CY1330A - Galenical compositions - Google Patents

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Publication number
CY1330A
CY1330A CY1330A CY133079A CY1330A CY 1330 A CY1330 A CY 1330A CY 1330 A CY1330 A CY 1330A CY 133079 A CY133079 A CY 133079A CY 1330 A CY1330 A CY 1330A
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CY
Cyprus
Prior art keywords
composition according
enteric
coating
sterol
poiyalkoxyalkylene
Prior art date
Application number
CY1330A
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Sandoz Ltd
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Publication of CY1330A publication Critical patent/CY1330A/en

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

1
GB 2 038 181 A
1
SPECIFICATION Galenical compositions
5 The invention provides a galenical compositions for oral application of ergot alkaloids which are characterised by a prolonged effect and a good bioavailability of the active agent.
It is undisputed amongst medicinal specialists, 10 that under many circumstances it is preferred to apply a drug once a day instead of more times a day. This may be achieved in so-called "retard systems" by retarding and delaying the release of the active agent, with the aim of producing a longer duration of 15 the therapeutic effect In the field of the ergot therapy, a retardation with classical systems, e.g. with a matrix system or with the aid of microencapsulation, induces each time an important decrease of the total bioavailability.
20 It is also known, that ergot alkaloids are stable in the presence of acids, which means that they do not disintegrate in the gastric juices, and that the resorption of ergot alkaloids takes place mainly in the intestinal tract. Enteric coated drugs containing an ergot 25 alkaloid are therefore not expected to provide an improved bioavailability.
It is therefore surprising that with the aid of an enteric coating one observes that the duration of action of an ergot alkaloid is not only significantly 30 prolonged but that, moreover, the total bioavailability is notably improved when the coated core contains, in addition to the ergot alkaloid, a polyalkox-yalkylene sterol ether.
The invention therefore provides, more specifi-35 cally, a solid enteric-coated composition for oral application, the core of the composition containing an ergot alkaloid and a poiyalkoxyalkylene sterol ether.
The invention also provides a process for the pro-40 duction of compositions according to the invention, by enteric coating a core comprising an ergot alkaloid and a poiyalkoxyalkylene sterol ether (hereinafter designated sterol ether).
The term "core" comprises any mixture of an 45 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" comprises, in a wide sense, not only tablets, pellets or granules but also capsules, e.g. 50 soft or hard gelatine capsules 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 55 they have preferably a hardness of from ca 10 to ca
•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 applica-60 tions of the compositions according to the invention are therefore tablets, pellets, granules or capsules.
The term "ergot alkaloids" comprises natural ergot alkaloids such as ergotamine, ergocristine, a-ergocryptine, /3-ergocryptine and ergocomine, 65 synthetic or semi-synthetic derivatives thereof such as ergovaline, dihydroergotoxine (also known as co-dergocrine) and dihydroergotamine in free base form or in the form of an acid addition salt with pharmaceutically acceptable organic or inorganic 70 acids such as methanesuphonic, maleic, tartaric or hydrochloric acid.
The acitve agents which are of special interest for use in the invention, are compounds of formula I
wherein
Ri is hydrogen or halogen,
85 R2 is hydrogen or C1_4alkyl,
R3 is isopropyl, sec.-butyl, isobutyl or benzyl, R4 is methyl, ethyl or isopropyl, and either
Rs is hydrogen and 90 R6 is hydrogen or methoxy or
R5 and Rs together are an additional bond, or mixtures thereof.
When R, is halogen, it is preferably bromine. 95 Especially preferred compositions of the invention contain dihydroergotoxine, bromocryptine or dihydroergotamine in free base form or, preferably, in acid addition salt form as active agent.
Preferred sterol ethers for use in the compositions 100 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 105 ethers. Especially suitable sterol ethers are sterols etherified with an average of 8 to 75, preferably 9 to 30 alkylene oxide units. The hydroxy group in the end alkylene unit of such sterol ethers may be partially or completely acylated, e.g. by acyl radicals of 110 aliphatic carboxylic acids, such as acetyl. Especially preferred are sterol ethers etherified with ethylene oxide and/or propylene oxide units.
manner by etherifying the sterol with the corresponding amount of epoxide and optionally acylating 115 the so obtained alcohols. They are in general available on the market and are e.g. offered for sale by the firm Amerchol underthe trade name Soluian®. Examples of Soluian® types which are available on the market and are suitable for use in the composi-120 tions according to the invention are such obtainable by alkoxylation of e.g.
a) 1 mol cholesterin with about 24 mol ethylene oxide (Soluian® C-24)
b) 1 equivalent of lanolinalcohols with about 16 125 equivalents ethylene oxide (Soluian® 16)
c) 1 equivalent of lanolinalcohols with about 25 equivalents ethylene oxide (Soluian® 25)
d) 1 equivalent of lanolinalcohols with about 75 equivalents ethylene oxide (Soluian® 16)
130 e) 1 equivalent of lanolinalcohols with about 10
BNSDOCID: <GB_
i 2038181A l_>
2
GB 2 038 181 A
2
equivalents propylene oxide (Soluian® PB-10) and also the f) partially acetyiated derivative of 1 equivalent of lanolinalcohols ethoxylated with about 10 equivalents ethylene oxide (Soluian® 98) and the g) completely acetyiated derivative of 1 equivalent of lanolinalcohols ethoxylated with about 9 equivalents ethylene oxide (Soluian® 97)
The term "about" in 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 ethyleneoxy- or propyleneoxy-groups.
Lanolinalcohols are also known as wool fat alcohols (Handbuch derKosmetika und riechstoffe, 2. Ed. 1950, Vol. I, page 1101 (Janistyn)) and area mixture of i.e. cholesterin, dihydrocholesterin and fanosterol.
The term "enteric coating" comprises any pharmaceutically acceptable coating preventing the release of the active agent in the stomach and sufficiently disintegrating in the intestinal tract (by contact with approximately neutral or alkaline intestine juices) to allow the resorption of the active agent through the walls of the intestinal tract Various in vitro tests for determining whether or not a coating is classified as an enteric coating have been published in the pharmacopoeia of various countries.
More specifically, the term "enteric coating" according to the invention refers to a coating which remains intact for at least 1 hour, e.g. 2 hours, in contact with artificial gastric juices such as HC1 of pH 1.2 at 36 to 38°C 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 may 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 fim, preferably 20-80 yxm, thickness. The coating is suitably selected from macromolecular polymers. Suitable polymers are listed in e.g. Hagers 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 comprisee.g. cellulose ester derivatives, cellulose ethers, acrylic resins, such as methylacrylate copolymers and copolymers of maleic acid and phthalic acid derivatives.
The preferred films are made from cellulose acetate phthalate; copolymers derived from methylac-rylic acid and esters thereof, containing at least 40% methylacrylic acid; and especially hydroxypropyl methylcellulose phthalate. An example of an appropriate cellulose acetate phthalate is the marketed product CAP (Eastman Kodak, Rochester N.Y., USA). Examples of suitable hydroxypropyl methyl cellulose phthalates are the marketed products HP 50 and HP 55 (Shinetsu, Tokyo, Japan).
EXAMPLE 1
Tablet cores consisting of 3 g dihydroergotamine, 75 g cholesterin which is ethoxylated with about 24 ml ethylene oxide (Soluian® (C-24)) and 22g disperse silicage! are heated to 30° during 10 minutes with the
BNSDOCID: <GB 2038181A_I_>
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 methylcejlulose phthalate (HP50) and 1.35 g di-n-butylphthalate in a 1:1 ethanol/acetone mixture, at a spray pressure of 1-1.5 bar using conventional interval spray coating procedures, and the so obtained coated tablets are then dried.
EXAMPLE2
One proceeds anafogous to Example 1, uses, however, 75 g lanolin alcohols ethoxylated with about 25 equivalents ethylene oxide (Soluian® 25) instead of 75 g cholesterin ethoxylated with about 24 mol ethylene oxide.
EXAMPLE 3—Coated tablets with cores in so/id solution form
15 g Dihydroergotoxine methanesulphonate, 1.05 g (Soluian® C-24), 33.95 g polyvinylpyrrolidone (average molecular weight 25,000) and 250 ml methanol are charged into a 1 litre round-bottomed flask. The flask is attached to a rotary evaporator and rotated at a bath temperature of 60° until the flask contents reach 60°, by which time a clear solution is obtained.
The bath temperature is maintained at 60° and the solvent evaporated 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 Torrfor ca. 12 hours, ground to a fine powder and dried again.
26.8 g of the so obtained solid solution are then mixed with the following adjuvants:
silicium dioxide
1.0 g
(Aerosil® 200, Degussa)
polyvinylpyrrolidone
8.0 g
(crosslinked)
com starch
20.0 g
Talc
30.0 g
Soluian® C-24
30.0 g cellulose granules
42.0 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 obtained cores are then, analogous to Example 1, sprayed with a solution of cellulose acetate
phthalate (CAP)
90.0g di-n-butylphthalate
22.5 g acetone
240.0 g ethanol
21.0 g dichloromethane
526.5 g
900.0 g until the cores are coated with ca. 10 mg of the cellulose acetate phthalate/di-n-butylphthalate mixture per core.
3
GB 2 038 181 A 3
The so obtained coated tablets are resistant against the gastric juices since the cores remain intact after a treatment of 1 hour with artificial gastric juices of pH = 1.2. The disintegration time in artificial 5 intestine juices is atpH 5.5 longerthan 1 hour, and lies at pH 6.0 between 23-28 minutes and at pH 6.8 between 12 and 16 minutes.
EXAMPLE 4
One proceeds analogous to Example 3, spraying, ■10 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 ethanoland 616 g acetone, until the cores are coated with ca. 9 mg of the hydroxypropyl methyl-15 cellulose phthalate/di-n-butylphthalate mixture (ratio 10:2) per core.
EXAMPLE 5
Analogous to Example 3 is obtained a solid solution of4g dihydroergotoxine methanesulphonate, 20 0.3 g Soluian® 16 and 9.1 g polyvinylpyrrolidone (average mol weight 2000).
This solid solution is then mixed with silicion dioxide 0.5 g polyvinylpyrrolidone 4.0 g
25 (average mol weight 2000)
cornstarch 10.0 g talc 15.0 g
Soluian® 16 15.0 g cellulose granules 21.0 g
30 (Elcema G 250)
lactose 61.1 g and this mixture pressed to tablets of 140.0 mg.
The so obtained tablet cores are then sprayed, analogous to Example 4, until each core is coated 35 eitherwith ca 10 mg or with ca 15 mg of the mixture ; hydroxypropyl methylcellulose phthalate/di-n-butylphthalate.
Analogous to the procedure described in the above Examples are obtained the tablets as listed 40 below in Table I.
In cases lb and Ic (see table) are used, the tablet cores are in solid solution form.
EXAMPLE
8
10
11
12
13
la
Dihydroergot-oxinemesylate Dihydroergot-oxinemesylate Soluian® C24 Polyvinylpyrrolidone Soluian® C24 Silicion dioxide corn starch Cellulose lactose
Magnesium stearate Kollidon CE 5050 Polyvinyl-pyrolidone (25)
talc
HPMCP* ;Di-n-butylphthalate ;4.0 ;0.3 ;9.1 15.0 2.4 24.0 72.0 110.8 2.4 ;26.0 ;4.0 ;0.3 ;9.1 15.0 2.4 24.0 72.0 110.8 2.4 ;7.0 ;4.0 ;0.3 ;9.1 31.7 0.5 10.0 21.0 44.4 ;4.0 ;7.2 1.8 ;4.0 ;0.3 ;9.1 7.3 0.5 10.0 21.0 68.8 ;4.0 ;15.0 9.0 ;4.0 ;0.3 ;9.1 23.7 0.5 10.0 21.0 52.4 ;4.0 ;15.0 9.0 ;4.0 ;15.3 0.5 10.0 ;21.0 ;61.1 ;4.0 ;9.1 15.0 ;9.0 ;6.0 ;22.9 3.6 36.0 108.0 166.4 3.6 ;13.5 ;7.2 1.8 ;6.0 0.4 ;13.5 22.5 3.6 36.0 108.0 166.4 3.6 ;7.2 1.8 ;total weight (mg) 266.0 ;* HPMCP = Hydroxypropyl methylcellulose phthalate
(1) the cores of these tablets were pressed to possess EXAMPLE 14: Tablet with an outer medicament layer (Mantle tablet)
45 a) The cores are prepared analogous to Example 3 by mixing 26.8 g of a solid solution (consisting of 8.0 g dihydroergotamine mesylate, 0.6 g Soluian® C-24 and 18.2 g polyvinylpyrrolidone) togetherwith 1.0 g highly disperse silicagel, 8.0 g crosslinked polyvinyl-50 pyrrolidone, 20 g corn starch, 47.4 g Soluian® C-24, 42.0 g cellulose granules, 104.8 g lactose and 30.0 g talc until the mixture is homogenous. The mixture is then pressed to cores of 140.0 mg.
b) The so obtained cores are sprayed with a solu-55 tion of 140.0 g hydroxypropyl methylcellulose phthalate and 28.0 g di-n-butylphthalate in a mixture of 616 g ethanol and 616 g acetone, until the cores are coated with ca. 10 mg per tablet.
247.0
149.0
149.0
149.0
149.0
(1) 369.0
(1) 369.0
a hardness of 50-60N
c) The outer medicament layer is prepared by mix-60 ing 4.0 g dihydroergotamine mesylate with 4.0 g disperse silica-gel, 6.0 g magnesium stearate, 166.8 g cellulose powder, 40.0 g talc, 191.2 g corn starch and 348.0 g calcium hydrogen phosphate until the mixture is homogenous. This mixture is then pres-65 sed with the coated tablets (according to Example 14b) to prepare tablets with an outer medicament layer, having a total weight of 530.0 mg per tablet. EXAMPLE 15 One proceeds analogous to any one of Examples 1 70 to 14, using 4 mg bromocryptine, 4 mg dihydroer-govaline or 4 mg dihydroergonine instead of dihydroergotoxine or dihydroergotamine, and obtains tablets containing the corresponding ergot alkaloid as active agent.
BNSDOCID: <GB 2038181 A_
4
GB 2 038 181 A
4
EXAMPLE 16: Clinical trial 5 position of dihydroergotoxine mesylate (composi-
The composition according to Example 4 was tion B).
compared with a solid solution of dihydroergotoxine Each person treated obtained 4 mg dihydroer-
mesyiate (composition A) and a conventional com- gotoxine mesylate.
The result is listed in the following table.
Composition
Example 4
A
B
Concentration in Plasma after 20'
40'
Max. conc. in plasma (ng.ml~1) Time (in hours) after which max. is reached
0.047+0.012 0.092+0.039 0.615+0.077
3.33+0.48
0.376± 0.078 0.472 +0.070 0.507 ±0.071
0.64+0.06
0.215+0.064 0.506+0.049 0.538±0.037
0.78±0.12
Bioavailability AUC (0-24 hours)
(ng, ml-1) % eliminated by urine (0.96 hours)
4.778+0.415 1.010+0.154
3.875+0.279 0.787+0.121
3.754±0.171 0.740±0.081
1 o The good retarding effect and the excellent bioavailability of the composition according to the invention is clearly illustrated by the figures in the above table. On the other hand, we found a clearly inferior bioavailability (60-70% of composition B) 15 when testing a marketed composition of dihydroer-gotoxin retarded according to conventional manner.
Analogous test with other compositions according to the invention give similar good results. Additionally, a marketed composition of dihydroergotamine 20 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 (29)

25 CLAIMS
1. A solid enteric-coated composition for oral application, the core of the composition containing an ergot alkaloid and a poiyalkoxyalkylene sterol ether.
30
2. A composition according to Claim 1 wherein the ergot alkaloid is a compound of formula I,
40 wherein
R, is hydrogen or halogen,
R2 is hydrogen or alkyl,
R3 is isopropyl, sec.-butyl, isobutyl or benzyl, R4 is methyl, ethyl or isopropyl, and 45 either
R5 is hydrogen and
R6 is hydrogen or methoxy or
Rs and Re together are an additional bond, or 50 mixtures thereof.
: <GB 2038181 A_l_>
3. A composition according to Claim 1 and 2 wherein the ergot alkaloid is dihydroergotamine.
4. A composition according to Claim 1 and 2 wherein the ergot alkaloid is dihydroergotoxine.
55 5. A composition according to Claim 1 and 2 wherein the ergot alkaloid is bromoergocryptine.
6. A composition according to anyone of Claims 1 to 5 wherein the poiyalkoxyalkylene sterol ether has an hydrophilic-lipophilic balance of from 10 to
60 20.
7. A composition according to Claim 6 wherein the poiyalkoxyalkylene sterol ether has a hydrophilic-lipophilic balance of from 12 to 16.
8. A composition according to anyone of claims 65 1 to 7 wherein the sterol part of the poiyalkoxyalkylene sterol ether is lanosterol, dihydrocholesterin and/or cholesterin.
9. A composition according to any one of Claims 1 to 8, wherein the poiyalkoxyalkylene sterol ether is
75 a sterol etherified with aboutSto 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.
80 11. A composition according to any of Claims 1 to 10 wherein the poiyalkoxyalkylene sterol ether, is a sterol etherified with ethylene oxide or propylene oxide.
12. A composition according to any of Claim 1 to 85 11 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 90 the enteric-coating is of cellulose acetate phthalate.
14. A composition according to Claim 12 wherein the enteric-coating is of hydroxypropyl methylcellulose phthalate.
15. A composition according to Claim 12 wherein 95 the enteric-coating is of methylacrylic acid and esters thereof, containing at least 40% methylacrylic acid.
5
GB 2 038 181 A
5
16. A composition acco rding to any one of Claims 1 to 15 wherein the enteric-coating contains a softener.
17. A composition according to Claim 16 wherein
* 5 the softener is di-n-butylphthalate.
18. A composition according to any one of Claims 1 to 17 in the form of tablets, granules, pellets or capsules.
19. A composition according to Claim 18 in tablet
10 form wherein the tablet additionally has an outer medicament layer surrounding the enteric-coating.
20. A composition according to any one of Claims 1 to 19 wherein the weight ratio ergot alkaloid poiyalkoxyalkylene sterol ether is from 1:1
15 to 1:25.
21. A composition according to Claim 20,
wherein the weight ratio ergot alkaloid : poiyalkoxyalkylene sterol ether is from 1:2 to 1:8.
22. A composition according to any one of
20 Claims 1 to 21 wherein the core is in solid solution form.
23. A composition according to Claim 22 wherein the core contains a polyalkylene glycol, polyvinylpyrrolidone and/ora copolymer of vinylpyrrolidone
25 and vinyl acetate as solid solvent.
24. A composition according to Claim 23,
wherein the weight ratio within the core of ergot alkaloid : poiyalkoxyalkylene sterol ether: solid solvent lies in the range 1:1-10:0.1-10.
30
25. A composition according to Claim 24 wherein the weight ratio lies in the range 1:2-8 : 0.1-10.
26. A composition according to Claim 25 wherein the weight ratio lies in the range 1:2-5: 0.1-5.
27. A composition according to any one of
35 Claims 22 to 26 wherein the core contains a stabilizer.
28. A composition according to Claim 27,
wherein the core is stabilised by adjusting its pH,
with an acid, at pH 4-6.
40
29. Process for the production of a composition as defined in any one of the preceding claims characterised by enteric-coating a core comprising an ergot alkaloid and a poiyalkoxyalkylene sterol ether.
30. Process according to Claim 29, wherein the
45 enteric-coating is applied in conventional manner.
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
50 in that the cores, before spraying, are warmed up at
25° up to 40°.
, Printed forHer Majesty's Stationery Office by The Tweeddale Press Ltd., Berwick-upon-Tweed, 1380.
Published at the Patent Office, 25 Southampton Buildings, London, WC2A1 AY, from which copies may be obtained.
BNSDOCID: <GB 2038181 A_J_>
CY1330A 1978-12-21 1979-12-19 Galenical compositions CY1330A (en)

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Application Number Priority Date Filing Date Title
CH1302178 1978-12-21
CH1301978 1978-12-21
CH56779 1979-01-19
CH56679 1979-01-19

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AU (1) AU534051B2 (en)
CA (1) CA1139222A (en)
CH (1) CH642259A5 (en)
CY (1) CY1330A (en)
DE (1) DE2950154A1 (en)
DK (1) DK154607C (en)
FI (1) FI793888A7 (en)
FR (1) FR2444463A1 (en)
GB (1) GB2038181B (en)
HK (1) HK37986A (en)
HU (1) HU182577B (en)
IE (1) IE49323B1 (en)
IL (1) IL59003A (en)
IT (1) IT1164029B (en)
KE (1) KE3617D (en)
MY (1) MY8500129A (en)
NL (1) NL187229C (en)
NZ (1) NZ192457A (en)
PH (1) PH25178A (en)
PT (1) PT70614A (en)
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Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE14379T1 (en) * 1981-04-27 1985-08-15 Haessle Ab PHARMACEUTICAL PREPARATION.
US4366145A (en) * 1981-06-24 1982-12-28 Sandoz, Inc. Soft gelatin capsule with a liquid ergot alkaloid center fill solution and method of preparation
HU192050B (en) * 1983-04-22 1987-05-28 Sandoz Ag Process for production of medical preparative containing co-dergocrin and one piridin-dicarbonic acid diesthertype calcium-antagonist
DE3413955A1 (en) * 1983-04-22 1984-10-25 Sandoz-Patent-GmbH, 7850 Lörrach Pharmaceutical product containing co-dergocrine and a calcium antagonist
HU198844B (en) * 1984-06-14 1989-12-28 Sandoz Ag Process for producing new galenic pharmaceutical composition ensuring retarded release of active ingredient
GB8426922D0 (en) * 1984-10-24 1984-11-28 Sandoz Ltd Galenic formulation
AT388101B (en) * 1985-02-05 1989-05-10 Sandoz Ag Process for the production of a pharmaceutical composition for oral administration with controlled release of active ingredient
CN1003978B (en) * 1987-09-05 1989-04-26 广州陈李济药厂 Preparation process of spleen-tonifying and intestine-benefiting pills

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3432593A (en) * 1963-09-18 1969-03-11 Key Pharm Inc Delayed and sustained release type pharmaceutical preparation
DE2528257C2 (en) * 1974-07-04 1986-02-13 Sandoz-Patent-GmbH, 7850 Lörrach New galenic preparation
DE2546577B2 (en) * 1975-10-17 1981-04-02 Sandoz-Patent-GmbH, 7850 Lörrach Solid substances made from polyvinylpyrrolidone and ergot alkaloids

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IT7951153A0 (en) 1979-12-20
FR2444463B1 (en) 1983-02-25
FR2444463A1 (en) 1980-07-18
NZ192457A (en) 1983-06-17
NL187229C (en) 1991-07-16
AU534051B2 (en) 1984-01-05
PT70614A (en) 1980-01-01
HK37986A (en) 1986-05-30
PH25178A (en) 1991-03-27
NL7909105A (en) 1980-06-24
KE3617D (en) 1986-04-18
IL59003A (en) 1982-12-31
IE792471L (en) 1980-06-21
WO1980001242A1 (en) 1980-06-26
DK529879A (en) 1980-06-22
HU182577B (en) 1984-02-28
DE2950154C2 (en) 1989-05-11
SE442265B (en) 1985-12-16
MY8500129A (en) 1985-12-31
CA1139222A (en) 1983-01-11
IT1164029B (en) 1987-04-08
AU5403179A (en) 1980-06-26
ATA803679A (en) 1983-02-15
GB2038181B (en) 1983-05-11
DE2950154A1 (en) 1980-07-10
FI793888A7 (en) 1981-01-01
DK154607B (en) 1988-12-05
DK154607C (en) 1989-06-05
IE49323B1 (en) 1985-09-18
GB2038181A (en) 1980-07-23
AT372279B (en) 1983-09-26
SE7910227L (en) 1980-06-22
CH642259A5 (en) 1984-04-13

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