EP1140030A2 - Medicament forms having controlled release and containing active substances which easily dissolve in water - Google Patents

Medicament forms having controlled release and containing active substances which easily dissolve in water

Info

Publication number
EP1140030A2
EP1140030A2 EP00904879A EP00904879A EP1140030A2 EP 1140030 A2 EP1140030 A2 EP 1140030A2 EP 00904879 A EP00904879 A EP 00904879A EP 00904879 A EP00904879 A EP 00904879A EP 1140030 A2 EP1140030 A2 EP 1140030A2
Authority
EP
European Patent Office
Prior art keywords
dosage form
water
controlled release
active ingredient
methacrylic acid
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00904879A
Other languages
German (de)
French (fr)
Inventor
Jörg Rosenberg
Jörg Neumann
Christiane Vollgraf
Ulrich Reinhold
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
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 Knoll GmbH filed Critical Knoll GmbH
Publication of EP1140030A2 publication Critical patent/EP1140030A2/en
Withdrawn legal-status Critical Current

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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—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
    • A61K9/20—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

Definitions

  • the present invention relates to drug forms with controlled release, containing active ingredients with a water solubility according to USP of up to 30 in a matrix based on acrylate polymers, which are obtained by melt extrusion.
  • the object of the present invention was to find pharmaceutical forms which enable the controlled release of readily water-soluble active substances.
  • readily water-soluble active ingredients are those which have a water solubility according to USP 23 of 1 to 10 (easily soluble) or 10 to 30 (soluble), preferably less than 1 (very easily soluble).
  • the numbers refer to how many parts of solvent are required per part of the substance to be dissolved.
  • Preferred active ingredients are metoprolol and its salts, particularly preferably metoprolol tartrate.
  • the active ingredients are homogeneously dispersed in a matrix based on acrylate polymers or dissolved in the form of a solid solution.
  • the active substance is preferably present in the matrix in X-ray amorphous form.
  • Solid solutions of the active ingredient are particularly preferably obtained.
  • acrylate polymers are particularly swellable polymers of the Eudragit ® type.
  • Suitable polymers are, for example, methacrylic acid copolymers (Eudragit L types) such as methacrylic acid-ethyl acrylate 1: 1 copolymers M 250,000, methacrylic acid-methyl methacrylate 1: 1 copolymers M 135,000, methacrylic acid-methyl methacrylate 1: 2 copolymers M 135,000 or dimethylaminoethyl methacrylic lat copolymers (Eudragit E) such as poly (butyl methacrylate (2-dimethylaminoethyl) methacrylate) -1: 2: 1 M 150,000.
  • Medragit L types such as methacrylic acid-ethyl acrylate 1: 1 copolymers M 250,000, methacrylic acid-methyl methacrylate 1: 1 copolymers M 135,000, methacrylic acid-methyl methacrylate 1: 2
  • the amounts of active ingredient and acrylate polymers are chosen so that the dosage forms contain 1 to 50% by weight, preferably 10 to 30% by weight, of active ingredient.
  • Formulations containing 1 to 80, preferably 10 to 40% by weight Eudragit RL and 1 to 50, preferably 5 to 20% by weight Eudragit RS are particularly suitable.
  • polymers can be contained in the matrix, for example homo- or copolymers of N-vinylpyrrolidone such as povidone or copovidone 6: 4 or preferably cellulose ethers such as
  • Hydroxypropylmethyl cellulose ethyl cellulose or hydroxypropyl cellulose.
  • auxiliaries can be added for additional retardation.
  • hydrophobizing auxiliaries such as lipids or their salts, for example stearic acid, palmitic acid, hydrogenated ricinoleic acid or similar, preferably magnesium stearate.
  • preparations can also contain other customary pharmaceutical auxiliaries in the amounts customary for this, for example stabilizers, antioxidants, colorants, flavorings, fillers or stabilizers such as, for example, highly disperse silicon dioxide or lubricants.
  • other customary pharmaceutical auxiliaries for example stabilizers, antioxidants, colorants, flavorings, fillers or stabilizers such as, for example, highly disperse silicon dioxide or lubricants.
  • the preparations according to the invention are produced by mixing the components using shear forces and supplying thermal energy. Mixing is preferably carried out in a single-screw or multi-screw extruder, particularly preferably in a twin-screw extruder. A melt of the mixture components is generated by supplying thermal energy. This is usually done by heating the extruder jacket to temperatures in the range from 50 to 180, preferably 80 to 130 ° C. The active ingredient can be mixed with the other components before or after the melting of the polymeric binder. The melts are solvent-free. This means that no water or organic solvents are added.
  • the molten mixture of the components is conveyed by the screw movement in the direction of the extruder outlet, which preferably consists of a nozzle. After extrusion through the nozzle, the still plastic mass is shaped into suitable medicinal forms.
  • Suitable dosage forms are preferably tablets, in particular bolus tablets, lenticular tablets or oblong tablets.
  • Tablets are preferably produced in accordance with the process described in EP-A 240 906 by passing the still plastic strand between two oppositely driven rollers with mutually opposite recesses in the roller shell. By appropriately choosing the shape of these recesses, tablets with score lines can also be obtained. Granules or pellets can be obtained by cold cutting or, preferably, by hot cutting.
  • the dosage forms can additionally be provided with coatings known per se which have no influence on the release behavior.
  • the combination according to the invention of the melt extrusion process with a corresponding formulation based on acrylate polymers can also be used to produce pharmaceutical forms with controlled release for highly water-soluble active ingredients.
  • the terms of their release bioequivalent to the metoprolol succinate-containing product market Toprol-ZOK ® are.
  • the tablets were produced by extrusion of the mixtures listed in the table below in a co-rotating twin-screw extruder of the type ZKS-40 from Werner & Pfleiderer and subsequent calendering to oblong tablets with a tablet weight of 500 mg according to that in EP-A 240 906 described methods. Temperature profile of the extruder:
  • Polyethylene glycol 6000 1.61 finely divided silica 0.15
  • the in vitro release was determined according to USP 23 in a paddle apparatus at 100 rpm in artificial intestinal juice at pH 6.8, no change, 24 h.
  • a tablet according to Example 11 was administered as a single dose to eight healthy male volunteers in the fasting state.
  • Beloc-ZOK (with the same amount of free metoprolol base) was administered as the reference substance under the same conditions.
  • the geometric mean of the plasma concentration is shown in FIG. The squares denote the extrudate form according to the invention, the diamonds the reference substance.

Abstract

The invention relates to a medicament form containing an active substance with a water-solubility, according to USP, ranging from 23 to 30 in a matrix that is based on acrylate polymers, whereby the medicament form can be obtained by melt extrusion.

Description

Arzneiformen mit gesteuerter Freisetzung, enthaltend gut wasserlösliche Wirkstoffe Drug forms with controlled release, containing well water-soluble active ingredients
Beschreibungdescription
Die vorliegende Erfindung betrifft Arzneiformen mit gesteuerter Freisetzung, enthaltend Wirkstoffe mit einer Wasserlöslichkeit gemäß USP von bis zu 30 in einer Matrix auf Basis von Acrylat- Polymeren, welche durch Schmelzextrusion erhalten werden.The present invention relates to drug forms with controlled release, containing active ingredients with a water solubility according to USP of up to 30 in a matrix based on acrylate polymers, which are obtained by melt extrusion.
Es ist allgemein bekannt, daß die gesteuerte Freisetzung, insbesondere eine retardierte lineare Freisetzung, bei gut wasserlöslichen Wirkstoffen problematisch ist. Insbesondere Metoprolol- Tartrat ist auf konventionelle Weise schwer zu retardieren.It is generally known that controlled release, in particular a delayed linear release, is problematic in the case of active substances which are readily water-soluble. Metoprolol tartrate in particular is difficult to retard in a conventional manner.
Aus der EP-A 240 904 ist bekannt, daß man Arzneiformen nach dem Schmelzextrusionsverfahren herstellen kann.From EP-A 240 904 it is known that drug forms can be produced by the melt extrusion process.
Aufgabe der vorliegenden Erfindung war es, Arzneiformen zu finden, die eine gesteuerte Freisetzung von gut wasserlöslichen Wirkstoffen ermöglichen.The object of the present invention was to find pharmaceutical forms which enable the controlled release of readily water-soluble active substances.
Demgemäß wurden die eingangs definierten Arzneiformen gefunden.Accordingly, the dosage forms defined at the outset were found.
Gut wasserlösliche Wirkstoffe sind erfindungsgemäß solche, die eine Wasserlöslichkeit gemäß USP 23 von 1 bis 10 (leicht löslich) oder 10 bis 30 (löslich) , bevorzugt kleiner 1 (sehr leicht löslich) , aufweisen. Die Zahlenangaben beziehen sich darauf, wieviel Teile Lösungsmittel pro Teil zu lösender Substanz benötigt werden.According to the invention, readily water-soluble active ingredients are those which have a water solubility according to USP 23 of 1 to 10 (easily soluble) or 10 to 30 (soluble), preferably less than 1 (very easily soluble). The numbers refer to how many parts of solvent are required per part of the substance to be dissolved.
Bevorzugte Wirkstoffe sind Metoprolol und seine Salze, besonders bevorzugt Metoprolol-Tartrat .Preferred active ingredients are metoprolol and its salts, particularly preferably metoprolol tartrate.
Die Wirkstoffe werden bei der Schmelzextrusion in einer Matrix auf Basis von Acrylat-Polymeren homogen dispergiert oder im Sinne einer festen Lösung gelöst. Bevorzugt liegt der Wirkstoff in der Matrix in röntgenamorpher Form vor. Besonders bevorzugt werden feste Lösungen des Wirkstoffs erhalten.During melt extrusion, the active ingredients are homogeneously dispersed in a matrix based on acrylate polymers or dissolved in the form of a solid solution. The active substance is preferably present in the matrix in X-ray amorphous form. Solid solutions of the active ingredient are particularly preferably obtained.
Als Acrylat-Polymere eignen sich insbesondere quellbare Polymere vom Eudragit®-Typ. Geeignete Polymere sind beispielsweise Meth- acrylsäure-Copolymere (Eudragit L-Typen)wie Methacrylsäure-Ethyl- acrylat-1: 1-Copolymere M 250.000, Methacrylsäure-Methylmeth- acrylat-1: 1-Copolymere M 135.000, Methacrylsäure-Methylmeth- acrylat-l:2-Copolymere M 135.000 oder Dimethylaminoethylmethacry- lat-Copolymere (Eudragit E)wie Poly(butylmethacrylat (2-dimethyla- minoethyl)methacrylat) -1: 2 : 1 M 150.000.Bevorzugt sind die pH-unabhängig quellenden Methacrylsäureester-Copolymere (Eudragit NE) wie Ethylacrylat-Methymethacrylat-2 : 1-Copolymer M 800.000, beson- ders bevorzugt Methylmethacrylat-Ethylacrylat-2 : 1-Copolymer mit 5 oder 10 % Trimethylammoniumethyl-methacrylatchlorid (Eudragit RS und RL-Typen)M 150.000.As acrylate polymers are particularly swellable polymers of the Eudragit ® type. Suitable polymers are, for example, methacrylic acid copolymers (Eudragit L types) such as methacrylic acid-ethyl acrylate 1: 1 copolymers M 250,000, methacrylic acid-methyl methacrylate 1: 1 copolymers M 135,000, methacrylic acid-methyl methacrylate 1: 2 copolymers M 135,000 or dimethylaminoethyl methacrylic lat copolymers (Eudragit E) such as poly (butyl methacrylate (2-dimethylaminoethyl) methacrylate) -1: 2: 1 M 150,000. 1-copolymer M 800,000, particularly preferably methyl methacrylate-ethyl acrylate 2: 1 copolymer with 5 or 10% trimethylammonium ethyl methacrylate chloride (Eudragit RS and RL types) M 150,000.
Es können auch Mischungen der genannten Polymere verwendet werden.Mixtures of the polymers mentioned can also be used.
Die Mengen an Wirkstoff und Acrylat-Polymeren werden so gewählt, daß die Arzneiformen 1 bis 50 Gew.-%, bevorzugt 10 bis 30 Gew.-% Wirkstoff enthalten. Insbesondere eignen sich Formulierungen, die 1 bis 80, bevorzugt 10 bis 40 Gew.-% Eudragit RL und 1 bis 50, bevorzugt 5 bis 20 Gew.-% Eudragit RS enthalten.The amounts of active ingredient and acrylate polymers are chosen so that the dosage forms contain 1 to 50% by weight, preferably 10 to 30% by weight, of active ingredient. Formulations containing 1 to 80, preferably 10 to 40% by weight Eudragit RL and 1 to 50, preferably 5 to 20% by weight Eudragit RS are particularly suitable.
Zusätzlich können weitere Polymere in der Matrix enthalten sein, beispielsweise Homo- oder Copolymere des N-Vinylpyrrolidons wie Povidon oder Copovidon-6:4 oder bevorzugt Celluloseether wieIn addition, further polymers can be contained in the matrix, for example homo- or copolymers of N-vinylpyrrolidone such as povidone or copovidone 6: 4 or preferably cellulose ethers such as
Hydroxypropylmethylcellulose, Ethylcellulose oder Hydroxypropyl- cellulose.Hydroxypropylmethyl cellulose, ethyl cellulose or hydroxypropyl cellulose.
Weiterhin können weitere übliche pharmazeutische Hilfsstoffe zur zusätzlichen Retardierung zugesetzt werden. Hierzu zählen insbesondere hydrophobisierende Hilfsstoffe wie Lipide oder deren Salze, zum Beispiel Stearinsäure, Palmitinsäure, hydrierte Ricinolsäure oder ähnliche, bevorzugt Magnesiumstearat .Furthermore, other customary pharmaceutical auxiliaries can be added for additional retardation. These include, in particular, hydrophobizing auxiliaries such as lipids or their salts, for example stearic acid, palmitic acid, hydrogenated ricinoleic acid or similar, preferably magnesium stearate.
Zusätzlich können die Zubereitungen noch weitere übliche Pharma- hilfsstoffe in den hierfür üblichen Mengen enthalten, beispielsweise Stabilisatoren, Antioxidantien, Farbstoffe, Aromastoffe, Füllstoffe oder Stabilisatoren wie beispielsweise hochdisperses Siliciumdioxid oder Gleitmittel.In addition, the preparations can also contain other customary pharmaceutical auxiliaries in the amounts customary for this, for example stabilizers, antioxidants, colorants, flavorings, fillers or stabilizers such as, for example, highly disperse silicon dioxide or lubricants.
Die Herstellung der erfindungsgemässen Zubereitungen erfolgt durch Vermischen der Komponenten unter Einsatz von Scherkräften und Zufuhr thermischer Energie. Bevorzugt erfolgt das Mischen in einem Ein- oder Mehrschneckenextruder, besonders bevorzugt einem ZweiSchneckenextruder. Durch Zufuhr thermischer Energie wird eine Schmelze der Mischungskomponenten erzeugt. Dies geschieht üblicherweise durch Aufheizen des Extrudermantels auf Temperaturen im Bereich von 50 bis 180, vorzugsweise 80 bis 130°C. Das Vermischen des Wirkstoffs mit den anderen Komponenten kann vor oder nach dem Schmelzen des polymeren Bindemittels erfolgen. Die Schmelzen sind lösungsmittelfrei. Damit ist gemeint, dass kein Wasser oder organische Lösungsmittel zugesetzt wird.The preparations according to the invention are produced by mixing the components using shear forces and supplying thermal energy. Mixing is preferably carried out in a single-screw or multi-screw extruder, particularly preferably in a twin-screw extruder. A melt of the mixture components is generated by supplying thermal energy. This is usually done by heating the extruder jacket to temperatures in the range from 50 to 180, preferably 80 to 130 ° C. The active ingredient can be mixed with the other components before or after the melting of the polymeric binder. The melts are solvent-free. This means that no water or organic solvents are added.
Die geschmolzene Mischung der Komponenten wird durch die Schneckenbewegung in Richtung auf den Extruderauslass, der vorzugsweise aus einer Düse besteht, gefördert. Nach Extrusion durch die Düse wird die noch plastische Masse zu geeigneten Arzneiformen verformt.The molten mixture of the components is conveyed by the screw movement in the direction of the extruder outlet, which preferably consists of a nozzle. After extrusion through the nozzle, the still plastic mass is shaped into suitable medicinal forms.
Geeignete Arzneiformen sind bevorzugt Tabletten, insbesondere Bolustabletten, linsenförmige Tabletten oder Oblongtabletten.Suitable dosage forms are preferably tablets, in particular bolus tablets, lenticular tablets or oblong tablets.
Die Herstellung von Tabletten erfolgt vorzugsweise gemäß dem in der EP-A 240 906 beschriebenen Verfahren durch Hindurchführen des noch plastischen Stranges zwischen zwei gegenläufig angetriebene Walzen mit einander gegenüberliegenden Vertiefungen im Walzenmantel. Durch entsprechende Wahl der Form dieser Vertiefungen können auch Tabletten mit Bruchkerben erhalten werden. Granulate oder Pellets können durch Kaltabschlag oder, bevorzugt, durch Heißabschlag gewonnen werden.Tablets are preferably produced in accordance with the process described in EP-A 240 906 by passing the still plastic strand between two oppositely driven rollers with mutually opposite recesses in the roller shell. By appropriately choosing the shape of these recesses, tablets with score lines can also be obtained. Granules or pellets can be obtained by cold cutting or, preferably, by hot cutting.
Die Arzneiformen können zusätzlich noch mit an sich bekannten Überzügen, die keinen Einfluß auf das Freisetzungsverhalten haben, versehen werden.The dosage forms can additionally be provided with coatings known per se which have no influence on the release behavior.
Überraschenderweise lassen sich durch die erfindungsgemäße Kombination des Schmelzextrusionsverfahrens mit einer entsprechenden Formulierung auf Basis von Acrylat-Polymeren auch für gut wasserlösliche Wirkstoffe Arzneiformen mit gesteuerter Freisetzung her- stellen. Insbesondere war nicht zu erwarten daß sich auf einfache Weise mit Hilfe der Schmelzextrusion und einer entsprechenden Rezeptur retardierte Metoprolol-Tartrat-Zubereitungen erhalten lassen, die hinsichtlich ihrer Freisetzung bioäquivalent zu dem Metoprolol-Succinat enthaltenden Marktprodukt Beloc-ZOK® sind.Surprisingly, the combination according to the invention of the melt extrusion process with a corresponding formulation based on acrylate polymers can also be used to produce pharmaceutical forms with controlled release for highly water-soluble active ingredients. In particular, it was not expected that using the melt extrusion and a corresponding formulation retarded easily metoprolol tartrate preparations can be obtained, the terms of their release bioequivalent to the metoprolol succinate-containing product market Toprol-ZOK ® are.
BeispieleExamples
Die Herstellung der Tabletten erfolgte durch Extrusion der in der nachstehenden Tabelle aufgeführten Mischungen in einem gleichsinnig drehenden ZweiSchneckenextruder des Typs ZKS-40 der Firma Werner & Pfleiderer und anschließender Kalandrierung zu Oblong-Tabletten mit einem Tablettengewicht von 500 mg gemäß dem in der EP-A 240 906 beschriebenen Verfahren. Temperaturprofil des Extruders:The tablets were produced by extrusion of the mixtures listed in the table below in a co-rotating twin-screw extruder of the type ZKS-40 from Werner & Pfleiderer and subsequent calendering to oblong tablets with a tablet weight of 500 mg according to that in EP-A 240 906 described methods. Temperature profile of the extruder:
Einzug: 20 bis 25°C, Schuß 1: 80°C, Schuß 2: 110°C, Schuß 3: 110°C, Schuß 4: 130°C, Düse: 130°C. Die Drehzahl lag bei 110 Upm; der Durchsatz bei 15 kg/h. Die Tabletten wurden anschließend gecoatet mit einer Menge von 15 mg per Tablette. Zusammensetzung des Coatings:Feed: 20 to 25 ° C, weft 1: 80 ° C, weft 2: 110 ° C, weft 3: 110 ° C, weft 4: 130 ° C, nozzle: 130 ° C. The speed was 110 rpm; the throughput at 15 kg / h. The tablets were then coated at 15 mg per tablet. Composition of the coating:
Hydroxypropylmethylcellulose 2920 6cp 58,04Hydroxypropylmethylcellulose 2920 6cp 58.04
Talkum 4,10 Polyethylen lykol 400 9,00Talc 4.10 polyethylene glycol 400 9.00
Titandioxid 15,43Titanium dioxide 15.43
Hydroxypropylmethylcellulose 15cp 5,76Hydroxypropylmethylcellulose 15cp 5.76
Hydroxypropylcellulose 5,76Hydroxypropyl cellulose 5.76
Polyethylenglycol 6000 1,61 Hochdisperses Siliciumdioxid 0,15Polyethylene glycol 6000 1.61 finely divided silica 0.15
Natriumdocusat 0,15Sodium documentate 0.15
Die in-vitro-Freisetzung wurde gemäß USP 23 in einer Paddle- Apparatur bei 100 Upm in künstlichem Darmsaft bei pH 6,8, No-Change, 24 h, ermittelt. The in vitro release was determined according to USP 23 in a paddle apparatus at 100 rpm in artificial intestinal juice at pH 6.8, no change, 24 h.
Tabelle: Mengenangaben in Gew.-% Table: Quantities in% by weight
* ) zum Vergleich* ) for comparison
*) Hydroxypropylmethylcellulose DAB/Ph. Eur. 2208 2) Klucel® EF*) Hydroxypropylmethylcellulose DAB / Ph. Eur. 2208 2 ) Klucel ® EF
In Figur 1 ist die in-vitro-Freisetzung einer Tablette gemäß Beispiel 11 (n=6) in Vergleich zu dem Marktprodukt Beloc-ZOK Retard (95 mg Metoprolol-Succinat ) dargestellt.FIG. 1 shows the in vitro release of a tablet according to Example 11 (n = 6) in comparison to the market product Beloc-ZOK Retard (95 mg metoprolol succinate).
Eine Tablette gemäß Beispiel 11 wurde als Einmaldosis acht gesunden männlichen Freiwilligen im Fastenzustand verabreicht. Unter den gleichen Bedingungen wurde Beloc-ZOK (mit der gleichen Menge an freier Metoprolol-Base) als Referenzsubstanz ver- abreicht. In Figur 2 ist das geometrische Mittel der Plasmakonzentration dargestellt. Die Quadrate bezeichnen die erfindungsgemäße Extrudatform, die Rauten die Referenzsubstanz. A tablet according to Example 11 was administered as a single dose to eight healthy male volunteers in the fasting state. Beloc-ZOK (with the same amount of free metoprolol base) was administered as the reference substance under the same conditions. The geometric mean of the plasma concentration is shown in FIG. The squares denote the extrudate form according to the invention, the diamonds the reference substance.

Claims

Patentansprüche claims
1. Arzneiform, enthaltend einen Wirkstoff mit einer Wasser- löslichkeit gemäß USP 23 von bis zu 30 in einer Matrix auf Basis von Acrylat-Polymeren, wobei die Arzneiform durch Schmelzextrusion erhalten wird.1. Dosage form containing an active ingredient with a water solubility according to USP 23 of up to 30 in a matrix based on acrylate polymers, the dosage form being obtained by melt extrusion.
2. Arzneiform nach Anspruch 1, in der der Wirkstoff amorph vorliegt.2. Pharmaceutical form according to claim 1, in which the active ingredient is amorphous.
3. Arzneiform nach Anspruch 1 oder 2, enthaltend als Matrixpolymer ein Methacrylsäure-Copolymer .3. Dosage form according to claim 1 or 2, containing a methacrylic acid copolymer as the matrix polymer.
4. Arzneiform nach einem der Ansprüche 1 bis 3, enthaltend als Matrix-Polymer ein Methacrylsäureester-Copolymer.4. Dosage form according to one of claims 1 to 3, containing a methacrylic acid ester copolymer as the matrix polymer.
5. Arzneiform nach einem der Ansprüche 1 bis 4, enthaltend eine Kombination aus einem Methacrylsäure- und einem Methacryl- säureester-Copolymer.5. Dosage form according to one of claims 1 to 4, containing a combination of a methacrylic acid and a methacrylic acid ester copolymer.
6. Arzneiform nach einem der Ansprüche 1 bis 5, enthaltend als Wirkstoff Metoprolol-Tartrat.6. Dosage form according to one of claims 1 to 5, containing metoprolol tartrate as the active ingredient.
7. Verfahren zur Herstellung einer Arzneiform gemäß einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß man eine Mischung aus Wirkstoff und Matrixpolymer schmelzextrudiert und der Formgebung unterwirft.7. A method for producing a pharmaceutical form according to any one of claims 1 to 6, characterized in that a mixture of active ingredient and matrix polymer is melt extruded and subjected to the shaping.
8. Verfahren nach Anspruch 7, dadurch gekennzeichnet, daß die Formgebung durch Kalandrierung erfolgt. 8. The method according to claim 7, characterized in that the shaping is carried out by calendering.
EP00904879A 1999-01-14 2000-01-07 Medicament forms having controlled release and containing active substances which easily dissolve in water Withdrawn EP1140030A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19901040A DE19901040A1 (en) 1999-01-14 1999-01-14 Controlled release dosage forms containing active ingredients which are readily soluble in water
DE19901040 1999-01-14
PCT/EP2000/000053 WO2000041481A2 (en) 1999-01-14 2000-01-07 Medicament forms having controlled release and containing active substances which easily dissolve in water

Publications (1)

Publication Number Publication Date
EP1140030A2 true EP1140030A2 (en) 2001-10-10

Family

ID=7894143

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00904879A Withdrawn EP1140030A2 (en) 1999-01-14 2000-01-07 Medicament forms having controlled release and containing active substances which easily dissolve in water

Country Status (5)

Country Link
EP (1) EP1140030A2 (en)
JP (1) JP2002534443A (en)
CA (1) CA2359381A1 (en)
DE (1) DE19901040A1 (en)
WO (1) WO2000041481A2 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2818552B1 (en) * 2000-12-26 2003-02-07 Servier Lab SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITIONS FOR THE CONTROLLED RELEASE OF IVABRADINE
CA2592605C (en) 2004-12-27 2010-12-07 Eisai R&D Management Co., Ltd. Method for stabilizing anti-dementia drug
WO2007085024A2 (en) * 2006-01-21 2007-07-26 Abbott Gmbh & Co. Kg Dosage form and method for the delivery of drugs of abuse
EP2068840A2 (en) * 2006-07-21 2009-06-17 LAB International SRL Hydrophobic abuse deterrent delivery system
JP2011511782A (en) 2008-02-12 2011-04-14 アボット・ラボラトリーズ Extended release hydrocodone acetaminophen and related methods and uses

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3830353A1 (en) * 1988-09-07 1990-03-15 Basf Ag METHOD FOR THE CONTINUOUS PRODUCTION OF SOLID PHARMACEUTICAL FORMS
PL175026B1 (en) * 1992-09-18 1998-10-30 Yamanouchi Pharma Co Ltd Prolonged action preparation of hydrogel type
DE19509807A1 (en) * 1995-03-21 1996-09-26 Basf Ag Process for the preparation of active substance preparations in the form of a solid solution of the active substance in a polymer matrix, and active substance preparations produced using this method

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0041481A2 *

Also Published As

Publication number Publication date
DE19901040A1 (en) 2000-07-20
JP2002534443A (en) 2002-10-15
WO2000041481A3 (en) 2000-09-28
CA2359381A1 (en) 2000-07-20
WO2000041481A2 (en) 2000-07-20

Similar Documents

Publication Publication Date Title
DE69532415T3 (en) MELT EXTRUDED ORAL ADMINISTRATIVE OPIOID FORMULATIONS
DE60027608T2 (en) Mesalazine-containing controlled release pharmaceutical compositions
EP0544144B1 (en) Solid pharmaceutical retard form
EP1001757B1 (en) Fast-acting analgesic
EP0864326B1 (en) Multiphasic preparation comprising an active agent
EP0760654B1 (en) Process for producing active agent preparations in the form of a solid solution of the active agent in a polymer matrix
EP0181515B1 (en) Process for the preparation of an aqueous coating dispersion and its use in the coating of pharmaceutical compositions
WO2000057854A2 (en) Mechanically stable pharmaceutical presentation form containing liquid or semi-solid surface-active substances
DE10026699A1 (en) Formulation based on heparin, glycosaminoglycan or heparinoid and use of the formulation and the formulation base
EP0596203A1 (en) Preparations in solid particle form containing active and water-soluble polymers
DE19509805A1 (en) Transparent, fast-release formulations of nonsteroidal analgesics
EP0485840B1 (en) Pharmaceutical oral composition and coating agent containing a polysaccharide degradable in the colon
WO2001000175A1 (en) Mechanically stable pharmaceutical dosage forms, containing liquid or semi-solid surface-active substances
DE19842753A1 (en) Multiple-unit retard oral dosage formulation having controlled release independent of agitation and food effect, containing particles of combination of drug and hydroxypropyl cellulose
WO2000064415A1 (en) Method for producing a water-insoluble amorphous or partially amorphous controlled release matrix
WO2000041481A2 (en) Medicament forms having controlled release and containing active substances which easily dissolve in water
EP0876141B1 (en) Preparations of non-steroidal analgesics
EP1142571B1 (en) Method to produce solid creatine dosage forms and dosage forms thus obtained
EP1202715A2 (en) Quick-release extrudates, method for preparing the same and compositions obtained from said extrudates
DE19800927A1 (en) Process for the preparation of solid dosage forms
EP1189614B1 (en) Solid preparations containing paroxetine
EP0998919A2 (en) Solid dosage form with copolymeric binder
DE19724181A1 (en) Multiple unit retard preparations and process for their preparation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010713

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ABBOTT GMBH & CO. KG

17Q First examination report despatched

Effective date: 20030902

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040313