitate as a fatty material.
17. A formulation according to claim 1, 2 or 3 containing the 9,10-dihydro ergot alkaloid in a fatty material matrix granulate, the granulate particles being in contact with a hydrophilic swelling substance.
18. A method for the preparation of a controlled release formulation for oral administration, which comprises mixing a 9,10-dihydro ergot alkaloid drug, a hydrophilic swelling substance and a fatty material.
19. A method according to claim 18, which comprises mixing the drug with the molten fatty material, solidifying and granulating the mixture and mixing the granulate particles with the porous swelling substance.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB858502889A GB8502889D0 (en) | 1985-02-05 | 1985-02-05 | Co-dergocrine compositions |
| GB8502889 | 1985-02-05 | ||
| GB8517604 | 1985-07-12 | ||
| GB858517604A GB8517604D0 (en) | 1985-07-12 | 1985-07-12 | Dihydroergotamine compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1263087A true CA1263087A (en) | 1989-11-21 |
Family
ID=26288767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000501011A Expired CA1263087A (en) | 1985-02-05 | 1986-02-03 | Pharmaceutical 9,10-dihydrogenated ergot alkaloid containing compositions |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS61183225A (en) |
| KR (1) | KR920010388B1 (en) |
| AU (1) | AU597570B2 (en) |
| BE (1) | BE904152A (en) |
| CA (1) | CA1263087A (en) |
| CH (1) | CH667592A5 (en) |
| CY (1) | CY1604A (en) |
| DE (1) | DE3602577A1 (en) |
| DK (1) | DK167138B1 (en) |
| ES (1) | ES8800040A1 (en) |
| FR (1) | FR2576787B1 (en) |
| GB (1) | GB2170407B (en) |
| GR (1) | GR860310B (en) |
| HK (1) | HK57191A (en) |
| HU (1) | HU195729B (en) |
| IE (1) | IE59293B1 (en) |
| IT (1) | IT1191255B (en) |
| LU (1) | LU86289A1 (en) |
| NL (1) | NL8600161A (en) |
| NZ (1) | NZ215020A (en) |
| PH (1) | PH23384A (en) |
| PT (1) | PT81954B (en) |
| SE (1) | SE8600496L (en) |
| SG (1) | SG56191G (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2610827B1 (en) * | 1987-02-18 | 1991-09-13 | Pf Medicament | DIHYDROERGOTAMINE (D.H.E.) TABLET OF THE HYDROPHILIC MATRIX TYPE AND MANUFACTURING METHOD THEREOF |
| YU47044B (en) * | 1987-03-11 | 1994-12-28 | LEK TOVARNA FARMACEVTSKIH IN KEMIČNIH IZDELKOV n.sol.o. | PROCEDURE FOR OBTAINING HIGH-MOLECULAR HYDROXYPROPYL-METHYLCELLULOSE PROLONGED TABLETS |
| MXPA02005291A (en) * | 1999-12-03 | 2004-06-21 | Polichem Sa | Methods for making sustained-release pharmaceutical compositions of ergot alkaloids having improved bioavailability and compositions thereof. |
| US7771746B2 (en) | 1999-12-03 | 2010-08-10 | Polichem Sa | Methods for making sustained-release pharmaceutical compositions of ergot alkaloids having improved bioavailability and compositions thereof |
| NZ504526A (en) * | 2000-05-12 | 2003-05-30 | Meracol Corp Ltd | Treating herpes simplex symptoms using a mixture of cetyl myristate and cetyl palmitate |
| ES2299484T3 (en) | 2000-05-12 | 2008-06-01 | Meracol Corporation Limited | TREATMENT OF THE SYNDROME OR IRRITABLE INTESTINE DISEASE. |
| US20030153620A1 (en) | 2000-05-12 | 2003-08-14 | Meakin Timothy David | Treating eczema and/or psoriasis |
| WO2001085163A1 (en) * | 2000-05-12 | 2001-11-15 | Meracol Corporation Limited | Treating eczema and/or psoriasis |
| WO2003026640A1 (en) * | 2001-09-28 | 2003-04-03 | Meracol Corporation Limited | Treating food allergies and/or food intolerances |
| CN111297815B (en) * | 2020-04-29 | 2022-04-15 | 宝利化（南京）制药有限公司 | Dihydroergotoxine mesylate sustained-release tablet and preparation method thereof |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3147187A (en) * | 1962-09-10 | 1964-09-01 | Don Hall Lab | Sustained release pharmaceutical |
| CH630257A5 (en) * | 1975-03-17 | 1982-06-15 | Hoffmann La Roche | Sustained release formulation |
| DE3124983A1 (en) * | 1981-06-25 | 1983-01-20 | Meditest Inst Fuer Medizinisch | ORAL ADMINISTRATIVE FORMS |
| CH649300A5 (en) * | 1981-08-07 | 1985-05-15 | Sandoz Ag | ERGOPEPTIN DERIVATIVES, THEIR PRODUCTION AND USE. |
| US4369172A (en) * | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
| DE3303616A1 (en) * | 1982-02-12 | 1983-08-25 | Sandoz-Patent-GmbH, 7850 Lörrach | MOTHER CORNAL CALOIDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS |
| US4421736A (en) * | 1982-05-20 | 1983-12-20 | Merrel Dow Pharmaceuticals Inc. | Sustained release diethylpropion compositions |
| JPS604120A (en) * | 1983-06-22 | 1985-01-10 | Shionogi & Co Ltd | Pharmaceutical preparation of pinacidil of long acting type |
| GB2154874B (en) * | 1984-02-29 | 1987-11-04 | Sandoz Ltd | Bromoscriptine compositions |
| GB8413795D0 (en) * | 1984-05-30 | 1984-07-04 | Sandoz Ltd | Organic compounds |
-
1986
- 1986-01-24 NL NL8600161A patent/NL8600161A/en not_active Application Discontinuation
- 1986-01-24 HU HU86361A patent/HU195729B/en not_active IP Right Cessation
- 1986-01-27 CH CH296/86A patent/CH667592A5/en not_active IP Right Cessation
- 1986-01-29 DE DE19863602577 patent/DE3602577A1/en not_active Ceased
- 1986-01-31 FR FR868601477A patent/FR2576787B1/en not_active Expired - Lifetime
- 1986-02-03 PT PT81954A patent/PT81954B/en not_active IP Right Cessation
- 1986-02-03 CA CA000501011A patent/CA1263087A/en not_active Expired
- 1986-02-03 KR KR1019860000698A patent/KR920010388B1/en not_active IP Right Cessation
- 1986-02-03 BE BE1/011431A patent/BE904152A/en not_active IP Right Cessation
- 1986-02-03 AU AU52942/86A patent/AU597570B2/en not_active Ceased
- 1986-02-03 GB GB08602602A patent/GB2170407B/en not_active Expired
- 1986-02-03 NZ NZ215020A patent/NZ215020A/en unknown
- 1986-02-03 IE IE29186A patent/IE59293B1/en not_active IP Right Cessation
- 1986-02-03 DK DK052086A patent/DK167138B1/en not_active IP Right Cessation
- 1986-02-03 GR GR860310A patent/GR860310B/en unknown
- 1986-02-04 LU LU86289A patent/LU86289A1/en unknown
- 1986-02-04 ES ES551635A patent/ES8800040A1/en not_active Expired
- 1986-02-04 JP JP61023666A patent/JPS61183225A/en active Pending
- 1986-02-04 PH PH33379A patent/PH23384A/en unknown
- 1986-02-04 SE SE8600496A patent/SE8600496L/en not_active Application Discontinuation
- 1986-02-05 IT IT47620/86A patent/IT1191255B/en active
-
1991
- 1991-07-16 SG SG561/91A patent/SG56191G/en unknown
- 1991-07-25 HK HK571/91A patent/HK57191A/en unknown
-
1992
- 1992-04-03 CY CY1604A patent/CY1604A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE8600496L (en) | 1986-08-06 |
| KR920010388B1 (en) | 1992-11-27 |
| IE59293B1 (en) | 1994-02-09 |
| AU5294286A (en) | 1986-08-14 |
| CY1604A (en) | 1992-04-03 |
| GB2170407A (en) | 1986-08-06 |
| IE860291L (en) | 1986-08-05 |
| DK167138B1 (en) | 1993-09-06 |
| PT81954A (en) | 1986-03-01 |
| SG56191G (en) | 1991-08-23 |
| NL8600161A (en) | 1986-09-01 |
| IT1191255B (en) | 1988-02-24 |
| GB8602602D0 (en) | 1986-03-12 |
| KR860006265A (en) | 1986-09-09 |
| FR2576787A1 (en) | 1986-08-08 |
| PT81954B (en) | 1988-07-01 |
| GR860310B (en) | 1986-05-27 |
| HUT41984A (en) | 1987-06-29 |
| JPS61183225A (en) | 1986-08-15 |
| GB2170407B (en) | 1988-10-26 |
| HK57191A (en) | 1991-08-02 |
| PH23384A (en) | 1989-07-26 |
| AU597570B2 (en) | 1990-06-07 |
| SE8600496D0 (en) | 1986-02-04 |
| DK52086D0 (en) | 1986-02-03 |
| ES8800040A1 (en) | 1987-10-16 |
| FR2576787B1 (en) | 1990-01-12 |
| IT8647620A0 (en) | 1986-02-05 |
| CH667592A5 (en) | 1988-10-31 |
| ES551635A0 (en) | 1987-10-16 |
| DE3602577A1 (en) | 1986-08-28 |
| DK52086A (en) | 1986-08-06 |
| LU86289A1 (en) | 1986-09-02 |
| NZ215020A (en) | 1989-07-27 |
| BE904152A (en) | 1986-08-04 |
| HU195729B (en) | 1988-07-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |