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EP1133271A1 - Method of producing solid dosage forms - Google Patents

Method of producing solid dosage forms

Info

Publication number
EP1133271A1
EP1133271A1 EP99959299A EP99959299A EP1133271A1 EP 1133271 A1 EP1133271 A1 EP 1133271A1 EP 99959299 A EP99959299 A EP 99959299A EP 99959299 A EP99959299 A EP 99959299A EP 1133271 A1 EP1133271 A1 EP 1133271A1
Authority
EP
European Patent Office
Prior art keywords
dosage forms
acid
solid dosage
annular groove
molding
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP99959299A
Other languages
German (de)
French (fr)
Other versions
EP1133271B1 (en
Inventor
Jörg Rosenberg
Werner Maier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Knoll GmbH filed Critical Knoll GmbH
Publication of EP1133271A1 publication Critical patent/EP1133271A1/en
Application granted granted Critical
Publication of EP1133271B1 publication Critical patent/EP1133271B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • 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
    • B30B11/165—Roll constructions

Definitions

  • the present invention relates to a method for producing solid dosage forms by producing a plastic mixture which contains at least one active ingredient and at least one polymeric binder, and molding the plastic mixture into the solid dosage forms in a mold calender with two counter-rotating molding rolls.
  • the form rollers of the form calender have depressions with corresponding contour lines on their surface.
  • the depressions on the surfaces of the shaping rollers briefly meet at the contact line of the shaping rollers to form molds for the active substance-containing melt and then strive apart again as the shaping rollers continue to rotate, the molded dosage forms being released.
  • This method has certain disadvantages.
  • the recesses on the surface of the shaping rollers with their outlines must lie exactly one above the other when shaping the plastic mixture in order to achieve a complete positive fit. Even the smallest displacements of the wells against each other, for example in the range of a few micrometers, immediately lead to a recognizable offset of the top and bottom of the dosage form.
  • segmentation of the forming rolls into individual roll disks which each contain only one or a few traces of depressions and can be combined in any way to form a multi-track roll, is impossible because the pressing forces occurring during calendering are easily "twisted" the individual segments.
  • this twisting means that the upper and lower halves of the tablet shapes do not lie exactly one above the other during rotation.
  • the segmentation of the form rollers is However, it is desirable, for example, if only one roller disc and not the entire roller has to be replaced if individual cavities are damaged, or in order to be able to combine different shapes in one roller as desired.
  • the present invention is therefore based on the object of providing a simple and inexpensive method for producing solid dosage forms, in which no problems arise with respect to an offset of the top and bottom halves of the dosage forms.
  • the present invention therefore relates to a process for the production of solid dosage forms
  • a molding calender with two counter-rotating molding rolls, characterized in that one molding roll has at least one circumferential annular groove and the other shaping roll has at least one circumferential rim of radially outwardly extending teeth has, which can engage in the annular groove.
  • the teeth are shaped in such a way that they fully fill the cross-section of the ring groove with maximum engagement in the ring groove, i.e. the cross-sectional profile of the ring groove and the teeth are essentially complementary.
  • Molding rolls to be used according to the invention are known as “prism rolls” from compacting technology. Reference is made to B. Pietsch, Aufaufungs-Technik 3 (1970) pp. 128-138. The use of such rollers for solidifying free-flowing bulk goods into granules is described there. Problems of a possible misalignment between the upper and lower half of the compresses formed are not addressed in this context.
  • pairs of rollers to be used according to the invention enable a considerable variety of shapes of the solid dosage forms thus produced.
  • the possible variations relate primarily to the formation of the annular groove and the formation of the space between successive teeth of a ring.
  • the ring groove can have a number of different cross-sectional profiles (projection onto a plane that contains the roller axis).
  • the ring groove can have a rectangular, triangular, rounded or other cross section.
  • it is preferred that the annular groove has a rounded cross-sectional profile for easier demolding of the shaped dosage forms.
  • the longitudinal profile of the spaces between successive teeth of a ring (i.e. the projection of the space on a plane perpendicular to the roller axis) is also subject to variation.
  • the gaps can have a triangular, parallelogram-shaped, rounded or other longitudinal profile. In general, however, it is preferred that the spaces between successive teeth of a ring have a rounded longitudinal profile.
  • the dosage forms obtained can be e.g. Have prism shape, prism shape, tetrahedral shape or saddle body shape, the saddle body shape being preferred.
  • the dosage forms are allowed to cool and solidify, e.g. on a cooling belt.
  • the present method of making solid dosage forms involves making a plastic mixture. This is usually done by mixing and melting at least one pharmacologically acceptable polymeric binder, at least one active pharmaceutical ingredient and, if appropriate, customary pharmaceutical additives in the presence or absence of a solvent. These process steps can be carried out in a known manner.
  • the components can first be mixed and then melted and homogenized. However, especially when using sensitive active ingredients, it has proven to be preferable to first melt and premix the polymeric binder, optionally together with customary pharmaceutical additives, the stirred kettles, agitators, solid-state mixers etc. optionally being operated alternately, and then the Mix in (the) sensitive active ingredient (s) in "intensive mixers" in the plastic phase with very short residence times (homogenization).
  • the active ingredient (s) can be used in solid form or as a solution or dispersion.
  • the melting and mixing takes place in a device which is customary for this purpose.
  • Extruders or heatable containers with stirrers, such as kneaders, (such as those mentioned below) are particularly suitable.
  • Devices which are used in plastics technology for mixing can also be used as a mixing apparatus. Suitable devices are described, for example, in “Mixing in the manufacture and processing of plastics", H. Pahl, VDI-Verlag, 1986.
  • Particularly suitable mixing devices are extruders and dynamic and static mixers, and stirred kettles, single-shaft stirrers with stripping devices, in particular so-called paste stirrers, multi-shaft Agitators, in particular PDSM mixers, solids mixers and preferably mixing kneading reactors (eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei or Ko-Kneaders from Buss), double-bowl kneaders (trough mixers) and stamp kneaders (Internal mixer) or rotor / stator systems (eg Dispax from IKA).
  • kneading reactors eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei or Ko-Kneaders from Buss
  • double-bowl kneaders trough mixers
  • stamp kneaders
  • the polymer binder is preferably first melted in an extruder and then the active substance is mixed in in a kneading reactor.
  • a rotor / stator system can be used for intensive dispersion of the active ingredient.
  • the mixing device is loaded continuously or discontinuously in the usual way.
  • Powdered components can be fed in free, e.g. be introduced via a differential dosing scale.
  • Plastic masses can be fed in directly from an extruder or fed in via a gear pump, which is particularly advantageous for high viscosities and high pressures.
  • Liquid media can be metered in using a suitable pump unit.
  • the mixture obtained by mixing and melting the binder, the active ingredient and optionally the additive or additives is pasty to viscous (thermoplastic) and therefore also extrudable.
  • the glass transition temperature of the mixture is below the decomposition temperature of all components contained in the mixture.
  • the binder should preferably be soluble or swellable in a physiological environment. Examples of suitable binders are:
  • the K values (according to H. Fikentscher, Cellulose-Chemie 13 (1932), pages 58-64, 71, 74) of the polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, for PVP> 17, especially 20 to 35.
  • Preferred polymeric binders are polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates, polyacrylates, alkyl celluloses and hydroxyalkyl celluloses.
  • the polymeric binder must soften or melt in the total mixture of all components in the range from 50 to 180 ° C., preferably 60 to 130 ° C.
  • the glass transition temperature of the mixture must therefore be below 180 ° C, preferably below 130 ° C. If necessary, it is reduced by conventional, pharmacologically acceptable plasticizing auxiliaries.
  • the amount of plasticizer is at most 30% by weight, based on the total weight of binder and plasticizer, so that storage-stable drug forms are formed which show no cold flow. However, the mixture preferably contains no plasticizer.
  • plasticizers examples include:
  • plasticizer long-chain alcohols, ethylene glycol, propylene glycol, glycerol, trimethylolpropane, triethylene glycol, butanediols, pentanols, such as pentaerythritol, hexanols, polyethylene glycols, polypropylene glycols, polyethylene propylene glycols, silicones, aromatic carboxylic acid esters (for example dialkyl phthalate, benzoate phthalate ester acid) Dicarboxylic acid esters (eg dialkyl adipates, 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 diethylsulfosuccinate.
  • concentration of plasticizer is generally 0.5 to 15, preferably 0.5 to 5 wt .-%, based on the total weight of the mixture.
  • Typical pharmaceutical auxiliaries are, for example, extenders or fillers, such as silicates or silica, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or their salts, for example the magnesium or calcium salt , Methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, polyvinyl alcohol, in particular in a concentration of 0.02 to 50, preferably 0.20 to 20% by weight, based on the total weight of the mixture.
  • Lubricants such as aluminum and calcium stearate, talc and silicone, in a concentration of 0.1 to 5, preferably 0.1 to 3% by weight, based on the total weight of the mixture.
  • Plasticizers such as animal or vegetable fats, especially in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50 ° C or higher. Triglycerides of Cj .2 -, C 14 -, C ⁇ 6 - and Ci ⁇ fatty acids are preferred. Waxes such as carnauba wax can also be used. These fats and waxes can advantageously be admixed alone or together with mono- and / or diglycerides or phosphatides, in particular lecithin. The mono- and diglycerides are preferably derived from the fatty acid types mentioned above. The total amount of fats, waxes, mono-, diglycerides and / or lecithins is 0.1 to 30, preferably 0.1 to 5% by weight, based on the total weight of the mass for the respective layer;
  • Dyes such as azo dyes, organic or inorganic pigments or dyes of natural origin, preference being given to inorganic pigments in a concentration of 0.001 to 10, preferably 0.5 to 3% by weight, based on the total weight of the mixture;
  • Stabilizers such as antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.
  • wetting agents, preservatives, disintegrants, adsorbents, mold release agents and blowing agents can also be added (cf. e.g. H. Sucker et al. Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978).
  • auxiliaries are, for example, pentaerythritol and pentaerythritol tetraacetate, polymers such as e.g. Polyethylene or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinyl pyrrolidone, surfactants such as polyoxyethylene 40 stearate and citric and succinic acid, bile acids, sterols and others such as e.g. in J.L. Ford, Pharm. Acta Helv. 61 (1986) pp. 69-88.
  • polymers such as e.g. Polyethylene or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinyl pyrrolidone, surfactants such as polyoxyethylene 40 stearate and citric and succinic acid, bile acids, sterols and others
  • auxiliaries Additions of bases and acids to control the solubility of an active ingredient are also considered pharmaceutical auxiliaries (see, for example, K. Thoma et al., Pharm. Ind. 51 (1989) 98-101). The only requirement for the suitability of auxiliaries is adequate temperature stability.
  • compositions in the sense of the invention are understood to mean all substances with a pharmaceutical effect and as few side effects as possible, provided that they do not decompose under the processing conditions.
  • the amount of active ingredient per dose unit and the concentration can vary within wide limits depending on the effectiveness and rate of release. The only condition is that they are sufficient to achieve the desired effect.
  • the active substance concentration can thus be in the range from 0.1 to 95, preferably from 20 to 80, in particular 30 to 70% by weight. Combinations of active substances can also be used.
  • Active substances in the sense of the invention are also vitamins and minerals, as well as plant treatment agents and insecticides.
  • the vitamins include the vitamins of the A group and the B group, which in addition to Bi, B 2 , B ß and B 12 and nicotinic acid and nicotimide also include compounds with vitamin B properties, such as adenine, choline, Pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-amine-topzoic acid, myo-inositol and lipoic acid as well as vitamin C, vitamins of the D group, E group, F group, H group, I - and J group, K group and P group. Active substances in the sense of the invention also include peptide therapeutic agents.
  • the method according to the invention is suitable, for example, for processing the following active ingredients:
  • Preferred active substances are ibuprofen (as racemate, enantiomer or enriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid, verapamil, paracetamol, nifedipine or captopril.
  • solid solutions can be formed.
  • solid solutions is familiar to the person skilled in the art, for example from the literature cited at the beginning.
  • fixed solutions Solutions of active pharmaceutical ingredients in polymers the active ingredient is molecularly dispersed in the polymer.
  • the mixture obtained is preferably solvent-free, i.e. it contains neither water nor an organic solvent.
  • the resulting mixture is then introduced into a mold calender discussed above.
  • the solid pharmaceutical forms which can be produced by the process according to the invention can also be provided in a conventional manner with film coatings which control the release of active ingredient or cover the taste.
  • suitable materials for coatings of this type are polyacrylates, such as the Eurogitit types, cellulose esters, such as the hydroxypropylmethylcellulose sephates, and cellulose ethers, such as ethylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose.
  • FIG. 1 Different designs of the annular groove present in a roller according to the invention
  • FIG. 2 Different designs of the spaces between successive teeth of a ring of teeth present on a roller according to the invention and the dosage forms obtainable therewith
  • FIG. 3 The construction principle of a pair of rollers to be used according to the invention using a concrete example.
  • the ring groove can have a rectangular (a), triangular (b) or rounded (c) cross-sectional profile.
  • At the bottom of the annular groove there can be a circumferential ridge (d) which leads to solid dosage forms which have a notch on one side of their surface.
  • the dosage forms with prism shape (a), prism shape (b) or saddle body shape (c) are shown, depending on the design of the spaces between successive teeth of a ring.
  • FIG. 3 illustrates the construction principle of a pair of rollers with two tracks, one roller having two circumferential ring grooves with a rounded cross-sectional profile and the other roller having two circumferential rings of radially outwardly extending teeth, the spaces between successive teeth having a rounded longitudinal profile.
  • FIG. 3 shows a cross section of the roller pair through the roller axes at the top.
  • Figure 3 shows a cross section of the roller pair perpendicular to the roller axes below.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Medicinal Preparation (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process for producing solid dosage forms by a) producing a plastic mixture which comprises at least one active ingredient and at least one polymeric binder, and b) shaping the plastic mixture to the solid dosage forms in a molding calender with two counterrotating molding rolls, wherein one molding roll has at least one annular groove running along its periphery and the other molding roll has at least one ring, running along its periphery, of teeth extending radially outward and able to engage in the annular groove is described.

Description

Verfahren zur Herstellung von festen DosierungsformenProcess for the preparation of solid dosage forms
Beschreibungdescription
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von festen Dosierungsformen durch Herstellen eines plastischen Gemisches, das wenigstens einen Wirkstoff und wenigstens ein polymeres Bindemittel enthält, und Formen des plastischen Gemisches zu den festen Dosierungsformen in einem Formkalander mit zwei gegenläufig rotierenden Formwalzen.The present invention relates to a method for producing solid dosage forms by producing a plastic mixture which contains at least one active ingredient and at least one polymeric binder, and molding the plastic mixture into the solid dosage forms in a mold calender with two counter-rotating molding rolls.
Ein derartiges Verfahren ist z.B. aus der US-A-4,880,585 bekannt. Bei diesem Verfahren wird eine Wirkstoff- und bindemittelhaltige Masse mit einem Extruder plastifiziert, und die erhalteneSuch a method is e.g. known from US-A-4,880,585. In this process, an active substance and binder-containing mass is plasticized with an extruder, and the resultant
Schmelze wird einer Formgebung in einem Formkalander unterworfen. Die Formwalzen des Formkalanders weisen auf ihrer Oberfläche Vertiefungen mit einander entsprechenden Umrißlinien auf. Die Vertiefungen auf den Oberflächen der Formwalzen treten an der Berüh- rungslinie der Formwalzen kurzzeitig zu Formen für die wirkstoff- haltige Schmelze zusammen und streben bei der Weiterrotation der Formwalzen anschließend wieder auseinander, wobei die geformten Dosierungsformen freigegeben werden. Dieses Verfahren weist bestimmte Nachteile auf. So müssen die Vertiefungen auf der Ober- fläche der Formwalzen mit ihren Umrißlinien bei der Formung des plastischen Gemisches genau übereinander liegen, um einen vollständigen Formschluß zu erreichen. Bereits kleinste Verschiebungen der Vertiefungen gegeneinander, z.B. im Bereich von wenigen Mikrometern, führen sofort zu einem erkennbaren Versatz von Ober- und Unterseite der Dosierungsform. Dies erfordert einerseits eine hohe Präzision bei der Herstellung der Formwalzen, andererseits müssen die Formwalzen im Kalander exakt im Gleichlauf zueinander bewegt werden. Dies ist nur mit aufwendigen Maschinenkonstruktionen möglich. Die Herstellung der Formwalzen ist aufwendig und ko- stenintensiv, weil in den Walzenoberflächen Kavitäten mit dreidimensionaler Struktur vorzusehen sind. Dies gilt insbesondere, wenn kompliziertere Geometrien, z.B. teilbare Tabletten mit einer Bruchkerbe, angestrebt sind. Aufgrund der Notwendigkeit der genauen Ausrichtung der beiden Formwalzen bei den bekannten Formka- landrierungs-Verfahren ist eine Segmentierung der Formwalzen in einzelne Walzenscheiben, die jeweils nur eine oder wenige Spuren von Vertiefungen beinhalten und beliebig zu einer mehrspurigen Walze kombiniert werden können, unmöglich, da durch die beim Kalandrieren auftretenden Preßkräfte die Einzelsegmente leicht "verdrillt" werden. Diese Verdrillung führt jedoch dazu, daß die Ober- und Unterhälften der Tablettenformen bei der Rotation nicht exakt übereinander liegen. Die Segmentierung der Formwalzen ist jedoch wünschenswert, um z.B. bei einer Beschädigung einzelner Kavitäten nur eine Walzenscheibe und nicht die gesamte Walze austauschen zu müssen oder um verschiedene Formen in einer Walze beliebig kombinieren zu können.Melt is subjected to shaping in a form calender. The form rollers of the form calender have depressions with corresponding contour lines on their surface. The depressions on the surfaces of the shaping rollers briefly meet at the contact line of the shaping rollers to form molds for the active substance-containing melt and then strive apart again as the shaping rollers continue to rotate, the molded dosage forms being released. This method has certain disadvantages. For example, the recesses on the surface of the shaping rollers with their outlines must lie exactly one above the other when shaping the plastic mixture in order to achieve a complete positive fit. Even the smallest displacements of the wells against each other, for example in the range of a few micrometers, immediately lead to a recognizable offset of the top and bottom of the dosage form. On the one hand, this requires a high degree of precision in the production of the forming rolls, on the other hand, the forming rolls in the calender have to be moved exactly in synchronization with each other. This is only possible with complex machine designs. The production of the forming rolls is complex and cost intensive because cavities with a three-dimensional structure have to be provided in the roll surfaces. This applies in particular if more complicated geometries, for example dividable tablets with a score line, are aimed for. Because of the necessity of the exact alignment of the two forming rolls in the known form calendering processes, segmentation of the forming rolls into individual roll disks, which each contain only one or a few traces of depressions and can be combined in any way to form a multi-track roll, is impossible because the pressing forces occurring during calendering are easily "twisted" the individual segments. However, this twisting means that the upper and lower halves of the tablet shapes do not lie exactly one above the other during rotation. The segmentation of the form rollers is However, it is desirable, for example, if only one roller disc and not the entire roller has to be replaced if individual cavities are damaged, or in order to be able to combine different shapes in one roller as desired.
Es ist bereits vorgeschlagen worden, eine Formwalze, die auf ihrer Oberfläche Vertiefungen trägt, mit einer zweiten Walze zu kombinieren, die keine Vertiefungen enthält (Glattwalze). Hier entfällt die Notwendigkeit der exakten Ausrichtung der beiden Walzen zueinander. Nachteilig ist hierbei jedoch, dass zumindest eine der beiden Walzen nach wie vor aufwendig hergestellt werden muß. Außerdem sind die Möglichkeiten der Gestaltung der Tablettenformen bei dieser Kombination sehr eingeschränkt.It has already been proposed to combine a shaping roller which has depressions on its surface with a second roller which does not contain any depressions (smooth roller). This eliminates the need for exact alignment of the two rollers with each other. The disadvantage here, however, is that at least one of the two rollers still has to be manufactured in a complex manner. In addition, the possibilities of designing the tablet shapes with this combination are very limited.
Der vorliegenden Erfindung liegt daher die Aufgabe zugrunde, ein einfaches und kostengünstiges Verfahren zur Herstellung von festen Dosierungsformen bereitzustellen, bei dem keine Probleme hinsichtlich eines Versatzes von Ober- und Unterhälfte der Dosierungsformen auftreten.The present invention is therefore based on the object of providing a simple and inexpensive method for producing solid dosage forms, in which no problems arise with respect to an offset of the top and bottom halves of the dosage forms.
Überraschenderweise wurde gefunden, dass diese Aufgabe gelöst wird, wenn die Formwalzen auf ihrer Oberfläche so gestaltet sind, dass sie ineinander greifen können.Surprisingly, it was found that this object is achieved if the surface of the shaping rollers is designed in such a way that they can interlock.
Gegenstand der vorliegenden Erfindung ist daher ein Verfahren zur Herstellung von festen Dosierungsformen durchThe present invention therefore relates to a process for the production of solid dosage forms
a) Herstellen eines plastischen Gemisches, das wenigstens einen Wirkstoff und wenigstens ein polymeres Bindemittel enthält, unda) producing a plastic mixture which contains at least one active ingredient and at least one polymeric binder, and
b) Formen des plastischen Gemisches zu den festen Dosierungsformen in einem Formkalander mit zwei gegenläufig rotierenden Formwalzen, dadurch gekennzeichnet, dass eine Formwalze wenigstens eine entlang ihres Umfangs verlaufende Ringnut und die andere Formwalze wenigstens einen entlang ihres Umfangs verlaufenden Kranz von radial sich nach außen erstreckenden Zähnen aufweist, die in die Ringnut eingreifen können. Die Zähne sind so geformt, dass sie bei maximalem Eingriff in die Ringnut den Querschnitt der Ringnut im Wesentlichen vollständig ausfüllen, d.h. das Quer- schnittsprofil der Ringnut und der Zähne sind im Wesentlichen komplementär .b) shaping the plastic mixture into the solid dosage forms in a molding calender with two counter-rotating molding rolls, characterized in that one molding roll has at least one circumferential annular groove and the other shaping roll has at least one circumferential rim of radially outwardly extending teeth has, which can engage in the annular groove. The teeth are shaped in such a way that they fully fill the cross-section of the ring groove with maximum engagement in the ring groove, i.e. the cross-sectional profile of the ring groove and the teeth are essentially complementary.
Durch das "Ineinandergreifen" der Formwalzen entfällt die Notwendigkeit der exakten Ausrichtung der beiden Einzelwalzen zueinan- der, da nur eine Walze des Walzenpaars eine winkelabhängige Oberflächenstruktur aufweist. Es ist daher möglich, wesentlich einfa- chere Maschinenkonstruktionen für die die Formwalzen aufnehmendenThe "interlocking" of the form rollers eliminates the need for exact alignment of the two individual rollers to one another, since only one roller of the pair of rollers has an angle-dependent surface structure. It is therefore possible to Chere machine constructions for the forming rollers
Kalander zu wählen.Calender to choose.
Erfindungsgemäß zu verwendende Formwalzen sind als "Prismenwal- zen" aus der Kompaktiertechnologie bekannt. Es wird hierzu auf B. Pietsch, Aufbereitungs-Technik 3 (1970) S. 128-138, verwiesen. Dort wird die Verwendung derartiger Walzen zum Verfestigen rieselfähiger Schüttgüter zu Granulaten beschrieben. Probleme eines möglichen Versatzes zwischen Ober- und Unterhälfte der gebildeten Komprimate sind in diesem Zusammenhang nicht angesprochen.Molding rolls to be used according to the invention are known as “prism rolls” from compacting technology. Reference is made to B. Pietsch, Aufaufungs-Technik 3 (1970) pp. 128-138. The use of such rollers for solidifying free-flowing bulk goods into granules is described there. Problems of a possible misalignment between the upper and lower half of the compresses formed are not addressed in this context.
Erfindungsgemäß zu verwendende Walzenpaare ermöglichen trotz der einfachen Walzenkonstruktion eine beträchtliche Formenvielfalt der so hergestellten festen Dosierungsformen. Die Variationsmög- lichkeiten betreffen in erster Linie die Ausbildung der Ringnut und die Ausbildung des Zwischenraums zwischen aufeinanderfolgenden Zähnen eines Kranzes. So kann die Ringnut eine Reihe unterschiedlicher Querschnittsprofile (Projektion auf eine Ebene, die die Walzenachse enthält) aufweisen. Die Ringnut kann einen recht- eckigen, dreieckigen, gerundeten oder einen sonstigen Querschnitt aufweisen. Im Allgemeinen ist bevorzugt, dass die Ringnut zur leichteren Entformung der geformten Dosierungsformen ein gerundetes Querschnittsprofil aufweist.Despite the simple roller construction, pairs of rollers to be used according to the invention enable a considerable variety of shapes of the solid dosage forms thus produced. The possible variations relate primarily to the formation of the annular groove and the formation of the space between successive teeth of a ring. For example, the ring groove can have a number of different cross-sectional profiles (projection onto a plane that contains the roller axis). The ring groove can have a rectangular, triangular, rounded or other cross section. In general, it is preferred that the annular groove has a rounded cross-sectional profile for easier demolding of the shaped dosage forms.
Das Längsprofil der Zwischenräume zwischen aufeinanderfolgenden Zähnen eines Kranzes (d.h. die Projektion des Zwischenraums auf eine Ebene senkrecht zur Walzenachse) unterliegt ebenfalls einer Variation. So können die Zwischenräume dreieckiges, parallelo- grammförmiges , gerundetes oder ein anderes Längsprofil aufweisen. Im Allgemeinen ist jedoch bevorzugt, dass die Zwischenräume zwischen aufeinanderfolgenden Zähnen eines Kranzes ein gerundetes Längsprofil aufweisen.The longitudinal profile of the spaces between successive teeth of a ring (i.e. the projection of the space on a plane perpendicular to the roller axis) is also subject to variation. The gaps can have a triangular, parallelogram-shaped, rounded or other longitudinal profile. In general, however, it is preferred that the spaces between successive teeth of a ring have a rounded longitudinal profile.
Die erhaltenen Dosierungsformen können auf diese Weise z.B. Pris- menform, Prismenstumpfform, Tetraederform oder Sattelkörperform aufweisen, wobei die Sattelkörperform bevorzugt ist.The dosage forms obtained can be e.g. Have prism shape, prism shape, tetrahedral shape or saddle body shape, the saddle body shape being preferred.
In einer bevorzugten Ausführungsform des erfindungsgemäßen Verfahrens befindet sich am Boden der Ringnut ein umlaufender Steg und die Zähne weisen eine entsprechende Aussparung auf. Auf diese Weise ist die Herstellung teilbarer Tabletten, die auf einer Seite ihrer Oberfläche eine Bruchkerbe aufweisen, möglich. Zwischen aufeinanderfolgenden Zähnen eines Kranzes kann sich ebenfalls ein Steg befinden, der sich nicht bis zur Mantelfläche der Walze erstreckt. Auf diese Weise ist ebenfalls die Herstellung teilbarer Tabletten mit einer Bruchkerbe möglich.In a preferred embodiment of the method according to the invention there is a circumferential web at the bottom of the annular groove and the teeth have a corresponding recess. In this way it is possible to produce divisible tablets which have a notch on one side of their surface. Between successive teeth of a ring there can also be a web that does not extend to the outer surface of the roller. In this way it is also possible to produce dividable tablets with a notch.
Um das Entformen der gebildeten Dosierungsformen aus der Ringnut, bzw. den Zahnzwischenräumen zu erleichtern, ist es möglich, den Anpreßdruck zwischen den beiden Formwalzen gering zu halten oder einen geringen Abstand zwischen den Formwalzen, z.B. 0,1-1 mm, vorzusehen. Auf diese Weise wird ein "Tablettenband" erhalten, in dem die einzelnen Dosierungsformen noch über schmale Grate miteinander verbunden sind. Die einzelnen Dosierungsformen können, insbesondere wenn das plastische Gemisch nach dem vollständigen Auskühlen eine höhere Sprödigkeit zeigt, leicht voneinander ge- trennt werden. Es kann sich anbieten, die erhaltenen Dosierungsformen anschließend zu entgraten.In order to facilitate the demolding of the dosage forms formed from the annular groove or the interdental spaces, it is possible to keep the contact pressure between the two shaping rollers low or to keep a small distance between the shaping rollers, e.g. 0.1-1 mm to be provided. In this way, a "tablet belt" is obtained in which the individual dosage forms are still connected to one another via narrow ridges. The individual dosage forms can be easily separated from one another, in particular if the plastic mixture shows greater brittleness after it has cooled completely. It may be advisable to subsequently deburr the dosage forms obtained.
Nach dem Formvorgang läßt man die Arzneiformen auskühlen und fest werden, z.B. auf einem Kühlband.After the molding process, the dosage forms are allowed to cool and solidify, e.g. on a cooling belt.
Das vorliegende Verfahren zur Herstellung von festen Dosierungsformen umfaßt das Herstellen eines plastischen Gemisches. Dies erfolgt in der Regel durch Vermischen und Aufschmelzen von mindestens einem pharmakologisch akzeptablen polymeren Bindemittel, mindestens einem pharmazeutischen Wirkstoff und gegebenenfalls üblichen pharmazeutischen Additiven in Gegenwart oder Abwesenheit eines Lösungsmittels. Diese Verfahrensschritte können auf bekannte Art und Weise durchgeführt werden.The present method of making solid dosage forms involves making a plastic mixture. This is usually done by mixing and melting at least one pharmacologically acceptable polymeric binder, at least one active pharmaceutical ingredient and, if appropriate, customary pharmaceutical additives in the presence or absence of a solvent. These process steps can be carried out in a known manner.
Die Komponenten können zuerst vermischt und dann aufgeschmolzen und homogenisiert werden. Insbesondere bei Verwendung von empfindlichen Wirkstoffen hat es sich aber als bevorzugt erwiesen, zuerst das polymere Bindemittel, gegebenenfalls zusammen mit üblichen pharmazeutischen Additiven, aufzuschmelzen und vorzuvermi- sehen, wobei die Rührkessel, Rührwerke, Feststoffmischer etc. gegebenenfalls im Wechsel betrieben werden, und dann den (die) empfindlichen Wirkstoff(e) in "Intensivmischern" in plastischer Phase bei sehr kleinen Verweilzeiten einzumischen (Homogenisieren). Der (die) Wirkstoff (e) kann (können) in fester Form oder als Lösung oder Dispersion eingesetzt werden.The components can first be mixed and then melted and homogenized. However, especially when using sensitive active ingredients, it has proven to be preferable to first melt and premix the polymeric binder, optionally together with customary pharmaceutical additives, the stirred kettles, agitators, solid-state mixers etc. optionally being operated alternately, and then the Mix in (the) sensitive active ingredient (s) in "intensive mixers" in the plastic phase with very short residence times (homogenization). The active ingredient (s) can be used in solid form or as a solution or dispersion.
Das Aufschmelzen und Vermischen erfolgt in einer für diesen Zweck üblichen Vorrichtung. Besonders geeignet sind Extruder oder beheizbare Behälter mit Rührwerk, z.B. Kneter, (wie der unten noch erwähnten Art). Als Mischapparat sind auch solche Vorrichtungen brauchbar, die in der Kunststofftechnologie zum Mischen eingesetzt werden. Geeignete Vorrichtungen sind beispielsweise beschrieben in "Mischen beim Herstellen und Verarbeiten von Kunststoffen", H. Pahl, VDI- Verlag, 1986. Besonders geeignete Mischapparaturen sind Extruder und dynamische und statische Mischer, sowie Rührkessel, einwellige Rührwerke mit AbstreifVorrichtungen, insbesondere sogenannte Pastenrührwerke, mehrwellige Rührwerke, insbesondere PDSM-Mi- scher, Feststoffmischer sowie vorzugsweise 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) .The melting and mixing takes place in a device which is customary for this purpose. Extruders or heatable containers with stirrers, such as kneaders, (such as those mentioned below) are particularly suitable. Devices which are used in plastics technology for mixing can also be used as a mixing apparatus. Suitable devices are described, for example, in "Mixing in the manufacture and processing of plastics", H. Pahl, VDI-Verlag, 1986. Particularly suitable mixing devices are extruders and dynamic and static mixers, and stirred kettles, single-shaft stirrers with stripping devices, in particular so-called paste stirrers, multi-shaft Agitators, in particular PDSM mixers, solids mixers and preferably mixing kneading reactors (eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei or Ko-Kneaders from Buss), double-bowl kneaders (trough mixers) and stamp kneaders (Internal mixer) or rotor / stator systems (eg Dispax from IKA).
Bei empfindlichen Wirkstoffen erfolgt vorzugsweise zunächst das Aufschmelzen des polymeren Bindemittels in einem Extruder und anschließend das Zumischen des Wirkstoffs in einem Misch-Knetreak- tor. Bei weniger empfindlichen Wirkstoffen kann man dagegen zum intensiven Dispergieren des Wirkstoffs ein Rotor/Stator-System einsetzen.In the case of sensitive active substances, the polymer binder is preferably first melted in an extruder and then the active substance is mixed in in a kneading reactor. In the case of less sensitive active ingredients, on the other hand, a rotor / stator system can be used for intensive dispersion of the active ingredient.
Das Beschicken der Mischvorrichtung erfolgt je nach deren Konzeption kontinuierlich oder diskontinuierlich in üblicher Weise. Pulverförmige Komponenten können im freien Zulauf, z.B. über eine Differentialdosierwaage eingeführt werden. Plastische Massen können direkt aus einem Extruder eingespeist oder über eine Zahnradpumpe, die insbesondere bei hohen Viskositäten und hohen Drücken von Vorteil ist, zugespeist werden. Flüssige Medien können über ein geeignetes Pumpenaggregat zudosiert werden.Depending on the design, the mixing device is loaded continuously or discontinuously in the usual way. Powdered components can be fed in free, e.g. be introduced via a differential dosing scale. Plastic masses can be fed in directly from an extruder or fed in via a gear pump, which is particularly advantageous for high viscosities and high pressures. Liquid media can be metered in using a suitable pump unit.
Das durch Vermischen und Aufschmelzen des Bindemittels, des Wirkstoffes und gegebenenfalls des Additivs oder der Additive erhaltene Gemisch ist teigig bis zähflüssig (thermoplastisch) und daher auch extrudierbar . Die Glasübergangstemperatur des Gemisches liegt unter der Zersetzungstemperatur aller in dem Gemisch enthaltenen Komponenten. Das Bindemittel soll vorzugsweise in physiologischer Umgebung löslich oder quellbar sein. Beispiele für geeignete Bindemittel sind:The mixture obtained by mixing and melting the binder, the active ingredient and optionally the additive or additives is pasty to viscous (thermoplastic) and therefore also extrudable. The glass transition temperature of the mixture is below the decomposition temperature of all components contained in the mixture. The binder should preferably be soluble or swellable in a physiological environment. Examples of suitable binders are:
Polyvinylpyrrolidon (PVP), Copolymerisate von N-Vinylpyrrolidon (NVP) und Vinylestern, insbesondere Vinylacetat, Copolymerisate von Vinylacetat und Crotonsäure, teilverseiftes Polyvinylacetat, Polyvinylalkohol, Polyhydroxyalkylacrylate, Polyhydroxyalkylme- thacrylate, Polyacrylate und Polymethacrylate (Eudragit-Typen) , Copolymerisate von Methylmethacrylat und Acrylsäure, Cellulose- ester, Celluloseether , insbesondere Methylcellulose und Ethylcel- lulose, Hydroxyalkylcellulosen, insbesondere Hydroxypropylcellu- lose, Hydroxyalkyl-Alkylcellulosen, insbesondere Hydroxypropyl- Ethylcellulose, Cellulosephthalate, insbesondere Celluloseace- tatphthalat und Hydroxypropylmethylcellulosephthalat, und Man- nane, insbesondere Galactomannane . Die K-Werte (nach H. Fikent- scher, Cellulose-Chemie 13 (1932), Seiten 58-64, 71, 74) der Polymere liegen im Bereich von 10 bis 100, vorzugsweise 12 bis 70, insbesondere 12 bis 35, für PVP > 17, insbesondere 20 bis 35.Polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl esters, in particular vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol, polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates and polymethacrylate methacrylate (E) acrylate and polymethacrylate methacrylates (E) acrylate and polymethacrylate methacrylate types (E) , Cellulose esters, cellulose ethers, especially methyl cellulose and ethyl cellulose, hydroxyalkyl celluloses, especially hydroxypropyl cellulose loose, hydroxyalkyl-alkyl celluloses, in particular hydroxypropyl ethyl cellulose, cellulose phthalates, in particular cellulose tritphthalate and hydroxypropyl methyl cellulose phthalate, and mannans, in particular galactomannans. The K values (according to H. Fikentscher, Cellulose-Chemie 13 (1932), pages 58-64, 71, 74) of the polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, for PVP> 17, especially 20 to 35.
Bevorzugte polymere Bindemittel sind Polyvinylpyrrolidon, Copoly- merisate von N-Vinylpyrrolidon und Vinylestern, Polyhydroxyal- kylacrylate, Polyhydroxyalkylmethacrylate, Polyacrylate, Polyme- thacrylate, Alkylcellulosen und Hydroxyalkylcellulosen. Das polymere Bindemittel muß in der Gesamtmischung aller Komponenten im Bereich von 50 bis 180°C, vorzugsweise 60 bis 130°C erweichen oder schmelzen. Die Glasübergangstemperatur der Mischung muß daher unter 180°C, vorzugsweise unter 130°C liegen. Erforderlichenfalls wird sie durch übliche, pharmakologisch akzeptable weichmachende Hilfsstoffe herabgesetzt. Die Menge an Weichmacher beträgt höchstens 30 Gew.-%, bezogen auf das Gesamtgewicht von Bindemittel und Weichmacher, damit lagerstabile Arzneiformen gebildet werden, die keinen kalten Fluß zeigen. Vorzugsweise aber enthält das Gemisch keinen Weichmacher.Preferred polymeric binders are polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates, polyacrylates, alkyl celluloses and hydroxyalkyl celluloses. The polymeric binder must soften or melt in the total mixture of all components in the range from 50 to 180 ° C., preferably 60 to 130 ° C. The glass transition temperature of the mixture must therefore be below 180 ° C, preferably below 130 ° C. If necessary, it is reduced by conventional, pharmacologically acceptable plasticizing auxiliaries. The amount of plasticizer is at most 30% by weight, based on the total weight of binder and plasticizer, so that storage-stable drug forms are formed which show no cold flow. However, the mixture preferably contains no plasticizer.
Beispiele für derartige Weichmacher sind:Examples of such plasticizers are:
langkettige Alkohole, Ethylenglykol , Propylenglykol, Glycerin, Trimethylolpropan, Triethylenglykol, Butandiole, Pentanole, wie Pentaerythrit, Hexanole, Polyethylenglykole, Polypropylenglykole, Polyethylen-propylenglykole, Silicone, aromatische Carbonsäure- ester (z.B. Dialkylphthalate, Trimellithsäureester, Benzoesäure- ester, Terephthalsäureester) oder aliphatische Dicarbonsäureester (z.B. Dialkyladipate, Sebacinsäureester, Azelainsäureester, Zitronen- und Weinsäureester), Fettsäureester, wie Glycerinmono-, Glycerindi- oder Glycerintriacetat oder Natriumdiethylsulfosucci- nat. Die Konzentration an Weichmacher beträgt im Allgemeinen 0,5 bis 15, vorzugsweise 0,5 bis 5 Gew.-%, bezogen auf das Gesamtgewicht des Gemisches.long-chain alcohols, ethylene glycol, propylene glycol, glycerol, trimethylolpropane, triethylene glycol, butanediols, pentanols, such as pentaerythritol, hexanols, polyethylene glycols, polypropylene glycols, polyethylene propylene glycols, silicones, aromatic carboxylic acid esters (for example dialkyl phthalate, benzoate phthalate ester acid) Dicarboxylic acid esters (eg dialkyl adipates, 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 diethylsulfosuccinate. The concentration of plasticizer is generally 0.5 to 15, preferably 0.5 to 5 wt .-%, based on the total weight of the mixture.
Übliche galenische Hilfsstoffe, deren Gesamtmenge bis zu 100 Gew.-% bezogen auf das Polymerisat, betragen kann, sind z.B. Streckmittel bzw. Füllstoffe, wie Silikate oder Kieselerde, Magnesiumoxid, Aluminiumoxid, Titanoxid, Stearinsäure oder deren Salze, z.B. das Magnesium- oder Kalziumsalz, Methylcellulose, Na- trium-Carboxymethylcellulose, Talkum, Saccharose, Lactose, Ge- treide- oder Maisstärke, Kartoffelmehl, Polyvinylalkohol, insbesondere in einer Konzentration von 0,02 bis 50, vorzugsweise 0,20 bis 20 Gew.-%, bezogen auf das Gesamtgewicht des Gemisches. Schmiermittel, wie Aluminium- und Calciumstearat, Talcum und Si- licone, in einer Konzentration von 0,1 bis 5, vorzugsweise 0,1 bis 3 Gew.-%, bezogen auf das Gesamtgewicht des Gemisches.Typical pharmaceutical auxiliaries, the total amount of which can be up to 100% by weight, based on the polymer, are, for example, extenders or fillers, such as silicates or silica, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or their salts, for example the magnesium or calcium salt , Methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, polyvinyl alcohol, in particular in a concentration of 0.02 to 50, preferably 0.20 to 20% by weight, based on the total weight of the mixture. Lubricants, such as aluminum and calcium stearate, talc and silicone, in a concentration of 0.1 to 5, preferably 0.1 to 3% by weight, based on the total weight of the mixture.
Fließmittel, wie tierische oder pflanzliche Fette, insbesondere in hydrierter Form und solche, die bei Raumtemperatur fest sind. Diese Fette haben vorzugsweise einen Schmelzpunkt von 50°C oder höher. Bevorzugt sind Triglyceride der Cj.2-, C14-, Cι6- und Ciβ-Fettsäuren. Auch Wachse, wie Carnaubawachs, sind brauchbar. Diese Fette und Wachse können vorteilhaft alleine oder zusammen mit Mono- und/oder Diglyceriden oder Phosphatiden, insbesondere Lecithin, zugemischt werden. Die Mono- und Diglyceride stammen vorzugsweise von den oben erwähnten Fettsäuretypen ab. Die Gesamtmenge an Fetten, Wachsen, Mono-, Diglyceriden und/oder Leci- thinen beträgt 0,1 bis 30, vorzugsweise 0,1 bis 5 Gew.-%, bezogen auf das Gesamtgewicht der Masse für die jeweilige Schicht;Plasticizers, such as animal or vegetable fats, especially in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50 ° C or higher. Triglycerides of Cj .2 -, C 14 -, Cι 6 - and Ciβ fatty acids are preferred. Waxes such as carnauba wax can also be used. These fats and waxes can advantageously be admixed alone or together with mono- and / or diglycerides or phosphatides, in particular lecithin. The mono- and diglycerides are preferably derived from the fatty acid types mentioned above. The total amount of fats, waxes, mono-, diglycerides and / or lecithins is 0.1 to 30, preferably 0.1 to 5% by weight, based on the total weight of the mass for the respective layer;
Farbstoffe, wie Azofarbstoffe, organische oder anorganische Pigmente oder Farbstoffe natürlicher Herkunft, wobei anorganische Pigmente in einer Konzentration von 0,001 bis 10, vorzugsweise 0,5 bis 3 Gew.-%, bezogen auf das Gesamtgewicht des Gemisches bevorzugt sind;Dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin, preference being given to inorganic pigments in a concentration of 0.001 to 10, preferably 0.5 to 3% by weight, based on the total weight of the mixture;
Stabilisatoren, wie Antioxidanzien, Lichtstabilisatoren, Hydrope- roxid-Vernichter, Radikalfänger, Stabilisatoren gegen mikrobiel- len Befall.Stabilizers, such as antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.
Ferner können Netz-, Konservierungs-, Spreng-, Adsorptions-, Formentrenn- und Treibmittel zugesetzt werden (vgl. z.B. H. Sucker et al. Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978).Wetting agents, preservatives, disintegrants, adsorbents, mold release agents and blowing agents can also be added (cf. e.g. H. Sucker et al. Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978).
Unter Hilfsstoffen im Sinne der Erfindung sind auch Substanzen zur Herstellung einer festen Lösung mit dem pharmazeutischen Wirkstoff zu verstehen. Diese Hilfsstoffe sind beispielsweise Pentaerythrit und Pentaerythrit-tetracaetat, Polymere wie z.B. Polyethylen- bzw. Polypropylenoxide und deren Blockcopolymere (Poloxamere) , Phosphatide wie Lecithin, Homo- und Copolymere des Vinylpyrrolidons, Tenside wie Polyoxyethylen-40-stearat sowie Zi- tronen- und Bernsteinsäure, Gallensäuren, Sterine und andere wie z.B. bei J. L. Ford, Pharm. Acta Helv. 61 (1986) S.69-88 angegeben.In the context of the invention, auxiliary substances are also to be understood as meaning substances for producing a solid solution with the active pharmaceutical ingredient. These auxiliaries are, for example, pentaerythritol and pentaerythritol tetraacetate, polymers such as e.g. Polyethylene or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinyl pyrrolidone, surfactants such as polyoxyethylene 40 stearate and citric and succinic acid, bile acids, sterols and others such as e.g. in J.L. Ford, Pharm. Acta Helv. 61 (1986) pp. 69-88.
Als pharmazeutische Hilfsstoffe gelten auch Zusätze von Basen und Säuren zur Steuerung der Löslichkeit eines Wirkstoffes (siehe beispielsweise K. Thoma et al., Pharm. Ind. 51 (1989) 98-101 ). Einzige Voraussetzung für die Eignung von Hilfsstoffen ist eine ausreichende Temperaturstabilität.Additions of bases and acids to control the solubility of an active ingredient are also considered pharmaceutical auxiliaries (see, for example, K. Thoma et al., Pharm. Ind. 51 (1989) 98-101). The only requirement for the suitability of auxiliaries is adequate temperature stability.
Unter pharmazeutischen Wirkstoffen im Sinne der Erfindung sind alle Stoffe mit einer pharmazeutischen Wirkung und möglichst geringen Nebenwirkungen zu verstehen, sofern sie sich unter den Verarbeitungsbedingungen nicht zersetzen. Die Wirkstoffmenge pro Dosiseinheit und die Konzentration können je nach Wirksamkeit und Freisetzungsgeschwindigkeit in weiten Grenzen variieren. Die ein- zige Bedingung ist, dasss sie zur Erzielung der gewünschten Wirkung ausreichen. So kann die Wirkstoffkonzentration im Bereich von 0,1 bis 95, vorzugsweise von 20 bis 80, insbesondere 30 bis 70 Gew.-% liegen. Auch Wirkstoff-Kombinationen können eingesetzt werden. Wirkstoffe im Sinne der Erfindung sind auch Vitamine und Mineralstoffe, sowie Pflanzenbehandlungsmittel und Insektizide. Zu den Vitaminen gehören die Vitamine der A-Gruppe, der B-Gruppe, worunter neben Bi, B2, Bß und B12 sowie Nicotinsäure und Nicotina- mid auch Verbindungen mit Vitamin B-Eigenschaften verstanden werden, wie z.B. Adenin, Cholin, Pantothensäure, Biotin, Adenyl- säure, Folsäure, Orotsäure, Pangamsäure, Carnitin, p-Amin- obenzoesäure, myo-lnosit 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.Pharmaceutical active substances in the sense of the invention are understood to mean all substances with a pharmaceutical effect and as few side effects as possible, provided that they do not decompose under the processing conditions. The amount of active ingredient per dose unit and the concentration can vary within wide limits depending on the effectiveness and rate of release. The only condition is that they are sufficient to achieve the desired effect. The active substance concentration can thus be in the range from 0.1 to 95, preferably from 20 to 80, in particular 30 to 70% by weight. Combinations of active substances can also be used. Active substances in the sense of the invention are also vitamins and minerals, as well as plant treatment agents and insecticides. The vitamins include the vitamins of the A group and the B group, which in addition to Bi, B 2 , B ß and B 12 and nicotinic acid and nicotimide also include compounds with vitamin B properties, such as adenine, choline, Pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-amine-topzoic acid, myo-inositol and lipoic acid as well as vitamin C, vitamins of the D group, E group, F group, H group, I - and J group, K group and P group. Active substances in the sense of the invention also include peptide therapeutic agents.
Das erfindungsgemäße Verfahren ist beispielsweise zur Verarbeitung folgender Wirkstoffe geeignet:The method according to the invention is suitable, for example, for processing the following active ingredients:
Acebutolol, Acetylcystein, Acetylsalicylsäure, Acyclovir, Alfa- calcidol, Allantoin, Allopurinol, Alprazolam, Ambroxol, Amikacin, Amilorid, Aminoessigsäure, Amiodaron, Amitriptylin, Amlodipin, Amoxicillin, Ampicillin, Ascorbinsäure, Aspartam, Astemizol, Ate- nolol, Beclomethason, Benserazid, Benzalkonium-Hydrochlorid, Ben- zocain, Benzoesäure, Betamethason, Bezafibrat, Biotin, Biperiden, Bisoprolol, Bromazepam, Bromhexin, Bromocriptin, Budesonid, Bufe- xamac, Buflomedil, Buspiron, Coffein, Campher, Captopril, Carba- mazepin, Carbidopa, Carboplatin, Cefachlor, Cefadroxil, Cefalexin, Cefazolin, Cefixim, Cefotaxim, Ceftazidim, Ceftriaxon, Cefu- roxim, Chloramphenicol, Chlorhexidin, Chlor-pheniramin, Chlorta- lidon, Cholin, Cyclosporin, Cilastatin, Cimetidin, Ciprofloxacin, Cisapride, Cisplatin, Clarithromycin, Clävulansäure, Clomipramin, Clonazepam, Clonidin, Clotrimazol, Codein, Cholestyramin, Cromog- lycinsäure, Cyanocobalamin, Cyproteron, Desogestrel, Dexametha- son, Dexpanthenol, Dextromethorphan, Dextropropoxiphen, Diazepam, Diclofenac, Digoxin, Dihydrocodein, Dihydroergotamin, Dihydroer- gotoxin, Diltiazem, Diphenhydramin, Dipyridamol, Dipyron, Disopy- ramid, Domperidon, Dopamin, doxocyclin, Enalapril, Ephedrin, Epi- nephrin, Ergocalciferol, Ergotamin, Erythromycin, Estradiol, Ethinylestradiol, Etoposid, Eucalyptus Globulus, Famotidin, Felo- dipin, Fenofibrat, Fenoterol, Fentanyl, Flavin-Mononucleotid, Fluconazol, Flunarizin, Fluorouracil, Fluoxetin, Flurbiprofen, Folinsäure, Furosemid, Gallopamil, Gemfibrozil, Gentamicin,Acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alfacalcidol, allantoin, allopurinol, alprazolam, ambroxol, amikacin, amilorid, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillartin, astaminsolonol, astorbicoleminol, azorbicoleminol, azorbicoleminol, azorbicoleminol, azorbicoleminol, azorbic acid Benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbidopazepine, carbamapazepine Cefachlor, Cefadroxil, Cefalexin, Cefazolin, Cefixim, Cefotaxim, Ceftazidim, Ceftriaxon, Cefuroxim, Chloramphenicol, Chlorhexidine, Chloropheniramine, Chloractidone, Choline, Cyclosporin, Cilastatin, Cimetacin, Ciprofinitoxin, Ciprofinitoxin, Ciprofinitoxin, Ciprofinicidine, Ciprofinidicine, Ciprofinidicine, Ciprofinicidine, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofin, Ciprofin, Ciprofin, Ciprofin Clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpantheno l, dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamol, dipyron, disopyramid, domperidon, dopamine, enphedrin, epoxyrilin, doxocryclin nephrin, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin-mononucleotide, fluconazole, flunarizine, folouracid, gallophenic acid, furoxiliprofen, furolemosilicate, furoxemic acid, furoxiliprofinic acid, fluoxaciliprofinic acid, furoxemic acid, furoxiliprofinic acid, fluoxaciliprofinic acid, furoxiliprofluoric acid, fluoxaciliprofluoric acid Gentamicin
Gingko Biloba, Glibenclamid, Glipizid, Clozapin, Glycyrrhiza gla- bra, Griseofulvin, Guaifenesin, Haloperidol, Heparin, Hyaluron- säure, Hydrochlorothiazid, Hydrocodon, Hydrocortison, Hydromor- phon, Ipratropium-Hydroxid, Ibuprofen, Imipenem, indomethacin, lohexol, Iopamidol, Isosorbid-Dinitrat, Isosorbid-Mononitrat, Isotretinoin, Ketotifen, Ketoconazol, Ketoprofen, Ketorolac, Labetalol, Lactulose, Lecithin, Levocarnitin, Levodopa, Levogluta- mid, Levonorgestrel, Levothyroxin, Lidocain, Lipase, Imipramin, Lisinopril, Loperamid, Lorazepam, Lovastatin, Medroxyprogesteron, Menthol, Methotrexat, Methyldopa, Methylprednisolon, Metoclopra- mid, Metoprolol, Miconazol, Midazolam, Minocyclin, Minoxidil, Mi- soprostol, Morphin, Multivitamin-Mischungen bzw. -Kombinationen und Mineralsalze, N-Methylephedrin, Naftidrofuryl, Naproxen, Neo- mycin, Nicardipin, Nicergolin, Nicotinamid, Nicotin, Nicotin- säure, Nifedipin, Nimodipin, Nitrazepam, Nitrendipin, Nizatidin, Norethisteron, Norfloxacin, Norgestrel, Nortriptylin, Nystatin, Ofloxacin, Omeprazol, Ondansetron, Pancreatin, Panthenol, Panto- thensäure, Paracetamol, Penicillin G, Penicillin V, Pentoxifyl- lin, Phenobarbital, Phenoxymethylpenicillin, Phenylephrin, Phe- nylpropanolamin, Phenytoin, Piroxicam, Polymyxin B, Povidon-Iod, Pravastatin, Prazepam, Prazosin, Prednisolon, Prednison, Propafe- non, Propranolol, Proxyphyllin, Pseudoephedrin, Pyridoxin, Quini- din, Ramipril, Ranitidin, Reserpin, Retinol, Riboflavin, Rifampi- cin, Rutosid, Saccharin, Salbutamol, Salcatonin, Salicylsäure, Selegilin, Simvastatin, Somatropin, Sotalol, Spironolacton, Su- cralfat, Sulbactam, Sulfamethoxazol, Sulfasalazin, Sulpirid, Ta- moxifen, Tegafur, Teprenon, Terazosin, Terbutalin, Terfenadin, Tetracyclin, Theophyllin, Thiamin, Ticlopidin, Timolol, Tranexamsäure, Tretinoin, Triamcinolon-Acetonid, Triamteren, Trimetho- prim, Troxerutin, Uracil, Valproinsäure, Vancomycin, Verapamil, Vitamin E, Zidovudin.Gingko biloba, glibenclamide, glipizide, clozapine, glycyrrhiza gla- bra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, indiphenol, imopen Isosorbide dinitrate, isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitin, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocain, lipidastam, lipopa, lupidastin, lopatin, lipopa, lopodin, lipopa Medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramid, metoprolol, miconazole, midazolam, minocycline, minoxidil, miisoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephrofuryl, naftide mycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norge strel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, pentoxifylline, phenobarbital, phenoxymethylpenicillin, phenylephrine, phenoxinoxymin, phenoxinoxinol, polynoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxynoxinoxinoxinoxinoxinoxinoxynoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxin, -Iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, propafone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharol, salcharin, salcatol , Salicylic acid, selegiline, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifene, tegafur, teprenone, terazosine, terbutaline, terfenadine, tetracyclolidine, tranoline , Tretinoin, triamcinolone acetonide, triamterene, trimethomprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, zidovudine.
Bevorzugte Wirkstoffe sind Ibuprofen (als Racemat, Enantiomer oder angereichertes Enantiomer), Ketoprofen, Flurbiprofen, Ace- tylsalicylsäure, Verapamil, Paracetamol, Nifedipin oder Capto- pril.Preferred active substances are ibuprofen (as racemate, enantiomer or enriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid, verapamil, paracetamol, nifedipine or captopril.
Im einzelnen kann es zur Ausbildung von festen Lösungen kommen. Der Begriff "feste Lösungen" ist dem Fachmann geläufig, bei- spielsweise aus der eingangs zitierten Literatur. In festen Lö- sungen von pharmazeutischen Wirkstoffen in Polymeren liegt der Wirkstoff molekulardispers im Polymer vor.In particular, solid solutions can be formed. The term “solid solutions” is familiar to the person skilled in the art, for example from the literature cited at the beginning. In fixed solutions Solutions of active pharmaceutical ingredients in polymers, the active ingredient is molecularly dispersed in the polymer.
Das erhaltene Gemisch ist vorzugsweise lösungsmittelfrei, d.h. es enthält weder Wasser noch ein organisches Lösungsmittel. Das erhaltene Gemisch wird anschließend in einen oben erörterten Formkalander eingeführt.The mixture obtained is preferably solvent-free, i.e. it contains neither water nor an organic solvent. The resulting mixture is then introduced into a mold calender discussed above.
Die mit dem erfindungsgemäßen Verfahren herstellbaren festen pharmazeutischen Formen können abschließend auch in üblicher Weise mit Filmüberzügen versehen werden, welche die Wirkstoff- freisetzung kontrollieren oder den Geschmack abdecken. Geeignete Materialien für derartige Überzüge sind Polyacrylate, wie die Eu- dragit-Typen, Celluloseester, wie die Hydroxypropylmethylcellulo- sephthalate, sowie Celluloseether, wie Ethylcellulose, Hydroxy- propylmethylcellulose oder Hydroxypropylcellulose.Finally, the solid pharmaceutical forms which can be produced by the process according to the invention can also be provided in a conventional manner with film coatings which control the release of active ingredient or cover the taste. Suitable materials for coatings of this type are polyacrylates, such as the Eurogitit types, cellulose esters, such as the hydroxypropylmethylcellulose sephates, and cellulose ethers, such as ethylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose.
Mit dem erfindungsgemäßen Verfahren ist es somit möglich, besonders exakt dimensionierte Arzneiformen herzustellen. Überraschen- derweise ist dieses Verfahren preiswert, läßt sehr große Stückzahlen pro Zeiteinheit erzielen und vermeidet jeglichen Abfall.With the method according to the invention it is thus possible to produce particularly precisely dimensioned dosage forms. Surprisingly, this process is inexpensive, allows very large quantities to be achieved per unit of time and avoids any waste.
Die Figuren erläutern die Erfindung ohne sie zu begrenzen. Die Figuren 1 bis 3 werden im folgenden kurz beschreiben.The figures explain the invention without limiting it. Figures 1 to 3 are briefly described below.
In den Zeichnungen zeigt:In the drawings:
Figur 1: Verschiedene Ausführungen der erfindungsgemäß in einer Walze vorhandenen Ringnut; Figur 2 : Verschiedene Ausführungen der Zwischenräume zwischen aufeinanderfolgenden Zähnen eines erfindungsgemäß auf einer Walze vorhandenen Kranzes von Zähnen und die damit erhältlichen Dosierungsformen; Figur 3 : Das Konstruktionsprinzip eines erfindungsgemäß zu ver- wendenden Walzenpaars an einem konkreten Beispiel.Figure 1: Different designs of the annular groove present in a roller according to the invention; FIG. 2: Different designs of the spaces between successive teeth of a ring of teeth present on a roller according to the invention and the dosage forms obtainable therewith; FIG. 3: The construction principle of a pair of rollers to be used according to the invention using a concrete example.
In Figur 1 sind verschiedene Ausführungen der Ringnut im Querschnitt dargestellt. Die Ringnut kann rechteckiges (a), dreieckiges (b) oder gerundetes (c) Querschnittsprofil aufweisen. Am Bo- den der Ringnut kann sich ein umlaufender Steg befinden (d), der zu festen Dosierungsformen führt, die auf einer Seite ihrer Oberfläche eine Bruchkerbe aufweisen. Gemäß Figur 2 sind die je nach Ausführung der Zwischenräume zwischen aufeinanderfolgenden Zähnen eines Kranzes erhältlichen Dosierungsformen mit Prismenform (a), Prismenstumpfform (b) oder Sattelkörperform (c) dargestellt.In Figure 1, different versions of the annular groove are shown in cross section. The ring groove can have a rectangular (a), triangular (b) or rounded (c) cross-sectional profile. At the bottom of the annular groove there can be a circumferential ridge (d) which leads to solid dosage forms which have a notch on one side of their surface. According to FIG. 2, the dosage forms with prism shape (a), prism shape (b) or saddle body shape (c) are shown, depending on the design of the spaces between successive teeth of a ring.
Figur 3 veranschaulicht das Konstruktionsprinzip eines Walzenpaares mit zwei Spuren, wobei eine Walze zwei umlaufende Ringnuten mit gerundetem Querschnittsprofil aufweist und die andere Walze zwei umlaufende Kränze von radial sich nach außen erstreckenden Zähnen aufweist, wobei die Zwischenräume zwischen aufeinanderfolgenden Zähnen ein gerundetes Längsprofil aufweisen. Figur 3 zeigt oben einen Querschnitt des Walzenpaars durch die Walzenachsen. Figur 3 zeigt unten einen Querschnitt des Walzenpaars senkrecht zu den Walzenachsen. FIG. 3 illustrates the construction principle of a pair of rollers with two tracks, one roller having two circumferential ring grooves with a rounded cross-sectional profile and the other roller having two circumferential rings of radially outwardly extending teeth, the spaces between successive teeth having a rounded longitudinal profile. FIG. 3 shows a cross section of the roller pair through the roller axes at the top. Figure 3 shows a cross section of the roller pair perpendicular to the roller axes below.

Claims

Patentansprüche claims
1. Verfahren zur Herstellung von festen Dosierungsformen durch1. Process for the preparation of solid dosage forms
a) Herstellen eines plastischen Gemisches, das wenigstens einen Wirkstoff und wenigstens ein polymeres Bindemittel enthält, unda) producing a plastic mixture which contains at least one active ingredient and at least one polymeric binder, and
b) Formen des plastischen Gemisches zu den festen Dosierungsformen in einem Formkalander mit zwei gegenläufig rotierenden Formwalzen, dadurch gekennzeichnet, dass eine Formwalze wenigstens eine entlang ihres Umfangs verlaufende Ringnut und die andere Formwalze wenigstens einen entlang ihres Umfangs verlaufenden Kranz von radial sich nach außen erstreckenden Zähnen aufweist, die in die Ringnut eingreifen können.b) shaping the plastic mixture into the solid dosage forms in a molding calender with two counter-rotating molding rolls, characterized in that one molding roll has at least one circumferential annular groove and the other shaping roll has at least one circumferential rim of radially outwardly extending teeth has, which can engage in the annular groove.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Ringnut ein gerundetes Querschnittsprofil aufweist.2. The method according to claim 1, characterized in that the annular groove has a rounded cross-sectional profile.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass die Zwischenräume zwischen aufeinanderfolgenden Zähnen eines Kranzes ein gerundetes Längsprofil aufweisen.3. The method according to claim 1 or 2, characterized in that the spaces between successive teeth of a ring have a rounded longitudinal profile.
4. Verfahren nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass sich am Boden der Ringnut ein umlaufender Steg befindet und die Zähne eine entsprechende Aussparung aufweisen.4. The method according to any one of the preceding claims, characterized in that there is a circumferential web at the bottom of the annular groove and the teeth have a corresponding recess.
5. Verfahren nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass die erhaltenen Dosierungsformen entgratet werden.5. The method according to any one of the preceding claims, characterized in that the dosage forms obtained are deburred.
6. Feste Dosierungsformen, erhältlich nach dem Verfahren nach einem der Ansprüche 1 bis 5. 6. Solid dosage forms, obtainable by the process according to one of claims 1 to 5.
EP99959299A 1998-11-23 1999-11-22 Method of producing solid dosage forms Expired - Lifetime EP1133271B1 (en)

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DE19853985A DE19853985A1 (en) 1998-11-23 1998-11-23 Producing solid dosage form, using molding calender of two cylinders with specific surface structures, avoids problems of misalignment of upper and lower halves of the product
DE19853985 1998-11-23
PCT/EP1999/008995 WO2000030586A1 (en) 1998-11-23 1999-11-22 Method of producing solid dosage forms

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