WO1980001242A1 - Preparations galeniques - Google Patents

Preparations galeniques Download PDF

Info

Publication number
WO1980001242A1
WO1980001242A1 PCT/CH1979/000160 CH7900160W WO8001242A1 WO 1980001242 A1 WO1980001242 A1 WO 1980001242A1 CH 7900160 W CH7900160 W CH 7900160W WO 8001242 A1 WO8001242 A1 WO 8001242A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation according
coating
core
ergot alkaloid
cores
Prior art date
Application number
PCT/CH1979/000160
Other languages
German (de)
English (en)
Inventor
J Franz
Original Assignee
Sandoz Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of WO1980001242A1 publication Critical patent/WO1980001242A1/fr

Links

Classifications

    • 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

Definitions

  • the invention relates to pharmaceutical preparations for oral application of ergot alkaloids which are characterized by a prolonged action and good bioavailability.
  • ergy compounds are acid stable, i.e. are not broken down in gastric juice and that the absorption of ergot alkaloids takes place predominantly in the intestinal tract.
  • bioavailability of ergot alkaloids can be influenced favorably by means of a stomach-resistant coating.
  • the invention therefore relates, more specifically, to a preparation provided with an enteric coating for oral application, the core of which is an ergot alkaloid and contains a polyalkoxyalkylene sterol ether.
  • the preparations are obtained according to the invention by providing a core which contains an enteric coating in ergot alkaloid and a polyalkoxyalkylene sterol ether (hereinafter referred to as sterol ether).
  • core encompasses any mixture of an ergot alkaloid and a sterol ether, optionally with other physiologically compatible auxiliaries, which can be covered with a stomach-resistant coating. It follows that the term “core”, in the broadest sense, not only tablets, pellets and granules, but also capsules, e.g. Soft gelatin capsule or hard gelatin capsule filled with a liquid or wax-like mixture of an ergot alkaloid, a sterol ether and optionally pharmacologically acceptable excipients. Such capsules can then be coated with an enteric film, for example analogously to known methods. If tablet cores are used, they preferably have a hardness of approximately 10 to approximately 70N.
  • the pellets or granules can be used as such or in capsules, e.g. Hardgelatin capsules are filled. Suitable forms of use of the preparations according to the invention are therefore tablets, pellets, granules or capsules.
  • ergot alkaloids encompasses natural ergot alkaloids such as ergotamine, ergocristin, ⁇ -ergocryptin, ⁇ -ergocryptin and ergocornin, synthetic or semi-synthetic derivatives thereof such as ergovalin, dihydroergotoxin (also known as co-dergocrin) and dihydroergotamine in free form or in the form their salts with pharmacologically acceptable organic or inorganic acids such as methanesulfonic acid, maleic acid, tartaric acid or hydrogen chloride.
  • the active ingredients to be administered in particular are compounds of the formula I
  • R 1 is hydrogen or halogen
  • R 2 represents hydrogen or an alkyl group with 1-4 carbon atoms, isopropyl, sec-butyl, isobutyl or benzyl,
  • R 4 represents methyl, ethyl or isopropyl, represents hydrogen, and represents hydrogen or methoxy, or
  • R 5 and R 6 together form a further bond or mixtures thereof.
  • R 1 is halogen, it is preferably bromine.
  • Particularly preferred embodiments of the present invention contain dihydroergotamine, bromocryptin or dihydroergotoxin in free form or preferably in salt form as the active ingredient.
  • the hydroxy substituent of the last alkylene part of such sterol ethers can optionally be partially or completely acylated, for example with an acyl residue of an aliphatic carboxylic acid such as acetyl.
  • Sterol ethers which are etherified with ethylene oxide or propylene oxide are particularly preferred.
  • the sterol ethers can be obtained by etherification of the sterol with the appropriate amount of epoxide and, if appropriate, subsequent acylation of the hydroxy ethers thus obtained.
  • Solulan ® Some of them are commercially available and are sold, among others, by the Amerchol company under the name Solulan ® . Examples of Solulan ® types that are commercially available and in the preparations according to the invention
  • Can be used are those which are obtained by alkoxylation of a) 1 mol of cholesterol with an average of 24 mol of ethylene oxide (Solulan ® C-24) b) 1 equivalent of lanolin alcohols with an average of 16 equivalents of ethylene oxide (Solulan ® 16) c) 1 equivalent of Lanolin alcohols with an average of 25 equivalents of ethylene oxide (Solulan ® 25) d) 1 equivalent of lanolin alcohols with an average of 75 equivalents of ethylene oxide (Solulan ® 75) e) 1 equivalent of lanolin alcohols with an average of 10 equivalents of propylene oxide (Solulan ® PB-10) or through f) partial acetylation of the reaction product of
  • average in connection with the specification of the equivalent amount of alkylene oxide which can be converted or is converted per mole of sterol means that the stated amount represents an average value, i.e. that a mixture of sterol ethers may be present, some of which carry more, and some less alkyleneoxy groups.
  • Lanolin alcohols are also known as wool fatty alcohols (Handbook of Cosmetics and Fragrances, 2nd Ed. 1950, Vol. I, page 1101 (Janistyn) and are a mixture of cholesterol, dihydrocholesterol and lanosterol, among others.
  • enteric coating includes any pharmacologically acceptable coating which prevents the release of the active ingredient in the stomach when the preparation passes through the stomach and which is sufficiently disintegrated in the intestinal tract (through contact with the approximately neutral to alkaline intestinal juices) to allow the active ingredient to be absorbed by the Allow walls of the intestinal tract.
  • the expression gastric juice-resistant coating in the sense of the invention comprises a coating which remains intact for at least 1 hour, for example 2 hours, in artificial gastric juices such as a hydrogen chloride solution of pH 1.2 and at a temperature of 36 to 38 ° C. and which subsequently remains in artificial intestinal juices, for example in a pH 6.8 buffered solution with KH 2 PO 4 , is dissolved within 30 minutes.
  • the thickness of the film depends on Degree of permeability of the film for water and acid and the desired retarding effect. In general, satisfactory results are obtained with a film thickness of 5-100 ⁇ m and in particular of 20-80 ⁇ m.
  • the film expediently consists of a macromolecular polymer.
  • Suitable polymers are listed, for example, in Hager's Handbook of Pharmaceutical Practice, 4th edition, vol. 7a, pages 739-742 and 776-778, and in Remingtons' Pharmaceutical Sciences, 13th edition, pages 1689-1691, and include in particular cellulose ester derivatives, Cellulose ethers, acrylic resins, such as methacrylate copolymers, and copolymers of maleic acid and derivatives of phthalic acid.
  • Preferred films are made from cellulose ethers such as cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate, and from copolymers of methacrylic acid and its esters, which contain at least 40% methacrylic acid.
  • cellulose ethers such as cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate
  • copolymers of methacrylic acid and its esters which contain at least 40% methacrylic acid.
  • methacrylic acid and its esters which contain at least 40% methacrylic acid.
  • An example of a suitable cellulose acetate phthalate is CAP (trade name), marketed by Eastman Kodak, Rochester N.Y., USA.
  • suitable hydroxypropylmethyl cellulose phthalates include the commercial products HP50 and HP55 distributed by Shinetsu, Tokyo, Japan.
  • the method according to the invention can be carried out analogously to methods known for applying a coating.
  • a coating For the production of coated tablets, pellets or granules, one proceeds, for example, by spraying the cores with a solution of the film-forming material.
  • Suitable solvents for the film-forming material are, for example, organic solvents, for example an alcohol such as ethanol, a ketone such as acetone, a halogenated hydrocarbon such as CH 2 Cl 2 or solvent mixtures such as ethanol / acetone 1: 1.
  • a plasticizer such as di-n-butyl phthalate is expediently added to the solution.
  • the cores are expediently heated to 25 to 40 ° C. before spraying, for example by means of warmer air from 40 to 70 ° C.
  • the spraying process is advantageously interrupted at certain time intervals and the cores warmed up again.
  • the spray pressure can vary, generally good results are obtained with a spray pressure of 1 to 1.5 bar.
  • the spraying process can also be carried out without interrupting the working process, for example by automatically regulating the spray quantity as a function of the exhaust air or core temperature.
  • the forms according to the invention provided with an enteric coating are characterized in that after po administration to humans, the maxima of the active substance concentration in the plasma are only reached about 4-6 hours after the application, while the initial peak after administration of a normal tablet already after 0. 5 - 1 hour occurs.
  • the retarding effect achieved is also evident in the determination of the amount excreted in the urine: after application of the form according to the invention, the maximum rate of excretion with urine is shifted from about 2 to 6 hours compared to a normal tablet.
  • the plasma levels after application of Form according to the invention between 6 and 24 hours higher than after application of a normal tablet. This is based on the area under the plasma level (AUC) and is a measure of the excellent bioavailability which is achieved with the preparations according to the invention.
  • the dosage form according to the invention accordingly leads to a therapeutically desired sustained release effect, which allows a single application per day. This increases the patient's comfort of use and the level of safety.
  • the forms provided with an enteric coating can additionally be coated with an outer layer of active substance.
  • this outer active ingredient layer contains e.g. an ergot alkaloid that is soluble or dispersible in the gastric juices and / or fillers, such as talc, microcrystalline cellulose, magnesium stearate, mannitol, polyvinylpyrrolidone, etc.
  • the active ingredient is rapidly absorbed through the stomach walls, initially having a high concentration of the active ingredient in the bloodstream is achieved.
  • the level of the active substance blood level is maintained by the delayed release of the active substance from the tablet core in the neutral or alkaline juices of the intestinal tract.
  • the optimal weight ratio of ergot alkaloid: sterol ether in the cores depends to a large extent on the physical properties of the sterol ether, the auxiliaries used and the type and size of the chosen administration form.
  • sterol ethers of the type ® Solulan 16, Solulan 25 and Solulan ® ® C-24 is not due to its waxy nature in unlimited Quantity tablettable.
  • the range 1: 2 to 1: 8 is particularly preferred if the cores are used in the form of a solid solution of ergot alkaloid, in particular if polyvinylpyrrolidone is used as the solid solvent.
  • auxiliaries such as binders, lubricants, fillers and wetting agents are processed in the cores.
  • An ergot alkaloid is mixed with a sterol ether and a pharmaceutically acceptable polymer which is at least slightly soluble in an aqueous medium, in particular one or more polyalkylene glycols.
  • a pharmaceutically acceptable polymer which is at least slightly soluble in an aqueous medium, in particular one or more polyalkylene glycols.
  • Suitable polyalkylene glycols include inter alia polyoxyethylene or polyoxypropylene polymers and their copolymers with a molecular weight of 200 to 20,000, in particular 4,000 to 15,000, preferably 6,000 to 13,000.
  • Polyvinylpyrrolidone means uncrosslinked poly-nvinylpyrrolidone-2 compounds with molecular weights of 10,000 to 100,000, in particular 11,500 to 40,000, preferably 20,000 to 30,000.
  • the copolymers of vinyl pyrrolidone and vinyl acetate preferably consist of approximately 60 parts by weight of vinyl pyrrolidone and 40 parts by weight of vinyl acetate and preferably have a molecular weight of 30,000 to 100,000, in particular 40,000 to 90,000.
  • additives requiring stability such as acids, in particular methanesulfonic acid, maleic acid, tartaric acid, are added.
  • the preferred pH of the preparation is between 4 and 6, in particular between 4 and 5.
  • the weight ratio ergot alkaloid: sterol ether: to polyalkylene glycols and / or polyvinylpyrrolidone and / or copolymers of vinyl acetate and vinylpyrrolidone used can vary between wide limits; in general, however, good results are achieved with ratios which vary between 1: 1-10: 0.1-10, in particular between 1: 2-8: 0.1-10, preferably between 1: 2-5: 0.1-5 .
  • the polymers are used in solid form to prepare the solid solution. If one of the polymers, for example a polyalkylene glycol with a molecular weight of about 200, which is liquid at room temperature, is used to produce the solid, it goes without saying that this is not used alone, but together with a solid polymer.
  • one of the polymers for example a polyalkylene glycol with a molecular weight of about 200, which is liquid at room temperature, is used to produce the solid, it goes without saying that this is not used alone, but together with a solid polymer.
  • a suitable solvent for example a lower alcohol, for example ethanol or methanol or chloroform
  • a suitable solvent for example a lower alcohol, for example ethanol or methanol or chloroform
  • the solvent is then removed in vacuo at temperatures from 30 to 70 ° C., preferably 40 to 60 ° C.
  • a suitable solvent for example a lower alcohol, for example ethanol or methanol or chloroform
  • the solvent is then removed in vacuo at temperatures from 30 to 70 ° C., preferably 40 to 60 ° C.
  • the resulting clear liquid is allowed to solidify at room temperature (15-25 ° C).
  • the product obtained is ground to a fine powder and in vacuo at about 30 ° C. dried until the solvent is completely removed.
  • the solid solution obtained by the above process (core of the administration form) is processed together with pharmacologically acceptable auxiliaries and, if appropriate, further portions of the sterol ether in a manner known per se.
  • the proportion of sterol ether added here, but also during the previous operation, should overall remain within the numerical limits above.
  • Tablet cores consisting of 3 g dihydroergotamine, 75 g cholesterol (Solulan ® C-24) ethoxylated with approx. 24 mol ethylene oxide and 22 g disperse silicic acid are in a coating pan with repeated turning of the cup, by means of supply air from 50 ° for 10 minutes to approx. 30 ° warmed.
  • the tablet cores are then covered with a. Solution of 5.4 g of hydroxypropylmethyl cellulose phthalate (HP-50) and 1.35 g of di-n-butyl phthalate in an ethanol / acetone mixture 1: 1, using a hand spray gun and at a spray pressure of 1-1.5 bar, by means of known interval spraying method, sprayed.
  • the coated tablet cores thus obtained are then dried.
  • Example 2 The procedure is analogous to Example 1, but tablet cores are used which contain instead of 75 g of ethoxylated cholesterol with approx. 24 mol of ethylene oxide, 75 g of lanolin alcohols ethoxylated with 25 equivalents of ethylene oxide.
  • Example 3 Tablet core in the form of a solid solution
  • Silicon dioxide 1.0 g (Aerosil ® 200, Degussa)
  • the tablets obtained in this way are enteric-resistant, ie the cores remain unharmed after 1 hour of treatment with artificial gastric juices of pH-1 f 2.
  • the intestinal juice disintegration time is longer than 60 minutes at pH 5.5 and between 23-28 minutes at pH 6.0 and between 12 to 16 minutes at pH 6.8.
  • Example 3 The procedure is analogous to Example 3, but the tablet cores of 140 mg are sprayed with a solution of 140 g of hydroxypropylmethyl cellulose phthalate (HP-50) and 28 g of di-n-butyl phthalate in a mixture of 616 g of ethanol and 616 g of acetone until the cores are mixed with 9 , 0 mg of the mixture of hydroxypropyl methyl cellulose phthalate and di-n-butyl phthalate (weight ratio 10: 2) are coated per tablet core.
  • hydroxypropylmethyl cellulose phthalate HP-50
  • di-n-butyl phthalate a mixture of 616 g of ethanol and 616 g of acetone
  • Polyvinyl pyrrolidone (average mol. Weight 25,000) produced.
  • the tablet cores obtained in this way are then sprayed analogously to Example 4 until the cores contain approximately 10 mg or about 15 mg of the mixture of hydroxypropyl methyl cellulose phthalate and di-n-nutyl phthalate are coated per tablet core.
  • the tablet cores are in the form of a solid solution.
  • Each of the 12 treated subjects was treated with 4 mg dihydroergotoxin mesilate.

Landscapes

  • 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)

Abstract

Les preparations pour l'application orale comprennent un revetement resistant au suc gastrique et un noyau constitue d'un alcaloide de l'ergot et d'un ether de sterol. Les preparations se distinguent par une liberation du principe actif amelioree et prolongee et une meilleure efficacite. Le noyau peut etre constitue d'une solution solide de l'alcaloide de l'ergot. Le revetement resistant au suc gastrique peut etre recouvert d'une couche externe du principe actif.
PCT/CH1979/000160 1978-12-21 1979-12-12 Preparations galeniques WO1980001242A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CH1301978 1978-12-21
CH13019/78 1978-12-21
CH1302178 1978-12-21
CH56679 1979-01-19
CH56779 1979-01-19

Publications (1)

Publication Number Publication Date
WO1980001242A1 true WO1980001242A1 (fr) 1980-06-26

Family

ID=27427929

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CH1979/000160 WO1980001242A1 (fr) 1978-12-21 1979-12-12 Preparations galeniques

Country Status (23)

Country Link
AT (1) AT372279B (fr)
AU (1) AU534051B2 (fr)
CA (1) CA1139222A (fr)
CH (1) CH642259A5 (fr)
CY (1) CY1330A (fr)
DE (1) DE2950154A1 (fr)
DK (1) DK154607C (fr)
FI (1) FI793888A (fr)
FR (1) FR2444463A1 (fr)
GB (1) GB2038181B (fr)
HK (1) HK37986A (fr)
HU (1) HU182577B (fr)
IE (1) IE49323B1 (fr)
IL (1) IL59003A (fr)
IT (1) IT1164029B (fr)
KE (1) KE3617D (fr)
MY (1) MY8500129A (fr)
NL (1) NL187229C (fr)
NZ (1) NZ192457A (fr)
PH (1) PH25178A (fr)
PT (1) PT70614A (fr)
SE (1) SE442265B (fr)
WO (1) WO1980001242A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3264867D1 (en) * 1981-04-27 1985-08-29 Haessle Ab New 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 (de) * 1983-04-22 1984-10-25 Sandoz-Patent-GmbH, 7850 Lörrach Pharmazeutisches praeparat enthaltend co-dergocrine und einen calcium-antagonisten
NL194389C (nl) * 1984-06-14 2002-03-04 Novartis Ag Werkwijze voor het bereiden van een vaste dispersie van een farmaceutisch actief middel dat een lage oplosbaarheid in water heeft, in een vaste matrix van een in water oplosbaar polyalkyleenglycol als drager.
GB8426922D0 (en) * 1984-10-24 1984-11-28 Sandoz Ltd Galenic formulation
AT388101B (de) * 1985-02-05 1989-05-10 Sandoz Ag Verfahren zur herstellung einer pharmazeutischen zusammensetzung zur oralen verabreichung mit kontrollierter wirkstofffreisetzung
CN1003978B (zh) * 1987-09-05 1989-04-26 广州陈李济药厂 一种补脾益肠丸的制备工艺

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1467976A1 (de) * 1963-09-18 1969-01-16 Key Pharma Traegermassen fuer Pharmazeutika und Verfahren zu ihrer Herstellung
FR2276833A1 (fr) * 1974-07-04 1976-01-30 Sandoz Sa Nouvelles compositions galeniques et leur preparation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2546577B2 (de) * 1975-10-17 1981-04-02 Sandoz-Patent-GmbH, 7850 Lörrach Feste Stoffe aus Polyvinylpyrrolidon und Ergotalkaloiden

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1467976A1 (de) * 1963-09-18 1969-01-16 Key Pharma Traegermassen fuer Pharmazeutika und Verfahren zu ihrer Herstellung
FR2276833A1 (fr) * 1974-07-04 1976-01-30 Sandoz Sa Nouvelles compositions galeniques et leur preparation

Also Published As

Publication number Publication date
MY8500129A (en) 1985-12-31
DK529879A (da) 1980-06-22
IL59003A (en) 1982-12-31
NL7909105A (nl) 1980-06-24
GB2038181A (en) 1980-07-23
IE49323B1 (en) 1985-09-18
NL187229C (nl) 1991-07-16
SE442265B (sv) 1985-12-16
IT7951153A0 (it) 1979-12-20
CY1330A (en) 1986-06-27
GB2038181B (en) 1983-05-11
AU534051B2 (en) 1984-01-05
PT70614A (fr) 1980-01-01
AT372279B (de) 1983-09-26
FR2444463A1 (fr) 1980-07-18
DE2950154C2 (fr) 1989-05-11
FR2444463B1 (fr) 1983-02-25
NZ192457A (en) 1983-06-17
IE792471L (en) 1980-06-21
CA1139222A (fr) 1983-01-11
AU5403179A (en) 1980-06-26
DK154607C (da) 1989-06-05
CH642259A5 (de) 1984-04-13
SE7910227L (sv) 1980-06-22
DE2950154A1 (de) 1980-07-10
HK37986A (en) 1986-05-30
HU182577B (en) 1984-02-28
DK154607B (da) 1988-12-05
IT1164029B (it) 1987-04-08
KE3617D (en) 1986-04-18
ATA803679A (de) 1983-02-15
PH25178A (en) 1991-03-27
FI793888A (fi) 1980-06-22

Similar Documents

Publication Publication Date Title
DE69629797T2 (de) Matrix zur gesteuerten freisetzung von arzneistoffen
EP1390023B1 (fr) Sels pharmaceutiques des composés 1-phenyl-3-dimethylamino-propaniques
US5019398A (en) Pharmaceutical composition providing the sustained-release of valproic acid
AT398165B (de) Verfahren zur herstellung einer pharmazeutischen kapsel zur oralen verabreichung mit verzögerter wirkstofffreisetzung bzw. kombinierter verzögerter/rascher wirkstofffreisetzung
AT392901B (de) Verfahren zur herstellung einer granulaeren form mit verzoegerter freisetzung von pharmazeutisch wirksamen substanzen
AT401870B (de) Stabilisiertes pharmazeutisches mittel, enthaltend einen hmg-coa-reduktase-inhibitor wirkstoff
AT408415B (de) Pharmazeutische zubereitung, die ein mycophenolatsalz enthält
EP0299211B1 (fr) Comprimé enrobé en DHP
DE3024858A1 (de) Anhaltend freigebende pharmazeutische zubereitung eines festen medikamentmaterials
DD202505A5 (de) Neue orale dipyridamolformen
DE3420283A1 (de) Nifedipin-trockenpraeparate und verfahren zu ihrer herstellung
DE4332394A1 (de) Budesonid-Pellets mit kontrolliertem Freigabeprofil und Verfahren zu ihrer Herstellung
DE2336218A1 (de) Neue orale arzneiform und verfahren zu ihrer herstellung
WO1987005511A1 (fr) Preparation combinee de nifedipine
DD292374A5 (de) Verfahren zum herstellen von ueberzugsmaterialien zur steuerung der arzneimittelfreisetzung bei langzeitwirkenden zubereitungen
AT400521B (de) Verfahren zur herstellung einer festen oralen pharmazeutischen ketotifenzusammensetzung
EP0722719B1 (fr) Procédé de fabrication de préparations à base de flavano-lignanes
WO1980001242A1 (fr) Preparations galeniques
DE60035579T2 (de) Multipartikuläre arzneizusammensetzungen mit gesteuerter wirkstoffabgabe enthaltend selektive inhibitoren der serotoninwiederaufnahme
DE2732335A1 (de) Neue pharmazeutische zusammensetzung und verfahren zu deren herstellung
DE69733752T2 (de) Arzneimittel enthaltend oxaprozin-natriumsalz,-kaliumsalz, oder-tris(hydroxymethyl)aminomethansalz
US4411882A (en) Galenical compositions
DE4131292A1 (de) Galactomannanderivate zur umhuellung oder einbettung von arzneimittelwirkstoffen
DE19850445A1 (de) Arzneimittel zur topischen Behandlung entzündlicher Darmerkrankungen
DE2802114A1 (de) Neue pharmazeutische zusammensetzung und verfahren zu deren herstellung

Legal Events

Date Code Title Description
AK Designated states

Designated state(s): CH