EP1693045A1 - Production of dosage forms from active molten substances - Google Patents

Production of dosage forms from active molten substances Download PDF

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Publication number
EP1693045A1
EP1693045A1 EP05003457A EP05003457A EP1693045A1 EP 1693045 A1 EP1693045 A1 EP 1693045A1 EP 05003457 A EP05003457 A EP 05003457A EP 05003457 A EP05003457 A EP 05003457A EP 1693045 A1 EP1693045 A1 EP 1693045A1
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EP
European Patent Office
Prior art keywords
release
melt
films
film
release films
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Withdrawn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
EP05003457A
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German (de)
French (fr)
Inventor
Jörg Rosenberg
Norbert Steiger
Harald Hach
Jörg Breitenbach
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
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Abbott GmbH and Co KG
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 Abbott GmbH and Co KG filed Critical Abbott GmbH and Co KG
Priority to EP05003457A priority Critical patent/EP1693045A1/en
Priority to ES06707060.7T priority patent/ES2445828T3/en
Priority to PCT/EP2006/001475 priority patent/WO2006087218A1/en
Priority to EP06707060.7A priority patent/EP1848394B1/en
Priority to JP2007555537A priority patent/JP2008529852A/en
Priority to US11/884,521 priority patent/US20090050262A1/en
Priority to CA2598168A priority patent/CA2598168C/en
Priority to DK06707060.7T priority patent/DK1848394T3/en
Publication of EP1693045A1 publication Critical patent/EP1693045A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B30—PRESSES
    • B30B—PRESSES IN GENERAL
    • B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
    • B30B11/16—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using pocketed rollers, e.g. two co-operating pocketed rollers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J2200/00—General characteristics or adaptations
    • A61J2200/20—Extrusion means, e.g. for producing pharmaceutical forms

Definitions

  • the present invention is a process for the preparation of dosage forms from a drug-containing melt.
  • WO 9707786 describes the use of lipids as an aid in the preparation of solid dosage forms by the melt extrusion process. Between 0.1-10 wt .-% lipids are added to the extrusion mixture as a mold release agent.
  • DE 4446467 describes a process for the production of lenticular tablets by melt calendering. It is referred to in this document that molding rolls can be used, which are provided with a release agent.
  • a release agent for example, a silicone varnish is suitable.
  • EP 0358105 describes a method for shaping extrudate masses. Here are two elastic bands with opposite recesses, which determine the tablet shape used.
  • WO 9619963 describes a process for the production of coated tablets by melt calendering, in which the active substance-containing melt is introduced into the calender forming rolls between two films of the wrapping material.
  • the invention is based on the object to provide a universally applicable method that allows the formation of active ingredient-containing melts without the problems occurring by sticking the melt on or in the mold.
  • the present invention relates to a process in which two release films are brought together in a defined region, an active-substance-containing melt is introduced between the release films so that a pocket for receiving a portion of the melt is formed in at least one of the release films and the release films are separated from one another to demold the portion.
  • one brings the release films in the gap of two counter-rotating forming rollers to each other, of which has at least one wells into which the release film can be pressed to form pockets.
  • both forming rollers on their surface on opposite recesses into which the release films can be pressed to form pockets are particularly preferably, both forming rollers on their surface on opposite recesses into which the release films can be pressed to form pockets.
  • the release film is deformed by the introduced into the trough-shaped space between the forming rollers melt and pressed to the surfaces of the wells.
  • the release film prevents direct contact of the melt with the roll surface, so that any adhesion / adhesion of the melt to the surface of the roll can be excluded.
  • the thickness of the release films used is generally in the range of 0.05 to 1.6 mm, preferably 0.1 to 1 mm and particularly preferably 0.1 to 0.5 mm.
  • the release films of an elastically deformable material since in this case by the relaxation of the release film when leaving the nip, a force occurs, which pushes the molding out of the cavity, so practically ejects the molding.
  • release films with low or negligible elasticity is preferred.
  • the formation of the pockets in the release films can be promoted by a slight softening of the films at the temperatures in the nip.
  • the softening point can be adjusted by the content of plasticizers in the release films.
  • the films are made of an elastomer, they have a tensile strength measured in accordance with DIN EN ISO 527-1 in the range from 3 to 40 MPa, preferably 7 to 30 MPa.
  • the elongation at break according to DIN EN ISO 527-1 is at least 200%, preferably at least 400%.
  • the release films may be passed through the nip by unwinding the film from a roll and passing through the nip onto a second roll is wound up.
  • the release film can be passed behind the roller through a scraper or a cleaning bath.
  • the release films are each closed to form an endless belt, which allows continuous process control.
  • the release film can rest on the outer surface of the forming rollers at the peripheries of the forming roller recesses
  • a variant of the method is to lead one or both release films spaced from the nip to the forming rollers and z. B. to lead over adjustable guide rollers in the gap.
  • tensioning screws which are attached to the guide rollers also permit precise adjustment of the thickness of the film in the calendering gap and thus the specific influence on the ejection forces with which the shaped bodies are pressed out of the cavities of the shaping roller.
  • the invention also relates to a device with shaping means, which consist of two forming rollers, which have at least one recess for receiving an active substance-containing melt.
  • the device is characterized in that the depression comprises a release film which can be reversibly transferred from a rest position into a deflected position by introducing the active substance-containing melt into the depression.
  • the material of the release films may be selected from elastomers and / or water-insoluble thermoplastic polymers.
  • elastomers such as silicone elastomers, acryllyl rubber, polyester urethane rubber, brominated butyl rubber, polybutadiene, chlorinated butyl rubber, chlorinated polyethylene, epichlorohydrin homo- / copolymer, polychloroprene, sulfurized polyethylene, ethylene-acrylate rubber, ethylene Propylene terpolymer, ethylene-propylene copolymer, polyether-urethane rubber, ethylene-vinyl acetate copolymer, fluororubber, fluorosilicone rubber, hydrogenated nitrile rubber, butyl rubber, dimethylpolysiloxane, nitrile rubber (low, medium, high ACN content , Natural rubber, thioplast, polyfluorophosphazenes, polynorbonene, styrene-butadiene rubber, and carboxy-group containing nitrile rubbers or mixtures thereof.
  • silicone elastomers such as
  • silicones which are accepted as product-contacting materials in pharmaceutical production processes, for example silicones. These silicone materials can addition-crosslinking, condensation-curing or free-radical crosslinking.
  • polyolefins and polyolefin derivatives or copolymers for example polyethylene, polypropylene, polyisobutylene, poly-4-methylpentene and vinyl acetate, vinyl alcohol, acrylic or methacrylic copolymers
  • vinyl polymers eg polystyrene and polystyrene terpolymers and block polymers, for example copolymers of styrene, acrylonitrile and butadiene
  • polyvinyl chloride and copolymers for example copolymers of vinyl chloride and vinyl acetate, methacrylate or acrylonitrile
  • polyvinyl acetate polyvinyl alcohol, polyvinyl methyl ether
  • fluoropolymers such as polytetrafluoroethylene, polyvinyldiene fluoride, polyvinyl fluoride, Polyacrylates and methacrylates such as Polyacrylonitrile, polymethyl methacrylate
  • thermoplastic polymers whose softening point is above the temperature of the active substance-containing melt when it enters the calendering gap.
  • preference is given to guiding the film as an endless belt through the calendering gap, since this does not result in any film waste.
  • profiled foils e.g. Noppenfolien
  • geometries of the dosage forms can be further changed.
  • the preparation of the dosage forms is carried out starting from a mixture containing one or more active pharmaceutical ingredients and one or more auxiliaries and which is doughy or viscous by melting or softening at least one component and therefore extrudable.
  • polymers for example Homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g. As polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone and vinyl acetate or vinyl propionate,
  • PVP polyvinylpyrrolidone
  • Cellulose esters and cellulose ethers in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, cellulose phthalates or succinates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate,
  • High molecular weight polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide,
  • Polyacrylates and polymethacrylates such as methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl methacrylate copolymers, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymers, poly (hydroxyalkyl acrylates), poly (hydroxyalkyl methacrylates),
  • Vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified polyvinyl alcohol),
  • Oligo- and polysaccharides such as carrageenans, galactomannans and xanthans, or mixtures of one or more thereof.
  • homopolymers or copolymers of vinylpyrrolidone are particularly preferred, for.
  • VP N-vinylpyrrolidone
  • VA vinyl acetate
  • a copolymer of 60 wt .-% VP and 40 wt .-% VA a copolymer of 60 wt .-% VP and 40 wt .-% VA.
  • active substances are to be understood as meaning all substances having a desired physiological action on the human or animal body or plants. These are in particular pharmaceutical active ingredients.
  • the amount of active ingredient per unit dose can vary within wide limits. It is usually chosen so that it is sufficient to achieve the desired effect. Also drug combinations can be used.
  • Active substances within the meaning of the invention are also vitamins and minerals.
  • the vitamins include the vitamins of the A group, the B group, which in addition to B 1 , B 2 , B 6 and B 12 and nicotinic acid and nicotinamide and compounds with vitamin B properties are understood, such.
  • adenine As adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoic acid and vitamin C, vitamins of the D group, E group, F group, H group , I and J group, K group and P group.
  • Active substances within the meaning of the invention also include peptide therapeutics and proteins.
  • For plant treatment agents include, for. Vinclozolin, epoxiconazole and quinmerac.
  • the process according to the invention is suitable, for example, for processing the following active substances:
  • the mass may also include various optional adjuvants.
  • optional adjuvants are:
  • Plasticizers such.
  • the concentration of plasticizer if present, is generally 0.5 to 30, preferably 0.5 to 10,% by weight, based on the total weight of polymer and plasticizer.
  • the amount of plasticizer is advantageously at most 30% by weight, based on the total weight of polymer and plasticizer, in order to form storage-stable formulations and dosage forms, which do not show any cold flow, in the area of solid forms.
  • Sugar alcohols such as sorbitol, xylitol, mannitol, maltitol; or sugar alcohol derivatives such as isomalt or hydrogenated condensed Palatinose as described in DE 102 62 005.
  • Solubilizers such as sorbitan fatty acid esters, polyalkoxylated fatty acid esters, such as. B polyalkoxylated glycerides, polyalkoxylated sorbitan fatty acid esters or fatty acid esters of polyalkylene glycols; or polyalkoxylated ethers of fatty alcohols.
  • a fatty acid chain in these compounds usually comprises 8 to 22 carbon atoms.
  • the polyalkylene oxide blocks comprise on average from 4 to 50 alkylene oxide units, preferably ethylene oxide units, per molecule.
  • Suitable sorbitan fatty acid esters are sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan tristearate, sorbitan trioleate, sorbitan monostearate, sorbitan monolaurate or sorbitan monooleate.
  • Suitable polyalkoxylated sorbitan fatty acid esters include, for example, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20) sorbitan trioleate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene (4 ) sorbitan monolaurate or polyoxyethylene (4) sorbitan monooleate.
  • Suitable polyalkoxylated glycerides are z. B. obtained by alkoxylation of natural or hydrogenated glycerides or by transesterification of natural or hydrogenated glycerides with polyalkylene glycols.
  • Commercial examples are Polyoxyethylenglycerolricinoleat-35, Polyoxyethylenglyceroltrihydroxystearat-40 (Cremophor® RH40, BASF AG) and polyalkoxylated glycerides as they are available under the trade names Gelucire® and Labrafil® from Gattefosse, z.
  • Gelucire® 44/14 (lauroyl-macrogol-32-glycerides prepared by transesterification of hydrogenated palm kernel oil with PEG 1500), Gelucire® 50/13 (stearoyl macrogol-32-glycerides prepared by transesterification of hydrogenated palm oil with PEG 1500 ) or Labrafil M1944 CS (oleoyl-macrogol-6-glycerides prepared by transesterification of apricot kernel oil with PEG 300).
  • a suitable fatty acid ester of polyalkylene glycols is e.g. B. PEG-660-hydroxystearic acid (polyglycol ester of 12-hydroxystearic acid (70 mol%) with 30 mol% ethylene glycol).
  • Suitable polyalkoxylated ethers of fatty alcohols are, for. Macrogol 6 cetyl stearyl ether or Macrogol 25 cetyl stearyl ether
  • Solubilizers are typically included in the powder mixture in an amount of 0.1 to 15% by weight, preferably 0.5 to 10% by weight.
  • Disintegrants such as crosslinked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose.
  • Extenders or fillers such as lactose, cellulose, silicates or silica
  • Lubricants such as magnesium and calcium stearate, sodium stearyl fumarate,
  • Dyes such as azo dyes, organic or inorganic pigments or dyes of natural origin
  • Stabilizers such as antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.
  • the components or a part of the components of the melt are mixed before heating to form a powder mixture.
  • the mixing of the components for powder mixing takes place in conventional mixers, such as plowshare mixers, shaker or free-fall mixers and the like.
  • the heating of the powder mixture takes place in a device customary for this purpose.
  • heatable extruders or kneaders such as mixing kneaders (eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei or Ko-Kneader from Buss), Doppelmulden kneaders (tray mixers) and die kneaders (Internal mixer) or rotor / stator systems (eg Dispax from IKA).
  • the residence time of the mass in the extruder is preferably less than 5 minutes, in particular less than 3 minutes.
  • twin-screw extruders rotating in the same direction or in opposite directions and optionally equipped with kneading disks.
  • co-rotating twin screw extruders are particularly preferred.
  • the feeding of the extruder or kneader takes place, depending on their design, continuously or discontinuously in the usual way.
  • the powder mixture is preferably in the free feed, z. B. be introduced via a differential dosing.
  • the pulverulent mixture of the polymer and the active ingredient is introduced at an inlet end into an elongated extruder housing; heats the mixture to obtain a melt; moves the melt through the extruder barrel to an exit end of the extruder barrel; and generates a sufficient back pressure in the Extruder housing, so that the melt emerges from an outlet end of the extruder housing as a coherent extrudate.
  • the resulting composition is then subjected to shaping according to the invention.
  • shaping according to the invention In this case, a variety of shapes, depending on the tool and type of molding, can be generated.
  • these forms can also be ground to powder and then compressed in the usual way to tablets.
  • tabletting aids such as colloidal silica, calcium hydrogen phosphate, lactose, microcrystalline cellulose, starch or magnesium stearate can be used.
  • the molding rolls usable in the invention for shaping the melt can be cooled or heated in a manner known per se, and the optimum surface temperature of the molding roll for the respective processing can be adjusted in this manner.
  • FIG. 1a shows a suitable apparatus 1 for carrying out the method according to the invention with counter-rotating forming rollers 2 and 3.
  • the forming rollers 2 and 3 have recesses 4 and 5 on their surface.
  • On the lateral surface of the forming rollers 2 and 3 is a release film 7.
  • the release film 7 is pressed in the nip in the wells 4 and 5. After leaving the nip, the portions of the melt 6 are removed from the mold.
  • FIG. 1 b shows an enlarged detail of the gap between the forming rollers 2 and 3 from FIG. 1 a and shows the separating film 7 in its rest position 8 or its deflected position 9.
  • Adjustable guide rollers 10 allow the separating films 7 to be guided at a distance from the forming rollers 2 and 3 outside the nip. Adjusted to the guide rollers 10 screws 11 and 12 (not shown in FIG. 2) allow the distance of the guide rollers 10 to vary and thus adjust the tension of the release film 7, when using elastic bands an accurate adjustment of the thickness of the release film 7 in the nip
  • a mixture containing 50% by weight of verapamil hydrochloride, 32% by weight of hydroxypropylcellulose (Klucel EF, Aqualon) and 18% by weight of hydroxypropyl methylcellulose (Methocel K4M; Colorcon) was used in a co-rotating twin-screw extruder at a screw speed of 80 U / min and a melt product temperature of 110 - 120 ° C extruded into a homogeneous extrudate melt.
  • the melt came directly after exiting the extruder head between a pair of counter-rotating mold rolls, the molding rolls each had recesses on their surface, with the help of which in the nip from the melt directly tablets could be formed.
  • the forming rolls were coated with an annular elastomeric film which had been cut out of the gum area of a rubber glove (Duo-Nit Co., material: latex mix, film thickness: 0.4 mm).
  • This elastomeric ring had a slightly smaller diameter than the forming rolls in the unstretched state and therefore sat firmly on the forming roll surface in a slightly stretched state.
  • a mold roll temperature of 10 ° C could be produced directly from the drug-containing melt direct elongated tablets of about 1000 mg in weight. There were no problems with melt sticking in the cavities of the forming rolls.
  • Example 2 The procedure was as in Example 1, but without using the elastomeric film on the rollers. The melt adhered too much to the calender roll surfaces, i. a demolding of the tablets did not succeed.
  • Example 2 The procedure was as described in Example 1, but with a mixture consisting of 50 wt .-% verapamil hydrochloride, 40 wt .-% hydroxypropyl cellulose (Klucel EF, Aqualon) and 10 wt .-% hydroxypropyl methylcellulose (Methocel K100M; Colorcon ).
  • the calendering was carried out with an elastomer ring (elastomeric film from the cuff area of a rubber glove, Berner, cytostatic rubber glove Bl-4021, material: natural latex, film thickness: 0.26 mm). There were no problems with melt sticking in the cavities of the forming rolls.
  • Example 3 The procedure was as in Example 3, but without the use of the rollers on the elastomeric film. The melt adhered too strongly to the calender roll surfaces, ie a demolding of the tablets did not succeed.
  • Example 2 The procedure was as described in Example 1, but with a mixture consisting of 55 wt .-% hydroxypropyl cellulose (Klucel EF, Aqualon) and 45 wt .-% mannitol (Merck).
  • the calendering was carried out using an elastomer ring (elastomeric film from the cuff area of a rubber glove, Reichelt Chemie-Technik, Thomastat-HSR-2020 15 MIL black gloves, material: soft plastic, film thickness: 0.15 mm). There were no problems with melt sticking in the cavities of the forming rolls.
  • Example 5 The procedure was as in Example 5, but without the use of the rollers on the elastomeric film. The melt adhered too much to the calender roll surfaces, i. a demolding of the tablets did not succeed.
  • the melt came directly after exiting the extruder head between a pair of counter-rotating mold rolls, the molding rolls each had depressions on their surface, with the help of which in the nip from the melt directly tablets could be formed.
  • the tablets were readily demoulded using the elastomeric film specified in Example 1. There were no problems with melt sticking in the cavities of the forming rolls.
  • Example 7 The procedure was as in Example 7, but without the use of the rollers on the elastomeric film. The melt adhered too much to the calender roll surfaces, i. a demolding of the tablets did not succeed.

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Abstract

The foil (7) exhibits a structured surface has a tensile strength of 40 Mpa and thickness of 0.05-1.6 mm; consists of silicone polymer and water-insoluble thermoplastic polymer; is laid out at the circumferences of the recesses (4, 5) on the form rollers (2, 3); is closed to continuous tape; and is led into the gap of oppositely rotating form rollers, which exhibit recesses on its surface, in which the foil is pressed for formation of the bag. The active agent containing melt (6) is led in between the foils and a bag is formed in the foil for admitting a portion of the melt. An independent claim is included for a device for the production of dosage forms.

Description

Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung von Dosierungsformen aus einer wirkstoffhaltigen Schmelze.The present invention is a process for the preparation of dosage forms from a drug-containing melt.

Bei der Herstellung von Dosierungsformen über Schmelzextrusionsverfahren in Verbindung mit einem Formgebungsverfahren wie der Kalandrierung, einem Verfahren bei dem die Schmelze im Spalt mindestens zwei gegenläufig rotierenden Formwalzen zur gewünschten Dosierungsform geformt wird, ist es entscheidend, dass die Schmelze keine übermäßige Haftung an den Formwerkzeugen aufweist, da ansonsten eine Entformung nicht gelingt. Die Begriffe Formwalzen und Kalander werden im folgenden synonym verwendet.In the production of dosage forms via melt extrusion processes in conjunction with a forming process such as calendering, a process in which the melt in the nip is formed into at least two counter-rotating forming rolls to the desired dosage form, it is critical that the melt not exhibit excessive adhesion to the forming dies. otherwise a demoulding does not succeed. The terms forming rollers and calenders are used synonymously below.

WO 9707786 beschreibt die Verwendung von Lipiden als Hilfsmittel bei der Herstellung von festen Arzneiformen nach dem Schmelzextrusionsverfahren. Zwischen 0,1-10 Gew.-% Lipide werden dabei der Extrusionsmischung als Formtrennmittel zugesetzt.WO 9707786 describes the use of lipids as an aid in the preparation of solid dosage forms by the melt extrusion process. Between 0.1-10 wt .-% lipids are added to the extrusion mixture as a mold release agent.

DE 4446467 beschreibt ein Verfahren zur Herstellung von linsenförmigen Tabletten durch Schmelzkalandrierung. Es wird in dieser Druckschrift darauf verwiesen, dass Formwalzen verwendet werden können, die mit einem Trennmittel versehen sind. Als Trennmittel ist beispielsweise ein Siliconlack geeignet.DE 4446467 describes a process for the production of lenticular tablets by melt calendering. It is referred to in this document that molding rolls can be used, which are provided with a release agent. As a release agent, for example, a silicone varnish is suitable.

Die EP 0358105 beschreibt ein Verfahren zur Formung von Extrudatmassen. Hierbei werden zwei elastische Bänder mit einander gegenüberliegenden Vertiefungen, die die Tablettenform bestimmen, verwendet.EP 0358105 describes a method for shaping extrudate masses. Here are two elastic bands with opposite recesses, which determine the tablet shape used.

Die WO 9619963 beschreibt ein Verfahren zur Herstellung von umhüllten Tabletten durch Schmelzkalandrierung, bei dem die wirkstoffhaltige Schmelze zwischen zwei Folien aus dem Umhüllungsmaterial in die Kalanderformwalzen eingeführt wird.WO 9619963 describes a process for the production of coated tablets by melt calendering, in which the active substance-containing melt is introduced into the calender forming rolls between two films of the wrapping material.

Der Erfindung liegt die Aufgabe zu Grunde, ein universell anwendbares Verfahren anzugeben, das die Formung wirkstoffhaltiger Schmelzen ohne die dabei auftretenden Probleme durch Festkleben der Schmelze am bzw. im Formwerkzeug erlaubt.The invention is based on the object to provide a universally applicable method that allows the formation of active ingredient-containing melts without the problems occurring by sticking the melt on or in the mold.

Gegenstand der vorliegenden Erfindung ist ein Verfahren, bei dem man zwei Trennfolien in einem definierten Bereich aneinander bringt, zwischen die Trennfolien eine wirkstoffhaltige Schmelze einbringt, so dass in wenigstens einer der Trennfolien eine Tasche zur Aufnahme einer Portion der Schmelze ausgebildet wird und die Trennfolien voneinander trennt, um die Portion zu entformen. In einer bevorzugten Ausführungsform bringt man die Trennfolien im Spalt zweier gegenläufig rotierender Formwalzen aneinander, von denen mindestens eine Vertiefungen aufweist, in die die Trennfolie zur Bildung von Taschen gedrückt werden kann. Besonders bevorzugt weisen beide Formwalzen auf ihrer Oberfläche einander gegenüberliegende Vertiefungen auf, in die die Trennfolien zur Bildung von Taschen gedrückt werden können.The present invention relates to a process in which two release films are brought together in a defined region, an active-substance-containing melt is introduced between the release films so that a pocket for receiving a portion of the melt is formed in at least one of the release films and the release films are separated from one another to demold the portion. In a preferred embodiment one brings the release films in the gap of two counter-rotating forming rollers to each other, of which has at least one wells into which the release film can be pressed to form pockets. Particularly preferably, both forming rollers on their surface on opposite recesses into which the release films can be pressed to form pockets.

Beim Formgebungsprozess wird die Trennfolie durch die in den trogförmigen Raum zwischen den Formwalzen eingebrachte Schmelze verformt und an die Oberflächen der Vertiefungen gepresst. Die Trennfolie verhindert dabei einen direkten Kontakt der Schmelze mit der Walzenoberfläche, so dass jegliche Haftung/Adhäsion der Schmelze an der Oberfläche der Walze ausgeschlossen werden kann.In the forming process, the release film is deformed by the introduced into the trough-shaped space between the forming rollers melt and pressed to the surfaces of the wells. The release film prevents direct contact of the melt with the roll surface, so that any adhesion / adhesion of the melt to the surface of the roll can be excluded.

Die Dicke der verwendeten Trennfolien liegt im Allgemeinen im Bereich von 0,05 bis 1,6 mm, bevorzugt 0,1 bis 1 mm und besonders bevorzugt 0,1 bis 0,5 mm.The thickness of the release films used is generally in the range of 0.05 to 1.6 mm, preferably 0.1 to 1 mm and particularly preferably 0.1 to 0.5 mm.

In einer bevorzugten Ausführungsform sind die Trennfolien aus einem elastisch verformbaren Material, da hierbei durch die Entspannung der Trennfolie beim Verlassen des Walzenspalts eine Kraft auftritt, die den Formling aus der Kavität herausdrückt, den Formling also praktisch auswirft.In a preferred embodiment, the release films of an elastically deformable material, since in this case by the relaxation of the release film when leaving the nip, a force occurs, which pushes the molding out of the cavity, so practically ejects the molding.

Sollte die Schmelze langsam erstarren und dabei beim Verlassen der Walzen noch sehr weich und plastisch sein, kann es durch die auftretende Spannung bei Verwendung von elastischen Trennfolien zu einer unerwünschten Deformation der Formlinge kommen. In diesen Fällen ist die Verwendung von Trennfolien mit geringer bzw. vernachlässigbarer Elastizität bevorzugt. Die Ausbildung der Taschen in den Trennfolien kann durch eine geringfügige Erweichung der Folien bei den Temperaturen im Walzenspalt begünstigt werden. Der Erweichungspunkt kann durch den Gehalt an Weichmachern in den Trennfolien eingestellt werden.Should the melt solidify slowly and still be very soft and vivid when leaving the rolls, undesirable deformation of the moldings can occur due to the occurring tension when using elastic release liners. In these cases, the use of release films with low or negligible elasticity is preferred. The formation of the pockets in the release films can be promoted by a slight softening of the films at the temperatures in the nip. The softening point can be adjusted by the content of plasticizers in the release films.

Sind die Folien aus einem Elastomeren, besitzen diese eine Zugfestigkeit gemessen nach DIN EN ISO 527-1 im Bereich von 3 bis 40 Mpa, bevorzugt 7 bis 30 Mpa. Die Bruchdehnung gemäss DIN EN ISO 527-1 liegt bei mindestens 200 %, bevorzugt bei mindestens 400 %.If the films are made of an elastomer, they have a tensile strength measured in accordance with DIN EN ISO 527-1 in the range from 3 to 40 MPa, preferably 7 to 30 MPa. The elongation at break according to DIN EN ISO 527-1 is at least 200%, preferably at least 400%.

Selbstverständlich ist es auch möglich, für das Verfahren zwei Trennfolien aus unterschiedlichem Material und/oder unterschiedlicher Dicke und/oder unterschiedlichem Weichmachergehalt zu wählen.Of course, it is also possible to choose for the process two release films of different material and / or different thickness and / or different plasticizer content.

Die Trennfolien können durch den Walzenspalt geführt werden, indem die Folie von einer Rolle abgewickelt und nach Führung durch den Walzenspalt auf eine zweite Rolle aufgewickelt wird. Zur Reinigung der Folie von Schmelzeresten kann die Trennfolie hinter der Walze durch einen Abstreifer oder ein Reinigungsbad geführt werden.The release films may be passed through the nip by unwinding the film from a roll and passing through the nip onto a second roll is wound up. To clean the film of melt residues, the release film can be passed behind the roller through a scraper or a cleaning bath.

In einer bevorzugten Ausführungsform sind die Trennfolien jeweils zu einem Endlosband geschlossen, was eine kontinuierliche Prozessführung ermöglicht.In a preferred embodiment, the release films are each closed to form an endless belt, which allows continuous process control.

Als Endlosband kann die Trennfolie dabei an der Mantelfläche der Formwalzen an den Umfängen der Formwalzenvertiefungen aufliegenAs an endless belt, the release film can rest on the outer surface of the forming rollers at the peripheries of the forming roller recesses

Eine Variante des Verfahrens besteht darin, eine oder beide Trennfolien außerhalb des Walzenspalts beabstandet zu den Formwalzen zu führen und z. B. über verstellbare Führrollen in den Spalt zu führen. An den Führrollen angebrachte Spannschrauben erlauben im Falle der Verwendung von elastischen Bändern zudem eine genaue Einstellung der Dicke der Folie im Kalanderspalt und damit die gezielte Einflussnahme auf die Auswurfkräfte mit denen die Formkörper aus den Kavitäten der Formwalze herausgedrückt werden.A variant of the method is to lead one or both release films spaced from the nip to the forming rollers and z. B. to lead over adjustable guide rollers in the gap. In the case of the use of elastic bands, tensioning screws which are attached to the guide rollers also permit precise adjustment of the thickness of the film in the calendering gap and thus the specific influence on the ejection forces with which the shaped bodies are pressed out of the cavities of the shaping roller.

Die Erfindung betrifft außerdem eine Vorrichtung mit Formgebungsmitteln, die aus zwei Formwalzen bestehen, die zumindest eine Vertiefung zur Aufnahme einer wirkstoffhaltigen Schmelze aufweisen. Die Vorrichtung zeichnet sich dadurch aus, dass die Vertiefung eine Trennfolie umfasst, die durch Einbringen der wirkstoffhaltigen Schmelze in die Vertiefung reversibel von einer Ruhelage in eine ausgelenkte Lage überführbar ist.The invention also relates to a device with shaping means, which consist of two forming rollers, which have at least one recess for receiving an active substance-containing melt. The device is characterized in that the depression comprises a release film which can be reversibly transferred from a rest position into a deflected position by introducing the active substance-containing melt into the depression.

Das Material der Trennfolien kann aus Elastomeren und/oder wasserunlöslichen thermoplastischen Polymeren ausgewählt werden.The material of the release films may be selected from elastomers and / or water-insoluble thermoplastic polymers.

Verwendung finden Elastomere, wie Silikon-Elastomere, Acrlylat-Kautschuk, PolyesterUrethan-Kautschuk, bromierter Butyl-Kautschuk, Polybutadien, chlorierter Butyl-Kautschuk, chloriertes Polyethylen, Epichlorhydrin- Homo-/Copolymer, Polychlorpropen, sulfuriertes Polyethylen, Ethylen-Acrylat Kautschuk, Ethylen-Propylen Terpolymer, Ethylen-Propylen Copolymer, Polyether-Urethan-Kautschuk, Ethylen-Vinylacetat Copolymer, Fluor-Kautschuk, Fluorsilicon-Kautschuk, hydrierter Nitril-Kautschuk, Butylkautschuk, Dimethylpolysiloxan, Nitril-Kautschuk (mit geringem, mittlerem, hohen ACN-Gehalt, Naturkautschuk, Thioplast, Polyfluorphosphazene, Polynorbonene, StyrolButadien-Kautschuk und Carboxy-Gruppenhaltige Nitril-Kautschuke oder Mischungen davon.Use is made of elastomers such as silicone elastomers, acryllyl rubber, polyester urethane rubber, brominated butyl rubber, polybutadiene, chlorinated butyl rubber, chlorinated polyethylene, epichlorohydrin homo- / copolymer, polychloroprene, sulfurized polyethylene, ethylene-acrylate rubber, ethylene Propylene terpolymer, ethylene-propylene copolymer, polyether-urethane rubber, ethylene-vinyl acetate copolymer, fluororubber, fluorosilicone rubber, hydrogenated nitrile rubber, butyl rubber, dimethylpolysiloxane, nitrile rubber (low, medium, high ACN content , Natural rubber, thioplast, polyfluorophosphazenes, polynorbonene, styrene-butadiene rubber, and carboxy-group containing nitrile rubbers or mixtures thereof.

Bevorzugt sind Elastomere, die als produktberührende Materialien in pharmazeutischen Herstellprozessen akzeptiert sind, z.B. Silikone. Diese Silikon-Materialien können additionsvernetzend, kondensationsvernetzend oder radikalisch vernetzend hergestellt sein.Preference is given to elastomers which are accepted as product-contacting materials in pharmaceutical production processes, for example silicones. These silicone materials can addition-crosslinking, condensation-curing or free-radical crosslinking.

Bei wasserunlöslichen Thermoplasten sind verwendbar: Polyolefine und Polyolefin-Derivate bzw.-copolymerisate (z. B. Polyethylen, Polypropylen, Polyisobutylen, Poly-4-methyl-penten sowie Vinylacetat-, Vinylalkohol-, Acryl-, Methacryl-Copolymerisate), Vinylpolymere (z.B. Polystyrol und Polystyrol-ter- und -blockpolymere, z.B. Copolymere aus Styrol, Acrylnitril und Butadien, Polyvinylchlorid und Copolymere, z.B. Copolymere aus Vinylchlorid und Vinylacetat, Methacrylat oder Acrylnitril), Polyvinylacetat, Polyvinylalkohol, Polyvinylmethylether, Fluoropolymere wie Polytetrafuorethylen, Polyvinyldienfluorid, Polyvinylfluorid, Polyacrylate und -methacrylate wie z.B. Polyacrylnitril, Polymethylmethacrylat, Polyoxymethylen-homo- und copolymerisate, Polyamide und Polyamid-Copolymerisate, Polycarbonate und Polycarbonat-Copolymere, Polyethylenterephthalate, Polysulfone und Polyarylsulfone, Polyaryletherketone, Polyimide, Polyurethane. Die genannten thermoplastischen Polymere können gegebenenfalls auch in Mischungen (Polymerblends) vorliegen. Voraussetzung für die Verwendung ist, dass die wirkstoffhaltige Schmelze nicht an der Thermoplast-Folie haftet und sich nicht mit ihr fest verbindet.In the case of water-insoluble thermoplastics, it is possible to use polyolefins and polyolefin derivatives or copolymers (for example polyethylene, polypropylene, polyisobutylene, poly-4-methylpentene and vinyl acetate, vinyl alcohol, acrylic or methacrylic copolymers), vinyl polymers ( eg polystyrene and polystyrene terpolymers and block polymers, for example copolymers of styrene, acrylonitrile and butadiene, polyvinyl chloride and copolymers, for example copolymers of vinyl chloride and vinyl acetate, methacrylate or acrylonitrile), polyvinyl acetate, polyvinyl alcohol, polyvinyl methyl ether, fluoropolymers such as polytetrafluoroethylene, polyvinyldiene fluoride, polyvinyl fluoride, Polyacrylates and methacrylates such as Polyacrylonitrile, polymethyl methacrylate, polyoxymethylene homopolymers and copolymers, polyamides and polyamide copolymers, polycarbonates and polycarbonate copolymers, polyethylene terephthalates, polysulfones and polyarylsulfones, polyaryletherketones, polyimides, polyurethanes. If appropriate, the stated thermoplastic polymers can also be present in mixtures (polymer blends). Prerequisite for use is that the active ingredient-containing melt does not adhere to the thermoplastic film and does not firmly bond with it.

Bevorzugt sind somit die Thermoplast-Polymere, deren Erweichungspunkt oberhalb der Temperatur der wirkstoffhaltigen Schmelze liegt, wenn sie in den Kalanderspalt eintritt. Bevorzugt ist auch hier, die Folie als Endlos-Band durch den Kalanderspalt zu führen, da dadurch kein Folien-Abfall entsteht.Preference is thus given to the thermoplastic polymers whose softening point is above the temperature of the active substance-containing melt when it enters the calendering gap. Here, too, preference is given to guiding the film as an endless belt through the calendering gap, since this does not result in any film waste.

Durch Wahl profilierter Folien z.B. Noppenfolien können zudem die Geometrien der Dosierungsformen weiter verändert werden. Möglich ist auch eine Folie, die auf ihrer Oberfläche Strukturen enthält, die jeweils einen Teil der Vertiefungen der Formwalzen ausfüllen und so zu gezielten Veränderungen der Geometrie der Dosierungsformen führen.By selecting profiled foils e.g. Noppenfolien also the geometries of the dosage forms can be further changed. Also possible is a film which contains structures on its surface, each filling a portion of the recesses of the forming rollers and thus lead to targeted changes in the geometry of the dosage forms.

Die Herstellung der Dosierungsformen erfolgt ausgehend von einer Mischung, die einen oder mehrere pharmazeutische Wirkstoffe sowie einen oder mehrere Hilfsstoffe enthält und die durch Schmelzen oder Erweichen mindestens einer Komponente teigig bis zähflüssig und daher extrudierbar wird.The preparation of the dosage forms is carried out starting from a mixture containing one or more active pharmaceutical ingredients and one or more auxiliaries and which is doughy or viscous by melting or softening at least one component and therefore extrudable.

Das sind insbesondere Mischungen die pharmakologisch akzeptable Polymere enthalten, beispielsweise Homopolymere und Copolymere von N-Vinyllactamen, insbesondere Homopolymeren und Copolymeren von N-Vinylpyrrolidon, z. B. Polyvinylpyrrolidon (PVP), Copolymeren von N-Vinylpyrrolidon und Vinylacetat oder Vinylpropionat,These are in particular mixtures containing pharmacologically acceptable polymers, for example Homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g. As polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone and vinyl acetate or vinyl propionate,

Celluloseester und Celluloseether, insbesondere Methylcellulose und Ethylcellulose, Hydroxyalkylcellulosen, insbesondere Hydroxypropylcellulose, Hydroxyalkylalkylcellulosen, insbesondere Hydroxypropylmethylcellulose, Cellulosephthalate oder Succinate, insbesondere Celluloseacetatephthalat und Hydroxypropylmethylcellulose phthalat, Hydroxypropylmethylcellulosesuccinat oder Hydroxypropylmethylcelluloseacetatsuccinat,Cellulose esters and cellulose ethers, in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, cellulose phthalates or succinates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate,

Hochmolekulare Polyalkylenoxide wie Polyethylenoxid und Polypropylenoxid und Copolymere von Ethylenoxid und Propylenoxid,High molecular weight polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide,

Polyacrylate und Polymethacrylate wie Methacrylsäure/Ethylacrylat Copolymere, Methacrylsäure/Methylmethacrylat Copolymere, Butylmethacrylat/2-dimethylaminoethyl methacrylat Copolymere, Poly(hydroxyalkylacrylate), Poly(hydroxyalkylmethacrylate),Polyacrylates and polymethacrylates such as methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl methacrylate copolymers, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymers, poly (hydroxyalkyl acrylates), poly (hydroxyalkyl methacrylates),

Polyacrylamide,polyacrylamides,

Vinylacetat Polymere wie Copolymere von Vinylacetat und Crotonsäure, teilweises hydrolisiertes Polyvinylacetat (auch als teilwesse verseifter Polyvinylalkohol bezeichnet),Vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified polyvinyl alcohol),

Polyvinylalkohol,polyvinyl alcohol,

Oligo- und Polysaccharide wie Carrageenane, Galactomannane und Xanthane, oder Mischungen von einem oder mehreren davon.Oligo- and polysaccharides such as carrageenans, galactomannans and xanthans, or mixtures of one or more thereof.

Davon sind Homo- oder Copolymere von Vinylpyrrolidon besonders bevorzugt, z. B. Polyvinylpyrrolidon mit K-Werten nach Fikentscher von 12 bis 100, vorzugsweise 17 bis 30, oder Copolymere von 30 bis 70 Gew.% N-Vinylpyrrolidon (VP) und 70 bis 30 Gew.-% Vinylacetat (VA), wie z. B. ein Copolymer aus 60 Gew.-% VP und 40 Gew.-% VA.Of these, homopolymers or copolymers of vinylpyrrolidone are particularly preferred, for. Example, polyvinylpyrrolidone with K values of Fikentscher from 12 to 100, preferably 17 to 30, or copolymers of 30 to 70 wt.% N-vinylpyrrolidone (VP) and 70 to 30 wt .-% vinyl acetate (VA), such as. Example, a copolymer of 60 wt .-% VP and 40 wt .-% VA.

Selbstverständlich können auch Gemische der genannten Polymere eingesetzt werden.Of course, mixtures of said polymers can be used.

Unter Wirkstoffen im Sinne der Erfindung sind alle Stoffe mit einer erwünschten physiologischen Wirkung auf den menschlichen oder tierischen Körper oder Pflanzen zu verstehen. Es handelt sich insbesondere um pharmazeutische Wirkstoffe. Die Wirkstoffmenge pro Dosiseinheit kann in weiten Grenzen variieren. Sie wird in der Regel so gewählt, dass sie zur Erzielung der gewünschten Wirkung ausreicht. Auch WirkstoffKombinationen können eingesetzt werden. Wirkstoffe im Sinne der Erfindung sind auch Vitamine und Mineralstoffe. Zu den Vitaminen gehören die Vitamine der A-Gruppe, der B-Gruppe, worunter neben B1, B2, B6 und B12 sowie Nicotinsäure und Nicotinamid auch Verbindungen mit Vitamin B-Eigenschaften verstanden werden, wie z. B. Adenin, Cholin, Pantothensäure, Biotin, Adenylsäure, Folsäure, Orotsäure, Pangamsäure, Carnitin, p-Aminobenzoesäure, myo-Inosit und Liponsäure sowie Vitamin C, Vitamine der D-Gruppe, E-Gruppe, F-Gruppe, H-Gruppe, I- und J-Gruppe, K-Gruppe und P-Gruppe. Zu Wirkstoffen im Sinne der Erfindung gehören auch Peptidtherapeutika und Proteine. Zu Pflanzenbehandlungsmitteln zählen z. B. Vinclozolin, Epoxiconazol und Quinmerac.For the purposes of the invention, active substances are to be understood as meaning all substances having a desired physiological action on the human or animal body or plants. These are in particular pharmaceutical active ingredients. The amount of active ingredient per unit dose can vary within wide limits. It is usually chosen so that it is sufficient to achieve the desired effect. Also drug combinations can be used. Active substances within the meaning of the invention are also vitamins and minerals. The vitamins include the vitamins of the A group, the B group, which in addition to B 1 , B 2 , B 6 and B 12 and nicotinic acid and nicotinamide and compounds with vitamin B properties are understood, such. As adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoic acid and vitamin C, vitamins of the D group, E group, F group, H group , I and J group, K group and P group. Active substances within the meaning of the invention also include peptide therapeutics and proteins. For plant treatment agents include, for. Vinclozolin, epoxiconazole and quinmerac.

Das erfindungsgemäße Verfahren ist beispielsweise zur Verarbeitung folgender Wirkstoffe geeignet:The process according to the invention is suitable, for example, for processing the following active substances:

Acebutolol, Acetylcystein, Acetylsalicylsäure, Aciclovir, Albrazolam, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikacin, Amilorid, Aminoessigsäure, Amiodaron, Amitriptylin, Amlodipin, Amoxicillin, Ampicillin, Ascorbinsäure, Aspartam, Astemizol, Atenolol, Beclomethason, Benserazid, Benzalkonium-Hydrochlorid, Benzocain, Benzoesäure, Betamethason, Bezafibrat, Biotin, Biperiden, Bisoprolol, Bromazepam, Bromhexin, Bromocriptin, Budesonid, Bufexamac, Buflomedil, Buspiron, Coffein, Campher, Captopril, Carbamazepin, Carbidopa, Carboplatin, Cefachlor, Cefalexin, Cefatroxil, Cefazolin, Cefixim, Cefotaxim, Ceftazidim, Ceftriaxon, Cefuroxim, Celedilin, Chloramphenicol, Chlorhexidin, Chlor-pheniramin, Chlortalidon, Cholin, Cyclosporin, Cilastatin, Cimetidin, Ciprofloxacin, Cisapride, Cisplatin, Clarithromycin, Clävulansäure, Clomibramin, Clonazepam, Clonidin, Clotrimazol, Codein, Cholestyramin, Cromoglycinsäure, Cyanocobalamin, Cyproteron, Desogestrel, Dexamethason, Dexpanthenol, Dextromethorphan, Dextropropoxiphen, Diazepam, Diclofenac, Digoxin, Dihydrocodein, Dihydroergotamin, Dihydroergotoxin, Diltiazem, Diphenhydramin, Dipyridamol, Dipyron, Disopyramid, Domperidon, Dopamin, Doxycyclin, Enalapril, Ephedrin, Epinephrin, Ergocalciferol, Ergotamin, Erythromycin, Estradiol, Ethinylestradiol, Etoposid, Eucalyptus Globulus, Famotidin, Felodipin, Fenofibrat, Fenofibrinsäure, Fenoterol, Fentanyl, FlavinMononucleotid, Fluconazol, Flunarizin, Fluorouracil, Fluoxetin, Flurbiprofen, Furosemid, Gallopamil, Gemfibrozil, Gentamicin, Gingko Biloba, Glibenclamid, Glipizid, Clozapin, Glycyrrhiza glabra, Griseofulvin, Guaifenesin, Haloperidol, Heparin, Hyaluronsäure, Hydrochlorothiazid, Hydrocodon, Hydrocortison, Hydromorphon, lpratropium-Hydroxid, lbuprofen, Imipenem, Indomethacin, Insulin, lohexol, lopamidol, lsosorbid-Dinitrat, Isosorbid-Mononitrat, lsotretinoin, Itraconazol, Ketotifen, Ketoconazol, Ketoprofen, Ketorolac, Labatalon, Lactulose, Lecithin, Levocarnitin, Levodopa, Levoglutamid, Levonorgestrel, Levothyroxin, Lidocain, Lipase, Lipramin, Lisinopril, Loperamid, Lopinavir, Lorazepam, Lovastatin, Medroxyprogesteron, Menthol, Methotrexat, Methyldopa, Methylprednisolon, Metoclopramid, Metoprolol, Miconazol, Midazolam, Minocyclin, Minoxidil, Misoprostol, Morphin, Multivitamin-Mischungen bzw. -Kombinationen und Mineralsalze, N-Methylephedrin, Naftidrofuryl, Naproxen, Neomycin, Nicardipin, Nicergolin, Nicotinamid, Nicotin, Nicotinsäure, Nifedipin, Nimodipin, Nitrazepam, Nitrendipin, Nizatidin, Norethisteron, Norfloxacin, Norgestrel, Nortriptylin, Nystatin, Ofloxacin, Omeprazol, Ondansetron, Pancreatin, Panthenol, Pantothensäure, Paracetamol, Penicillin G, Penicillin V, Phenobarbital, Phenoxifyllin, Phenoxymethylpenicillin, Phenylephrin, Phenylpropanolamin, Phenytoin, Piroxicam, Polymyxin B, Povidon-lod, Pravastatin, Prazepam, Prazosin, Prednisolon, Prednison, Promocriptin, Propafenon, Propranolol, Proxyphyllin, Pseudoephedrin, Pyridoxin, Quinidin, Ramipril, Ranitidin, Reserpin, Retinol, Riboflavin, Rifampicin, Ritonavir, Rutosid, Saccharin, Salbutamol, Salcatonin, Salicylsäure, Simvastatin, Somatropin, Sotalol, Spironolacton, Sucralfat, Sulbactam, Sulfamethoxazol, Sulfasalazin, Sulpirid, Tamoxifen, Tegafur, Teprenon, Terazosin, Terbutalin, Terfenadin, Tetracyclin, Theophyllin, Thiamin, Ticlopidin, Timolol, Tranexamsäure, Tretinoin, Triamcinolon-Acetonid, Triamteren, Trimethoprim, Troxerutin, Uracil, Valproinsäure, Vancomycin, Verapamil, Vitamin E, Volinsäure, Zidovudin.Acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, albrazolam, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol, beclomethasone, benserazide, benzalkonium hydrochloride, Benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefatroxil, cefazolin, cefixime, Cefotaxime, Ceftazidime, Ceftriaxone, Cefuroxime, Celediline, Chloramphenicol, Chlorhexidine, Chloropheniramine, Chlortalidone, Choline, Cyclosporine, Cilastatin, Cimetidine, Ciprofloxacin, Cisapride, Cisplatin, Clarithromycin, Clavulanic Acid, Clomibramine, Clonazepam, Clonidine, Clotrimazole, Codeine, Cholestyramine, Cromoglycic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dext romethorphan, dextropropoxyphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxine, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus Globulus, famotidine, felodipine, fenofibrate, fenofibric acid, fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibrozil, gentamicin, gingko biloba, glibenclamide, glipizide, clozapine, glycyrrhiza glabra, griseofulvin, guaifenesin , Haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, lpratropium hydroxide, lbuprofen, imipenem, indomethacin, insulin, lohexol, lopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin, itraconazole, ketotifen, ketoconazole, ketoprofen, ketorolac , Labatalon, lactulose, lecithin, levocarnitine, levodopa , Levoglutamide, levonorgestrel, Levothyroxine, lidocaine, lipase, lipramine, lisinopril, loperamide, lopinavir, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures or Combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, Pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, phenoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, promocriptine, propafenone, propranolol , Proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retin ol, riboflavin, rifampicin, ritonavir, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine, tetracycline, Theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, valine, zidovudine.

Die Masse kann daneben verschiedene fakultative Hilfsstoffe umfassen. Derartige fakultative Hilfsstoffe sind:The mass may also include various optional adjuvants. Such optional adjuvants are:

Weichmacher wie z. B. C7-C30-Alkanole, Ethylenglycol, Propylenglycol, Glycerin, Trimethylolpropan, Triethylenglycol, Butandiole, Pentanole, wie Pentaerythrit und Hexanole, Polyalkylenglycole, vorzugsweise mit einem Molekulargewicht von 200 bis 1000, wie z.B. Polyethylenglycole, Polypropylenglycole und Polyethylenpropylenglycole, Silicone, aromatische Carbonsäureester (z.B. Dialkylphthalate, Trimellithsäureester, Benzoesäureester, Terephthalsäureester) oder aliphatische Dicarbonsäureester (z.B. Dialkyladipate, Sebacinsäureester, Azelainsäureester, Zitronen- und Weinsäureester), Fettsäureester, wie Glycerinmono-, Glycerindi- oder Glycerintriacetat oder Natriumdiethylsulfosuccinat. Die Konzentration an Weichmacher beträgt soweit vorhanden im Allgemeinen 0,5 bis 30, vorzugsweise 0,5 bis 10 Gew.-%, bezogen auf das Gesamtgewicht von Polymer und Weichmacher. Die Menge an Weichmacher beträgt vorteilhafterweise höchstens 30 Gew.-%, bezogen auf das Gesamtgewicht von Polymer und Weichmacher, damit - im Bereich fester Formen - lagerstabile Formulierungen und Dosierungsformen gebildet werden, die keinen kalten Fluss zeigen.Plasticizers such. B. C 7 -C 30 alkanols, ethylene glycol, propylene glycol, glycerol, trimethylolpropane, triethylene glycol, butanediols, pentanols such as pentaerythritol and hexanols, polyalkylene glycols, preferably having a molecular weight of 200 to 1000, such as polyethylene glycols, polypropylene glycols and polyethylene glycols, silicones, aromatic carboxylic acid esters (for example dialkyl phthalates, trimellitic acid esters, benzoic acid esters, terephthalic esters) or aliphatic dicarboxylic acid esters (for example dialkyladipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters), fatty acid esters, such as glycerol mono-, glycerol di- or glycerol triacetate or sodium diethyl sulphosuccinate. The concentration of plasticizer, if present, is generally 0.5 to 30, preferably 0.5 to 10,% by weight, based on the total weight of polymer and plasticizer. The amount of plasticizer is advantageously at most 30% by weight, based on the total weight of polymer and plasticizer, in order to form storage-stable formulations and dosage forms, which do not show any cold flow, in the area of solid forms.

Zuckeralkohole wie Sorbit, Xylit, Mannit, Maltitol; oder Zuckeralkoholderivate wie Isomalt oder hydrierte kondensierte Palatinose wie in der DE 102 62 005 beschrieben.Sugar alcohols such as sorbitol, xylitol, mannitol, maltitol; or sugar alcohol derivatives such as isomalt or hydrogenated condensed Palatinose as described in DE 102 62 005.

Solubilisatoren, wie Sorbitanfettsäureester, polyalkoxylierte Fettsäureester, wie z. B polyalkoxylierte Glyceride, polyalkoxylierte Sorbitanfettsäureester oder Fettsäureester von Polyalkylenglycolen; oder polyalkoxylierte Ether von Fettalkoholen. Eine Fettsäurekette in diesen Verbindungen umfasst in der Regel 8 bis 22 Kohlenstoffatome. Die Polyalkylenoxid-Blöcke umfassen pro Molekül durchschnittlich 4 bis 50 Alkylenoxideinheiten, vorzugsweise Ethylenoxideinheiten.Solubilizers, such as sorbitan fatty acid esters, polyalkoxylated fatty acid esters, such as. B polyalkoxylated glycerides, polyalkoxylated sorbitan fatty acid esters or fatty acid esters of polyalkylene glycols; or polyalkoxylated ethers of fatty alcohols. A fatty acid chain in these compounds usually comprises 8 to 22 carbon atoms. The polyalkylene oxide blocks comprise on average from 4 to 50 alkylene oxide units, preferably ethylene oxide units, per molecule.

Geeignete Sorbitanfettsäureester sind Sorbitanmonolaurat, Sorbitanmonopalmitat, Sorbitanmonostearat, Sorbitanmonooleat, Sorbitantristearat, Sorbitantrioleat, Sorbitanmonostearat, Sorbitanmonolaurat oder Sorbitanmonooleat.Suitable sorbitan fatty acid esters are sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan tristearate, sorbitan trioleate, sorbitan monostearate, sorbitan monolaurate or sorbitan monooleate.

Geeignete polyalkoxylierte Sorbitanfettsäurester sind beispielsweise Polyoxyethylen(20)sorbitanmonolaurat, Polyoxyethylen(20)sorbitanmonopalmitat, Polyoxyethylen(20)sorbitanmonostearat, Polyoxyethylen(20)sorbitanmonooleat, Polyoxyethylen(20)sorbitantristearat, Polyoxyethylen(20)sorbitantrioleat, Polyoxyethylen(4)sorbitanmonostearat, Polyoxyethylen(4)sorbitanmonolaurat oder Polyoxyethylen(4)sorbitanmonooleat.Suitable polyalkoxylated sorbitan fatty acid esters include, for example, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20) sorbitan trioleate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene (4 ) sorbitan monolaurate or polyoxyethylene (4) sorbitan monooleate.

Geeignete polyalkoxylierte Glyceride werden z. B. durch Alkoxylierung von natürlichen oder hydrierten Glyceriden bzw. durch Umesterung von natürlichen oder hydrierten Glyceriden mit Polyalkylenglycolen erhalten. Handelsübliche Beispiele sind Polyoxyethylenglycerolricinoleat-35, Polyoxyethylenglyceroltrihydroxystearat-40 (Cremophor® RH40, BASF AG) sowie polyalkoxylierte Glyceride wie sie unter den Handelsnamen Gelucire® und Labrafil® von Gattefosse erhältlich sind, z. B. Gelucire® 44/14 (Lauroyl-Macrogol-32-glyceride, hergestellt durch Umesterung von hydriertem Palmkernöl mit PEG 1500), Gelucire® 50/13 (Stearoyl-Macrogol-32-glyceride, hergestellt durch Umesterung von hydriertem Palmöl mit PEG 1500) oder Labrafil M1944 CS (Oleoyl-Macrogol-6-glyceride, hergestellt durch Umesterung von Aprikosenkernöl mit PEG 300).Suitable polyalkoxylated glycerides are z. B. obtained by alkoxylation of natural or hydrogenated glycerides or by transesterification of natural or hydrogenated glycerides with polyalkylene glycols. Commercial examples are Polyoxyethylenglycerolricinoleat-35, Polyoxyethylenglyceroltrihydroxystearat-40 (Cremophor® RH40, BASF AG) and polyalkoxylated glycerides as they are available under the trade names Gelucire® and Labrafil® from Gattefosse, z. Gelucire® 44/14 (lauroyl-macrogol-32-glycerides prepared by transesterification of hydrogenated palm kernel oil with PEG 1500), Gelucire® 50/13 (stearoyl macrogol-32-glycerides prepared by transesterification of hydrogenated palm oil with PEG 1500 ) or Labrafil M1944 CS (oleoyl-macrogol-6-glycerides prepared by transesterification of apricot kernel oil with PEG 300).

Ein geeigneter Fettsäureester von Polyalkylenglycolen ist z. B. PEG-660-Hydroxystearinsäure (Polyglycolester der 12-Hydroxystearinsäure (70 mol-%) mit 30 mol-% Ethylenglycol).A suitable fatty acid ester of polyalkylene glycols is e.g. B. PEG-660-hydroxystearic acid (polyglycol ester of 12-hydroxystearic acid (70 mol%) with 30 mol% ethylene glycol).

Geeignete polyalkoxylierte Ether von Fettalkoholen sind z. B. Macrogol-6-Cetylstearylether oder Macrogol-25-CetylstearyletherSuitable polyalkoxylated ethers of fatty alcohols are, for. Macrogol 6 cetyl stearyl ether or Macrogol 25 cetyl stearyl ether

Solubilisatoren werden typischerweise in einer Menge von 0,1 bis 15 Gew.-%, vorzugsweise 0,5 bis 10 Gew.-% in der Pulvermischung mitverwendet.Solubilizers are typically included in the powder mixture in an amount of 0.1 to 15% by weight, preferably 0.5 to 10% by weight.

Sprengmittel, wie vernetztes Polyvinylpyrrolidon und vernetzte Natriumcarboxymethylcellulose.Disintegrants such as crosslinked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose.

Streckmittel bzw. Füllstoffe, wie Lactose, Cellulose, Silikate oder Kieselsäure,Extenders or fillers, such as lactose, cellulose, silicates or silica,

Schmiermittel, wie Magnesium- und Calciumstearat, Natriumstearylfumarat,Lubricants, such as magnesium and calcium stearate, sodium stearyl fumarate,

Farbstoffe, wie Azofarbstoffe, organische oder anorganische Pigmente oder Farbstoffe natürlicher Herkunft,Dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin,

Stabilisatoren, wie Antioxidanzien, Lichtstabilisatoren, Hydroperoxid-Vernichter, Radikalfänger, Stabilisatoren gegen mikrobiellen Befall.Stabilizers, such as antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.

Zweckmäßigerweise mischt man die Komponenten oder einen Teil der Komponenten der Schmelze vor dem Erwärmen zu einer Pulvermischung. Das Vermischen der Komponenten zur Pulvermischung erfolgt in üblichen Mischern, wie Pflugscharmischern, Schüttel- bzw. Freifallmischern und dergleichen.Conveniently, the components or a part of the components of the melt are mixed before heating to form a powder mixture. The mixing of the components for powder mixing takes place in conventional mixers, such as plowshare mixers, shaker or free-fall mixers and the like.

Das Erwärmen der Pulvermischung erfolgt in einer für diesen Zweck üblichen Vorrichtung. Besonders geeignet sind beheizbare Extruder oder Kneter, wie Misch-Knetreaktoren (z. B. ORP, CRP, AP, DTB der Firma List oder Reactotherm der Firma Krauss-Maffei oder Ko-Kneter der Fa. Buss), Doppelmuldenkneter (Trogmischer) und Stempelkneter (Innenmischer) oder Rotor/Stator-Systeme (z. B. Dispax der Firma IKA). Die Verweildauer der Masse im Extruder beträgt vorzugsweise weniger als 5 Minuten, insbesondere weniger als 3 Minuten.The heating of the powder mixture takes place in a device customary for this purpose. Particularly suitable are heatable extruders or kneaders, such as mixing kneaders (eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei or Ko-Kneader from Buss), Doppelmulden kneaders (tray mixers) and die kneaders (Internal mixer) or rotor / stator systems (eg Dispax from IKA). The residence time of the mass in the extruder is preferably less than 5 minutes, in particular less than 3 minutes.

Als Extruder kann man Einschneckenmaschinen, kämmende Schneckenmaschinen oder auch Mehrwellextruder, insbesondere Zweischnecken-Extruder, gleichsinnig oder gegensinnig drehend und gegebenenfalls mit Knetscheiben ausgerüstet, einsetzen. Besonders bevorzugt sind gleichsinnig drehende Doppelschneckenextruder.As extruder one can use single-screw machines, intermeshing screw machines or even multi-shaft extruders, in particular twin-screw extruders, rotating in the same direction or in opposite directions and optionally equipped with kneading disks. Particularly preferred are co-rotating twin screw extruders.

Das Beschicken des Extruders bzw. Kneters erfolgt je nach deren Konzeption kontinuierlich oder diskontinuierlich in üblicher Weise. Die Pulvermischung wird vorzugsweise im freien Zulauf, z. B. über eine Differentialdosierwaage eingeführt werden.The feeding of the extruder or kneader takes place, depending on their design, continuously or discontinuously in the usual way. The powder mixture is preferably in the free feed, z. B. be introduced via a differential dosing.

Die Verwendung kontinuierlich arbeitender Kneter bzw. Extruder ist bevorzugt. Dabei führt man das pulverförmiges Gemisch des Polymers und des Wirkstoffs an einem Eintrittsende in ein längliches Extrudergehäuse ein; erwärmt das Gemisch, um eine Schmelze zu erhalten; bewegt die Schmelze durch das Extrudergehäuse zu einem Austrittsende des Extrudergehäuses; und erzeugt einen ausreichenden Gegendruck im Extrudergehäuse, damit die Schmelze aus einem Austrittsende des Extrudergehäuses als ein zusammenhängendes Extrudat austritt.The use of continuous kneader or extruder is preferred. In this process, the pulverulent mixture of the polymer and the active ingredient is introduced at an inlet end into an elongated extruder housing; heats the mixture to obtain a melt; moves the melt through the extruder barrel to an exit end of the extruder barrel; and generates a sufficient back pressure in the Extruder housing, so that the melt emerges from an outlet end of the extruder housing as a coherent extrudate.

Die erhaltene Masse wird anschließend erfindungsgemäß einer Formgebung unterzogen. Dabei kann eine Vielzahl von Formen, je nach Werkzeug und Art der Formung, erzeugt werden.The resulting composition is then subjected to shaping according to the invention. In this case, a variety of shapes, depending on the tool and type of molding, can be generated.

Unter Umständen können diese Formen auch zu Pulver gemahlen und dann in üblicher Weise zu Tabletten verpresst werden. Hierbei können Tablettierhilfsmittel wie kolloidale Kieselsäure, Calciumhydrogenphosphat, Lactose, mikrokristalline Cellulose, Stärke oder Magnesiumstearat mitverwendet werden.Under certain circumstances, these forms can also be ground to powder and then compressed in the usual way to tablets. In this case tabletting aids such as colloidal silica, calcium hydrogen phosphate, lactose, microcrystalline cellulose, starch or magnesium stearate can be used.

Die im Rahmen der Erfindung zur Formgebung der Schmelze verwendbaren Formwalzen können in an sich bekannter Weise gekühlt oder geheizt werden, und die für den jeweiligen Verarbeitungsprozeß optimale Oberflächentemperatur der Formwalze kann auf diese Weise eingestellt werden.The molding rolls usable in the invention for shaping the melt can be cooled or heated in a manner known per se, and the optimum surface temperature of the molding roll for the respective processing can be adjusted in this manner.

Die Erfindung wird anhand der Figuren 1 und 2 und durch die nachstehenden Beispiele näher veranschaulicht.The invention will be further illustrated with reference to Figures 1 and 2 and by the following examples.

Fig. 1a zeigt eine zur Durchführung des erfindungsgemäßen Verfahrens geeignete Vorrichtung 1 mit gegenläufig rotierenden Formwalzen 2 und 3. Die Formwalzen 2 und 3 weisen auf ihrer Oberfläche Vertiefungen 4 und 5 auf. Auf der Mantelfläche der Formwalzen 2 und 3 liegt eine Trennfolie 7 auf. Beim Einbringen einer wirkstoffhaltigen Schmelze 6 zwischen die Formwalzen 2 und 3 wird die Trennfolie 7 im Walzenspalt in die Vertiefungen 4 und 5 gedrückt. Nach dem Verlassen des Walzenspaltes werden die Portionen der Schmelze 6 entformt.1a shows a suitable apparatus 1 for carrying out the method according to the invention with counter-rotating forming rollers 2 and 3. The forming rollers 2 and 3 have recesses 4 and 5 on their surface. On the lateral surface of the forming rollers 2 and 3 is a release film 7. When introducing an active substance-containing melt 6 between the forming rollers 2 and 3, the release film 7 is pressed in the nip in the wells 4 and 5. After leaving the nip, the portions of the melt 6 are removed from the mold.

Fig. 1 b ist ein vergrößerter Ausschnitt des Spalts zwischen den Formwalzen 2 und 3 aus Fig. 1a und zeigt die Trennfolie 7 in ihrer Ruhelage 8 bzw. ihrer ausgelenkten Lage 9.1 b shows an enlarged detail of the gap between the forming rollers 2 and 3 from FIG. 1 a and shows the separating film 7 in its rest position 8 or its deflected position 9.

Fig. 2 zeigt eine weitere zur Durchführung des Verfahrens geeignete Vorrichtung 1 mit gegenläufig rotierenden Formwalzen 2 und 3. Die Formwalzen 2 und 3 weisen auf ihrer Oberfläche Vertiefungen 4 und 5 auf. Verstellbare Führrollen 10 erlauben es, außerhalb des Walzenspaltes die Trennfolien 7 beabstandet zu den Formwalzen 2 und 3 zu führen. An den Führrollen 10 angebrachte Stellschrauben 11 und 12 (in der Fig. 2 nicht dargestellt) erlauben den Abstand der Führrollen 10 zu variieren und damit die Spannung der Trennfolie 7, bei Verwendung elastischer Bänder eine genaue Einstellung der Dicke der Trennfolie 7 im Walzenspalt einzustellen2 shows another device 1 suitable for carrying out the method with counter-rotating forming rollers 2 and 3. The forming rollers 2 and 3 have recesses 4 and 5 on their surface. Adjustable guide rollers 10 allow the separating films 7 to be guided at a distance from the forming rollers 2 and 3 outside the nip. Adjusted to the guide rollers 10 screws 11 and 12 (not shown in FIG. 2) allow the distance of the guide rollers 10 to vary and thus adjust the tension of the release film 7, when using elastic bands an accurate adjustment of the thickness of the release film 7 in the nip

Beispiele:Examples: Beispiel 1:Example 1:

Eine Mischung enthaltend 50 Gew.-% Verapamil-Hydrochlorid, 32 Gew.-% Hydroxypropylcellulose (Klucel EF, Aqualon) und 18 Gew.-% Hydroxypropyl-methylcellulose (Methocel K4M; Colorcon) wurde in einem gleichsinnig drehenden Zweischneckenextruder bei einer Schneckendrehzahl von 80 U/min und einer Schmelze-Produkttemperatur von 110 - 120 °C zu einer homogenen Extrudat-Schmelze extrudiert. Die Schmelze gelangte direkt nach Austritt aus dem Extruderkopf zwischen ein gegenläufig drehendes Formwalzenpaar, wobei die Formwalzen auf ihrer Oberfläche jeweils Vertiefungen aufwiesen, mit deren Hilfe im Walzenspalt aus der Schmelze direkt Tabletten geformt werden konnten. Die Formwalzen waren mit einer ringförmigen Elastomer-Folie überzogen, die aus dem Stulpenbereich eines Gummihandschuhs ausgeschnitten worden war (Fa. Duo-Nit, Material: Latex-Mix, Foliendicke: 0,4 mm). Dieser Elastomer-Ring hatte im nicht-gedehnten Zustand einen leicht geringeren Durchmesser als die Formwalzen und saß daher in leicht gedehntem Zustand fest auf der Formwalzenoberfläche. Bei einer Formwalzentemperatur von 10 °C konnten mit diesem Verfahren aus der wirkstoffhaltigen Schmelze direkt längliche Tabletten von etwa 1000 mg Gewicht hergestellt werden. Es traten keinerlei Probleme mit Festkleben der Schmelze in den Kavitäten der Formwalzen auf.A mixture containing 50% by weight of verapamil hydrochloride, 32% by weight of hydroxypropylcellulose (Klucel EF, Aqualon) and 18% by weight of hydroxypropyl methylcellulose (Methocel K4M; Colorcon) was used in a co-rotating twin-screw extruder at a screw speed of 80 U / min and a melt product temperature of 110 - 120 ° C extruded into a homogeneous extrudate melt. The melt came directly after exiting the extruder head between a pair of counter-rotating mold rolls, the molding rolls each had recesses on their surface, with the help of which in the nip from the melt directly tablets could be formed. The forming rolls were coated with an annular elastomeric film which had been cut out of the gum area of a rubber glove (Duo-Nit Co., material: latex mix, film thickness: 0.4 mm). This elastomeric ring had a slightly smaller diameter than the forming rolls in the unstretched state and therefore sat firmly on the forming roll surface in a slightly stretched state. At a mold roll temperature of 10 ° C could be produced directly from the drug-containing melt direct elongated tablets of about 1000 mg in weight. There were no problems with melt sticking in the cavities of the forming rolls.

Beispiel 2 (Vergleichsbeispiel):Example 2 (Comparative Example)

Die Durchführung erfolgte wie in Beispiel 1, aber ohne Verwendung der auf den Walzen befindlichen Elastomer-Folie. Die Schmelze haftete zu stark auf den Kalanderwalzen-Oberflächen, d.h. eine Entformung der Tabletten gelang nicht.The procedure was as in Example 1, but without using the elastomeric film on the rollers. The melt adhered too much to the calender roll surfaces, i. a demolding of the tablets did not succeed.

Beispiel 3:Example 3:

Die Durchführung erfolgte wie in Beispiel 1 angegeben, aber mit einer Mischung bestehend aus 50 Gew.-% Verapamil-Hydrochlorid, 40 Gew.-% Hydroxypropylcellulose (Klucel EF, Aqualon) und 10 Gew.-% Hydroxypropyl-methylcellulose (Methocel K100M; Colorcon). Die Kalandrierung erfolgte mit einem Elastomer-Ring (Elastomer-Folie aus dem Stulpenbereich eines Gummihandschuhs, Fa. Berner, Zytostatika-Gummihandschuh Bl-4021 , Material: Natur-Latex, Foliendicke: 0,26 mm). Es traten keinerlei Probleme mit Festkleben der Schmelze in den Kavitäten der Formwalzen auf.The procedure was as described in Example 1, but with a mixture consisting of 50 wt .-% verapamil hydrochloride, 40 wt .-% hydroxypropyl cellulose (Klucel EF, Aqualon) and 10 wt .-% hydroxypropyl methylcellulose (Methocel K100M; Colorcon ). The calendering was carried out with an elastomer ring (elastomeric film from the cuff area of a rubber glove, Berner, cytostatic rubber glove Bl-4021, material: natural latex, film thickness: 0.26 mm). There were no problems with melt sticking in the cavities of the forming rolls.

Beispiel 4 (Vergleichsbeispiel):Example 4 (comparative example)

Die Durchführung erfolgte wie in Beispiel 3, aber ohne Verwendung der auf den Walzen befindlichen Elastomer-Folie. Die Schmelze haftete zu stark auf den Kalanderwalzen-Oberflächen, d.h. eine Entformung der Tabletten gelang nicht.The procedure was as in Example 3, but without the use of the rollers on the elastomeric film. The melt adhered too strongly to the calender roll surfaces, ie a demolding of the tablets did not succeed.

Beispiel 5:Example 5:

Die Durchführung erfolgte wie in Beispiel 1 angegeben, aber mit einer Mischung bestehend aus 55 Gew.-% Hydroxypropylcellulose (Klucel EF, Aqualon) und 45 Gew.-% Mannit (Fa. Merck). Die Kalandrierung erfolgte mit einem Elastomer-Ring (Elastomer-Folie aus dem Stulpenbereich eines Gummihandschuhs; Fa. Reichelt Chemie-Technik, Thomastat-HSR-2020 15 MIL black gloves, Material: Weichplast, Foliendicke: 0,15 mm). Es traten keinerlei Probleme mit Festkleben der Schmelze in den Kavitäten der Formwalzen auf.The procedure was as described in Example 1, but with a mixture consisting of 55 wt .-% hydroxypropyl cellulose (Klucel EF, Aqualon) and 45 wt .-% mannitol (Merck). The calendering was carried out using an elastomer ring (elastomeric film from the cuff area of a rubber glove, Reichelt Chemie-Technik, Thomastat-HSR-2020 15 MIL black gloves, material: soft plastic, film thickness: 0.15 mm). There were no problems with melt sticking in the cavities of the forming rolls.

Beispiel 6 (Vergleichsbeispiel):Example 6 (Comparative Example)

Die Durchführung erfolgte wie in Beispiel 5, aber ohne Verwendung der auf den Walzen befindlichen Elastomer-Folie. Die Schmelze haftete zu stark auf den Kalanderwalzen-Oberflächen, d.h. eine Entformung der Tabletten gelang nicht.The procedure was as in Example 5, but without the use of the rollers on the elastomeric film. The melt adhered too much to the calender roll surfaces, i. a demolding of the tablets did not succeed.

Beispiel 7:Example 7:

Eine Mischung enthaltend 40 Gew-% Ibuprofen, 20 Gew.-% Natriumcarbonat, 10,2 Gew.-%, Isomaltol (Isomalt F), 23,8 Gew.-% Polyvinylpyrrolidon (Kollidon K30, BASF), 5 Gew.-% quervernetztes Polyvinylpyrrolidon (Kollidon Cl, BASF), 1 Gew.-% Aerosil 200 wurde in einem gleichsinnig drehenden Zweischneckenextruder bei einer Schneckendrehzahl von 100 U/min und einer Schmelze-Produkttemperatur von 120 - 130 °C zu einer homogenen Extrudat-Schmelze extrudiert. Die Schmelze gelangte direkt nach Austritt aus dem Extruderkopf zwischen ein gegenläufig drehendes Formwalzenpaar, wobei die Formwalzen auf ihrer Oberfläche jeweils Vertiefungen besaßen, mit deren Hilfe im Walzenspalt aus der Schmelze direkt Tabletten geformt werden konnten. Die Tabletten ließen sich bei Verwendung der in Beispiel 1 angegebenen Elastomerfolie gut entformen. Es traten keinerlei Probleme mit Festkleben der Schmelze in den Kavitäten der Formwalzen auf.A mixture containing 40% by weight of ibuprofen, 20% by weight of sodium carbonate, 10.2% by weight, isomaltol (isomalt F), 23.8% by weight of polyvinylpyrrolidone (Kollidon K30, BASF), 5% by weight Crosslinked polyvinylpyrrolidone (Kollidon Cl, BASF), 1 wt .-% Aerosil 200 was extruded in a co-rotating twin-screw extruder at a screw speed of 100 rev / min and a melt product temperature of 120 - 130 ° C to form a homogeneous extrudate melt. The melt came directly after exiting the extruder head between a pair of counter-rotating mold rolls, the molding rolls each had depressions on their surface, with the help of which in the nip from the melt directly tablets could be formed. The tablets were readily demoulded using the elastomeric film specified in Example 1. There were no problems with melt sticking in the cavities of the forming rolls.

Beispiel 8 (Vergleichsbeispiel):Example 8 (Comparative Example)

Die Durchführung erfolgte wie in Beispiel 7, aber ohne Verwendung der auf den Walzen befindlichen Elastomer-Folie. Die Schmelze haftete zu stark auf den Kalanderwalzen-Oberflächen, d.h. eine Entformung der Tabletten gelang nicht.The procedure was as in Example 7, but without the use of the rollers on the elastomeric film. The melt adhered too much to the calender roll surfaces, i. a demolding of the tablets did not succeed.

Claims (17)

Verfahren zur Herstellung von Dosierungsformen, bei dem man i. zwei Trennfolien in einem definierten Bereich aneinander bringt, ii. zwischen die Trennfolien eine wirkstoffhaltige Schmelze einbringt, so dass in wenigstens einer der Trennfolien eine Tasche zur Aufnahme einer Portion der Schmelze ausgebildet wird, und iii. die Trennfolien voneinander trennt, um die Portion zu entformen. Process for the preparation of dosage forms in which i. brings two release films together in a defined area, ii. introducing an active substance-containing melt between the separating films, so that a pocket for receiving a portion of the melt is formed in at least one of the separating films, and iii. separates the release liners to remove the portion. Verfahren nach Anspruch 1, bei dem man die Trennfolien im Spalt zweier gegenläufig rotierender Formwalzen aneinander bringt, die auf ihrer Oberfläche einander gegenüber liegende Vertiefungen aufweisen, in die die Trennfolie zur Bildung von Taschen gedrückt werden können.A method according to claim 1, wherein the release films are brought into contact with each other in the nip of two counter-rotating mold rolls having on their surface opposite recesses into which the release film can be pressed to form pockets. Verfahren nach Anspruch 1 oder 2, bei dem man die Trennfolien jeweils zu einem Endlosband geschlossen sind.The method of claim 1 or 2, wherein the release films are each closed to an endless belt. Verfahren nach Anspruch 2, bei dem die Trennfolien an den Umfängen der Vertiefungen auf den Formwalzen aufliegen.The method of claim 2, wherein the release sheets rest on the peripheries of the recesses on the forming rollers. Verfahren nach einem der vorhergehenden Ansprüche, bei dem die Trennfolien eine Dicke von 0,05 bis 1,6 mm aufweisen.A method according to any one of the preceding claims, wherein the release sheets have a thickness of 0.05 to 1.6 mm. Verfahren nach einem der vorhergehenden Ansprüche, bei dem die Trennfolien elastisch verformbar sind.Method according to one of the preceding claims, in which the release films are elastically deformable. Verfahren nach Anspruch 6, bei dem die Trennfolien eine Zugfestigkeit gemäß DIN EN ISO 527-1 von 3 bis 40 Mpa aufweisen.The method of claim 6, wherein the release films have a tensile strength according to DIN EN ISO 527-1 of 3 to 40 Mpa. Verfahren nach Anspruch 6 oder 7, bei dem die Trennfolien aus Silikon-Elastomeren bestehen.The method of claim 6 or 7, wherein the release films are made of silicone elastomers. Verfahren nach einem der Ansprüche 1 bis 5, bei dem die Trennfolie aus einem wasserunlöslichen thermoplastischen Polymer bestehtMethod according to one of claims 1 to 5, wherein the release film consists of a water-insoluble thermoplastic polymer Verfahren nach einem der vorhergehenden Ansprüche, bei dem wenigstens eine der Trennfolien eine strukturierte Oberfläche aufweist.Method according to one of the preceding claims, wherein at least one of the release films has a structured surface. Vorrichtung zur Herstellung von Dosierungsformen mit Formgebungsmitteln (1), bestehend aus zwei Formwalzen (2) und (3), die zumindest eine Vertiefung (4), (5) zur Aufnahme einer wirkstoffhaltigen Schmelze (6) aufweisen, dadurch gekennzeichnet, das die Vertiefung (4) (5) eine Trennfolie (7) umfasst, die durch Einbringen der wirkstoffhaltigen Schmelze in die Vertiefung reversibel von einer Ruhelage (8) in eine ausgelenkte Lage (9) überführbar ist.Device for producing dosage forms with shaping means (1), consisting of two forming rolls (2) and (3), which have at least one depression (4), (5) for receiving a melt containing active substance (6), characterized in that the depression (4) (5) comprises a release film (7) passing through Introducing the active substance-containing melt in the recess reversibly from a rest position (8) in a deflected position (9) can be transferred. Vorrichtung nach Anspruch 11, dadurch gekennzeichnet, dass die Trennfolie (7) in der ausgelenkten Lage der Form der Vertiefung (4), (5) angepasst ist.Apparatus according to claim 11, characterized in that the release film (7) in the deflected position of the shape of the recess (4), (5) is adapted. Vorrichtung nach einem der Ansprüche 11 oder 12, dadurch gekennzeichnet, dass die Trennfolie (7) elastisch verformbar ist.Device according to one of claims 11 or 12, characterized in that the release film (7) is elastically deformable. Vorrichtung nach einem der Ansprüche 11 bis 13, dadurch gekennzeichnet , dass die Formgebungsmittel (1) zwei gegenläufig rotierende Formwalzen (2), (3) umfassen, wobei zumindest eine der Formwalzen auf ihrer Oberfläche Vertiefungen (4) zur Aufnahme der wirkstoffhaltigen Schmelze aufweist.Device according to one of claims 11 to 13, characterized in that the shaping means (1) comprise two counter-rotating forming rollers (2), (3), wherein at least one of the forming rollers on its surface recesses (4) for receiving the active substance-containing melt. Vorrichtung gemäß Anspruch 14, dadurch gekennzeichnet, dass beide Formwalzen (2), (3) auf ihren Oberflächen einander gegenüberliegende Vertiefungen (4), (5) aufweisen.Apparatus according to claim 14, characterized in that both forming rollers (2), (3) on their surfaces mutually opposite depressions (4), (5). Vorrichtung gemäß Anspruch 15, dadurch gekennzeichnet, dass die Trennfolien (7) jeweils zu einem Endlosband geschlossen sind.Apparatus according to claim 15, characterized in that the release films (7) are each closed to an endless belt. Vorrichtung gemäß Anspruch 16, dadurch gekennzeichnet, dass jede Formwalze (2) (3) von einer Trennfolie (7) umgeben ist.Apparatus according to claim 16, characterized in that each forming roller (2) (3) is surrounded by a separating film (7).
EP05003457A 2005-02-17 2005-02-17 Production of dosage forms from active molten substances Withdrawn EP1693045A1 (en)

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EP05003457A EP1693045A1 (en) 2005-02-17 2005-02-17 Production of dosage forms from active molten substances
ES06707060.7T ES2445828T3 (en) 2005-02-17 2006-02-17 Obtaining dosage forms from mergers containing active products
PCT/EP2006/001475 WO2006087218A1 (en) 2005-02-17 2006-02-17 Production of dosing molds from active substance-containing melts
EP06707060.7A EP1848394B1 (en) 2005-02-17 2006-02-17 Production of dosage forms from active molten substances
JP2007555537A JP2008529852A (en) 2005-02-17 2006-02-17 Production of dosage forms consisting of active substance-containing melts
US11/884,521 US20090050262A1 (en) 2005-02-17 2006-02-17 Production of Dosing Molds from Active Substance-Containing Melts
CA2598168A CA2598168C (en) 2005-02-17 2006-02-17 Production of dosing molds from active substance-containing melts
DK06707060.7T DK1848394T3 (en) 2005-02-17 2006-02-17 Preparation of dosage forms of hot melt containing active ingredients

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DK1848394T3 (en) 2014-01-20
EP1848394B1 (en) 2013-10-09
CA2598168A1 (en) 2006-08-24
CA2598168C (en) 2014-09-23
EP1848394A1 (en) 2007-10-31
ES2445828T3 (en) 2014-03-05
WO2006087218A1 (en) 2006-08-24
JP2008529852A (en) 2008-08-07

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