EP1848394B1 - 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
EP1848394B1
EP1848394B1 EP06707060.7A EP06707060A EP1848394B1 EP 1848394 B1 EP1848394 B1 EP 1848394B1 EP 06707060 A EP06707060 A EP 06707060A EP 1848394 B1 EP1848394 B1 EP 1848394B1
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EP
European Patent Office
Prior art keywords
melt
separating
films
separating films
film
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EP06707060.7A
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German (de)
French (fr)
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EP1848394A1 (en
Inventor
Jörg Rosenberg
Norbert Steiger
Harald Hach
Jörg Breitenbach
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AbbVie Deutschland GmbH and Co KG
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Abbott GmbH and Co KG
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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 producing 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.
  • the EP 0358105 describes a method for shaping extrudate masses. Here are two elastic bands with opposite recesses, which determine the tablet shape used.
  • the 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 sheets of the wrapping material.
  • the SU 1824158 describes an apparatus for molding viscoplastic praline masses.
  • the device comprises a hopper with two chambers. Under the hopper, a molding roll with cells for receiving and shaping the candy mass is arranged. The forming roll is covered with an elastic band. Under pressure, a first mass is forced out of the first chamber into the cells, whereby the elastic band is partially deflected. The forming roll continues to rotate and a second mass is forced out of the second chamber into the cells, with maximum deflection of the elastic band. Upon further rotation of the chocolate mass molding is ejected by the elasticity of the tape from the cells.
  • the JP 02 063699 A discloses a Druckgranuliervorraum with two counter-rotating rollers and two elastic films which rest on the rollers at least in the contact area of the rollers. Recesses are provided on the surface of the rollers or films. A powder is compressed between the rollers and maintains the shape of the recesses.
  • 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.
  • the release film is expediently brought into contact with the heat-sink, at least in the area of the pocket, with the side facing away from the melt. Heat is removed from the melt via the release film and the melt solidifies. In addition, the thermal load on the release film is reduced and increases its life.
  • the incoming melt usually has a temperature of more than 70 ° C, usually more than 80 ° C, for. B. 80 to 180 ° C.
  • the release films are brought into contact with each other in the nip of two counterrotating molding rolls, at least one of which has depressions 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 mold rolls melt and to the surfaces the wells pressed.
  • 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 forming rollers also act as heat sinks and are for this purpose made of a highly thermally conductive material, preferably a metal, such as stainless steel or non-ferrous alloys.
  • the heat dissipation can passively be effected by heat radiation from the forming rolls to the environment or by active cooling of the forming rolls, e.g. B. by circulating a coolant through holes in the interior of the molding rolls. Only when the release film is completely pressed into the recess of the mold roll and the bag formed is completely filled with melt, the release film touches the surface of the mold roll. Only then begins a noticeable cooling and solidification of the melt. Premature solidification, which could lead to incomplete filling of the wells with melt, is largely avoided. This gives moldings which are very uniform in their shape and mass.
  • 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 winding it onto a second roll after passing through the nip.
  • 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 a mixing and plasticizing unit for the formation of an active ingredient-containing melt and shaping means, which consist of two molding rolls, which have at least one recess for receiving a melt containing active substance.
  • 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 silicone
  • elastomers that are accepted as product-contacting materials in pharmaceutical manufacturing processes, e.g. Silicones. These silicone materials can be produced by addition-curing, condensation-curing or free-radical crosslinking. Other preferred materials are natural rubber and synthetic rubber, with natural rubber being particularly preferred.
  • Preferred release film materials have one or more, preferably all of the following properties:
  • property unit preferably particularly preferred hardness Shore A 35 - 90 45 - 75 tear strength [N / mm 2 ] 15 - 30 15 - 30 elongation at break [%] 100 - 900 200 - 900 Tear strength [N / mm] ⁇ 3,2
  • property unit preferably particularly preferred hardness Shore A 35 - 95 45 - 75 tear strength [N / mm 2 ] 6 - 50 8 - 50 elongation at break [%] 100 - 800 200 - 800 Tear resistance [N / mm] > 25
  • property unit preferably particularly preferred hardness Shore A 5 - 80 45 - 75 tear strength [N / mm 2 ] 2.4 - 9.5 6 - 9.5 elongation at break [%] 100 - 600 200 - 600 Tear strength [N / mm] 4.4 - 52.5
  • 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 ter and block polymers, eg 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, poly
  • 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.
  • 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.
  • 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 in DE 102 62 005 described.
  • 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 are, 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.
  • Commercially available examples are Polyoxyethylenglycerolricinoleat-35, Polyoxyethylenglyceroltrihydroxystearat-40 (Cremophore 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.
  • Mixing 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 mixing and plasticizing unit 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 elongate 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 sufficient back pressure in the extruder barrel to allow the melt to exit from an exit end of the extruder barrel as a continuous 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.
  • the invention is based on the FIGS. 1 and 2 and illustrated by the examples below.
  • Fig. 1a shows a device 1 suitable 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 is an enlarged section of the gap between the forming rollers 2 and 3 from Fig. 1a and shows the release film 7 in its rest position 8 and its deflected position.
  • Fig. 2 shows a further suitable for carrying out the method device 1 with counter-rotating forming rollers 2 and 3.
  • the forming rollers 2 and 3 have recesses 4 and 5 on its 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.
  • On the guide rollers 10 mounted screws 11 and 12 (in the Fig. 2 not shown) allow the distance between 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 hydroxypropylmethylcellulose (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 Formwalzentemperatur of 10 ° C could with this process from the active ingredient-containing melt directly elongated tablets of about 1000 mg in weight are produced. 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 BI-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 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 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.
  • 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 cross-linked polyvinylpyrrolidone (Kollidon Cl, BASF), 1 wt .-% Aerosil 200 was extruded in a co-rotating twin-screw extruder at a screw speed of 100 U / 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.
  • 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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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 producing 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.The 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.The 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 sheets of the wrapping material.

Die SU 1824158 beschreibt eine Vorrichtung zum Formen von viskoplastischen Pralinenmassen. Die Vorrichtung umfasst einen Fülltrichter mit zwei Kammern. Unter dem Fülltrichter ist eine Formwalze mit Zellen zur Aufnahme und Formung der Pralinenmasse angeordnet. Die Formwalze ist mit einem elastischen Band bedeckt. Unter Druck wird aus der ersten Kammer eine erste Masse in die Zellen gedrückt, wobei das elastische Band teilweise ausgelenkt wird. Die Formwalze dreht sich weiter und aus der zweiten Kammer wird eine zweite Masse in die Zellen gedrückt, wobei das elastische Band maximal ausgelenkt wird. Beim Weiterdrehen wird der Pralinenmassenformling durch die Elastizität des Bandes aus den Zellen ausgeworfen.The SU 1824158 describes an apparatus for molding viscoplastic praline masses. The device comprises a hopper with two chambers. Under the hopper, a molding roll with cells for receiving and shaping the candy mass is arranged. The forming roll is covered with an elastic band. Under pressure, a first mass is forced out of the first chamber into the cells, whereby the elastic band is partially deflected. The forming roll continues to rotate and a second mass is forced out of the second chamber into the cells, with maximum deflection of the elastic band. Upon further rotation of the chocolate mass molding is ejected by the elasticity of the tape from the cells.

Die JP 02 063699 A offenbart eine Druckgranuliervorrichtung mit zwei gegenläufig rotierenden Walzen und zwei elastischen Folien, die zumindest im Kontaktbereich der walzen auf den Walzen aufliegen. Auf der Oberfläche der Walzen oder der Folien sind Vertiefungen vorgesehen. Ein Pulver wird zwischen den Walzen komprimiert und erhält die Gestalt der Vertiefungen.The JP 02 063699 A discloses a Druckgranuliervorrichtung with two counter-rotating rollers and two elastic films which rest on the rollers at least in the contact area of the rollers. Recesses are provided on the surface of the rollers or films. A powder is compressed between the rollers and maintains the shape of the recesses.

Weder die SU 1824158 noch die JP 02 063699 A betreffen die Formung von Schmelzen, d. h. von Massen, die bei erhöhter Temperatur plastisch sind und die bei Abkühlung erstarren.Neither the SU 1824158 still the JP 02 063699 A relate to the formation of melts, ie masses which are plastic at elevated temperature and which solidify on cooling.

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. Damit sich die Portion der Schmelze ausreichend verfestigt und beim Entformen die eingenommene Gestalt im Wesentlichen beibehält, bringt man die Trennfolie zweckmäßigerweise zumindest im Bereich der Tasche mit der der Schmelze abgewandten Seite mit einer Wärmesenke in Kontakt. Über die Trennfolie wird der Schmelze Wärme entzogen und die Schmelze verfestigt sich. Außerdem wird die thermische Belastung der Trennfolie vermindert und ihre Lebensdauer erhöht.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 order for the portion of the melt to solidify sufficiently and essentially retain the assumed shape during demolding, the release film is expediently brought into contact with the heat-sink, at least in the area of the pocket, with the side facing away from the melt. Heat is removed from the melt via the release film and the melt solidifies. In addition, the thermal load on the release film is reduced and increases its life.

Die eintretende Schmelze weist üblicherweise eine Temperatur von mehr als 70 °C, meist mehr als 80 °C auf, z. B. 80 bis 180 °C. Im Allgemeinen hält man eine Temperaturdifferenz zwischen der einzubringenden Schmelze und der Wärmesenke von wenigstens 30 °C, insbesondere wenigstens 40 °C, besonders bevorzugt wenigstens 50 °C, ein.The incoming melt usually has a temperature of more than 70 ° C, usually more than 80 ° C, for. B. 80 to 180 ° C. In general, a temperature difference between the melt to be introduced and the heat sink of at least 30 ° C., in particular at least 40 ° C., particularly preferably at least 50 ° C., is maintained.

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.In a preferred embodiment, the release films are brought into contact with each other in the nip of two counterrotating molding rolls, at least one of which has depressions 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 mold rolls melt and to the surfaces the wells pressed. 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 Formwalzen wirken außerdem als Wärmesenken und sind zu diesem Zweck aus einem gut wärmeleitenden Material, vorzugsweise einem Metall, wie Edelstahl oder Buntmetalllegierungen, gefertigt. Die Wärmeabfuhr kann passiv durch Wärmeabstrahlung von den Formwalzen an die Umgebung oder durch aktives Kühlen der Formwalzen erfolgen, z. B. durch Zirkulieren eines Kühlmittels durch Bohrungen im Innern der Formwalzen. Erst wenn die Trennfolie vollständig in die Vertiefung der Formwalze gedrückt und die gebildete Tasche vollständig mit Schmelze gefüllt ist, berührt die Trennfolie die Oberfläche der Formwalze. Erst dann beginnt eine merkliche Abkühlung und Verfestigung der Schmelze. Ein vorzeitiges Verfestigen, das zu einem unvollständigen Ausfüllen der Vertiefungen mit Schmelze führen könnte, wird weitgehend vermieden. Man erhält auf diese Weise Formlinge, die hinsichtlich ihrer Gestalt und ihrer Masse sehr einheitlich sind.The forming rollers also act as heat sinks and are for this purpose made of a highly thermally conductive material, preferably a metal, such as stainless steel or non-ferrous alloys. The heat dissipation can passively be effected by heat radiation from the forming rolls to the environment or by active cooling of the forming rolls, e.g. B. by circulating a coolant through holes in the interior of the molding rolls. Only when the release film is completely pressed into the recess of the mold roll and the bag formed is completely filled with melt, the release film touches the surface of the mold roll. Only then begins a noticeable cooling and solidification of the melt. Premature solidification, which could lead to incomplete filling of the wells with melt, is largely avoided. This gives moldings which are very uniform in their shape and mass.

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. In der Regel sind jedoch zwei identische Trennfolien bevorzugt.Of course, it is also possible for the process two release films of different material and / or different thickness and / or different To select softener content. In general, however, two identical release films are preferred.

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 winding it onto a second roll after passing through the nip. 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 einer Misch- und Plastifiziereinheit zur Bildung einer wirkstoffhaltigen Schmelze und 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 a mixing and plasticizing unit for the formation of an active ingredient-containing melt and shaping means, which consist of two molding rolls, which have at least one recess for receiving a melt containing active substance. 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. Weitere bevorzugte Materialien sind Naturkautschuk und Synthesekautschuk, wobei Naturkautschuk besonders bevorzugt ist.Preferred are elastomers that are accepted as product-contacting materials in pharmaceutical manufacturing processes, e.g. Silicones. These silicone materials can be produced by addition-curing, condensation-curing or free-radical crosslinking. Other preferred materials are natural rubber and synthetic rubber, with natural rubber being particularly preferred.

Bevorzugte Trennfolien-Materialien weisen eine oder mehrere, vorzusweise alle der folgenden Eigenschaften auf:Preferred release film materials have one or more, preferably all of the following properties:

Naturkautschuknatural rubber

Eigenschaftproperty Einheitunit vorzugsweisepreferably besonders bevorzugtparticularly preferred Härtehardness Shore AShore A 35 - 9035 - 90 45 - 7545 - 75 Reißfestigkeittear strength [N/mm2][N / mm 2 ] 15 - 3015 - 30 15 - 3015 - 30 Reißdehnungelongation at break [%][%] 100 - 900100 - 900 200 - 900200 - 900 WeiterreißwiderstandTear strength [N/mm][N / mm] ≥3,2≥3,2

Synthesekautschuksynthetic rubber

Eigenschaftproperty Einheitunit vorzugsweisepreferably besonders bevorzugtparticularly preferred Härtehardness Shore AShore A 35 - 9535 - 95 45 - 7545 - 75 Reißfestigkeittear strength [N/mm2)[N / mm 2 ] 6 - 506 - 50 8 - 508 - 50 Reißdehnungelongation at break [%][%] 100 - 800100 - 800 200 - 800200 - 800 WeiterreißwiederstandTear resistance [N/mm][N / mm] >25> 25

Silikonesilicones

Eigenschaftproperty Einheitunit vorzugsweisepreferably besonders bevorzugtparticularly preferred Härtehardness Shore AShore A 5 - 805 - 80 45 - 7545 - 75 Reißfestigkeittear strength [N/mm2][N / mm 2 ] 2,4 - 9,52.4 - 9.5 6 - 9,56 - 9.5 Reißdehnungelongation at break [%][%] 100 - 600100 - 600 200 - 600200 - 600 WeiterreißwiderstandTear strength [N/mm][N / mm] 4,4 - 52,54.4 - 52.5

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 ter and block polymers, eg 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 homo- 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, beispielsweiseThese are in particular mixtures containing pharmacologically acceptable polymers, for example

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,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. As 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, Ipratropium-Hydroxid, Ibuprofen, Imipenem, Indomethacin, Insulin, Iohexol, lopamidol, Isosorbid-Dinitrat, Isosorbid-Mononitrat, Isotretinoin, 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, ipratropium hydroxide, ibuprofen, imipenem, indomethacin, insulin, iohexol, 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 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, rami pril, ranitidine, reserpine, retinol, 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 in DE 102 62 005 described.

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 are, 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 (Cremophore 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. Commercially available examples are Polyoxyethylenglycerolricinoleat-35, Polyoxyethylenglyceroltrihydroxystearat-40 (Cremophore 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. Mixing 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 Mischund Plastifiziereinheit. 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 mixing and plasticizing unit 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 elongate 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 sufficient back pressure in the extruder barrel to allow the melt to exit from an exit end of the extruder barrel as a continuous 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 is based on the FIGS. 1 and 2 and illustrated by the examples below.

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. Fig. 1a shows a device 1 suitable 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. Fig. 1 b is an enlarged section of the gap between the forming rollers 2 and 3 from Fig. 1a and shows the release film 7 in its rest position 8 and 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 einzustellen Fig. 2 shows a further suitable for carrying out the method device 1 with counter-rotating forming rollers 2 and 3. The forming rollers 2 and 3 have recesses 4 and 5 on its 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. On the guide rollers 10 mounted screws 11 and 12 (in the Fig. 2 not shown) allow the distance between 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 hydroxypropylmethylcellulose (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 Formwalzentemperatur of 10 ° C could with this process from the active ingredient-containing melt directly elongated tablets of about 1000 mg in weight are produced. 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 BI-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 BI-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 much to the calender roll surfaces, i. 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 cross-linked polyvinylpyrrolidone (Kollidon Cl, BASF), 1 wt .-% Aerosil 200 was extruded in a co-rotating twin-screw extruder at a screw speed of 100 U / 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 (18)

  1. A process for the production of dose forms, in which
    i. two separating films are brought together in a defined area,
    ii. an active substance-containing melt is introduced between the separating films, such that in at least one of the separating films a pocket for receiving a portion of the melt is formed, the separating film is brought into contact with a heat sink in the area of the pocket with the side facing away from the melt and
    iii. the separating films are separated from one another in order to demold the portion.
  2. The process as claimed in claim 1, in which a temperature difference of at least 30°C is maintained between the melt to be introduced and the heat sink.
  3. The process as claimed in claim 1 or 2, in which the separating films are brought together in the gap between two counterrotating shaping rolls, which have hollows on their surface opposite to one another, into which the separating film can be pressed for the formation of pockets.
  4. The process as claimed in one of the preceding claims, in which the separating films are in each case closed to give an endless belt.
  5. The process as claimed in claim 4, in which the separating films lie on the shaping rolls at the peripheries of the hollows.
  6. The process as claimed in one of the preceding claims, in which the separating films have a thickness of 0.05 to 1.6 mm.
  7. The process as claimed in one of the preceding claims, in which the separating films are elastically deformable.
  8. The process as claimed in claim 7, in which the separating films have a tensile strength according to DIN EN ISO 527-1 of 3 to 40 Mpa.
  9. The process as claimed in claim 7 or 8, in which the separating films consist of natural rubber, synthetic rubber or silicone elastomers.
  10. The process as claimed in one of claims 1 to 6, in which the separating film consists of a water-insoluble thermoplastic polymer.
  11. The process as claimed in one of the preceding claims, in which at least one of the separating films has a structured surface.
  12. A device for the production of dose forms having a mixing and plasticizing unit for the formation of an active substance-containing melt and shaping means (1), consisting of two shaping rolls (2) and (3), which have at least one hollow (4), (5) for receiving the active substance-containing melt (6), wherein the hollow (4), (5) comprises a separating film (7), which is reversibly translatable from a resting position (8) to a deflected position (9) by introduction of the active substance-containing melt into the hollow, characterized in that the shaping rolls are formed as heat sinks.
  13. The device as claimed in claim 12, characterized in that the separating film (7) is adjusted to the shape of the hollow (4), (5) in the deflected position.
  14. The device as claimed in one of claims 12 or 13, characterized in that the separating film (7) is elastically deformable.
  15. The device as claimed in one of claims 12 to 14, characterized in that the shaping means (1) comprise two counterrotating shaping rolls (2), (3), at least one of the shaping rolls having hallows (4) on its surface for receiving the active substance-containing melt.
  16. The device as claimed in claim 15, characterized in that both shaping rolls (2), (3) have hollows (4), (5) lying opposite one another on their surfaces.
  17. The device as claimed in claim 16, characterized in that the separating films (7) are in each case closed to give an endless belt.
  18. The device as claimed in claim 17, characterized in that each shaping roll (2) (3) is surrounded by a separating film (7).
EP06707060.7A 2005-02-17 2006-02-17 Production of dosage forms from active molten substances Active EP1848394B1 (en)

Priority Applications (1)

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EP05003457A EP1693045A1 (en) 2005-02-17 2005-02-17 Production of dosage forms from active molten substances
PCT/EP2006/001475 WO2006087218A1 (en) 2005-02-17 2006-02-17 Production of dosing molds from active substance-containing melts
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US20090317355A1 (en) * 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
TW200950776A (en) * 2008-01-24 2009-12-16 Abbott Gmbh & Co Kg Abuse resistant melt extruded formulation having reduced alcohol interaction
US9226907B2 (en) 2008-02-01 2016-01-05 Abbvie Inc. Extended release hydrocodone acetaminophen and related methods and uses thereof
CN108309796A (en) * 2018-01-17 2018-07-24 刘雅文 A kind of compression prepared slices of Chinese crude drugs and preparation method thereof
KR102585933B1 (en) * 2022-09-21 2023-10-06 주식회사 태성공영 equipment of manufacturing for globular
CN117698024B (en) * 2023-12-18 2024-06-25 青岛环球输送带有限公司 Energy-saving rubber vulcanizing machine

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SU1600670A2 (en) * 1987-12-03 1990-10-23 Кемеровский технологический институт пищевой промышленности Device for forming masses
JPH0263699A (en) * 1988-08-29 1990-03-02 Fuji Paudaru Kk Compression granulating device
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DE4446468A1 (en) * 1994-12-23 1996-06-27 Basf Ag Process for the production of coated tablets

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CA2598168A1 (en) 2006-08-24
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CA2598168C (en) 2014-09-23
US20090050262A1 (en) 2009-02-26
EP1848394A1 (en) 2007-10-31
JP2008529852A (en) 2008-08-07
DK1848394T3 (en) 2014-01-20

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