WO1997015268A1 - Moulding strip calender - Google Patents

Moulding strip calender Download PDF

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Publication number
WO1997015268A1
WO1997015268A1 PCT/EP1996/004600 EP9604600W WO9715268A1 WO 1997015268 A1 WO1997015268 A1 WO 1997015268A1 EP 9604600 W EP9604600 W EP 9604600W WO 9715268 A1 WO9715268 A1 WO 9715268A1
Authority
WO
WIPO (PCT)
Prior art keywords
rollers
product
pair
product mass
recesses
Prior art date
Application number
PCT/EP1996/004600
Other languages
German (de)
French (fr)
Other versions
WO1997015268B1 (en
Inventor
Reinhard Spengler
Original Assignee
Knoll Aktiengesellschaft
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 Aktiengesellschaft filed Critical Knoll Aktiengesellschaft
Priority to AU74911/96A priority Critical patent/AU705657B2/en
Priority to JP9516273A priority patent/JPH11514275A/en
Priority to KR1019980702910A priority patent/KR19990066977A/en
Priority to EP96937213A priority patent/EP0957884A1/en
Priority to SI9620112A priority patent/SI9620112A/en
Priority to SK506-98A priority patent/SK50698A3/en
Priority to BR9611239A priority patent/BR9611239A/en
Publication of WO1997015268A1 publication Critical patent/WO1997015268A1/en
Publication of WO1997015268B1 publication Critical patent/WO1997015268B1/en
Priority to NO981795A priority patent/NO981795L/en

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Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B30PRESSES
    • B30BPRESSES IN GENERAL
    • B30B11/00Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
    • B30B11/16Presses 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
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23PSHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00Shaping or working of foodstuffs characterised by the products
    • A23P10/20Agglomerating; Granulating; Tabletting
    • A23P10/28Tabletting; Making food bars by compression of a dry powdered mixture
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23PSHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P30/00Shaping or working of foodstuffs characterised by the process or apparatus
    • A23P30/10Moulding
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS 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
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/06Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2095Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893Tablet coating processes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B30PRESSES
    • B30BPRESSES IN GENERAL
    • B30B5/00Presses characterised by the use of pressing means other than those mentioned in the preceding groups
    • B30B5/04Presses characterised by the use of pressing means other than those mentioned in the preceding groups wherein the pressing means is in the form of an endless band
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS 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
    • A61J2200/00General characteristics or adaptations
    • A61J2200/20Extrusion means, e.g. for producing pharmaceutical forms

Definitions

  • the present invention relates to a device and a method for producing flat shapes, in particular tablets, from a product mass containing active ingredients.
  • melt calendering A known method for the production of tablets is the so-called melt calendering. Such a process is described, for example, in DE-A-17 66 546 and US-A-4,880,585 b . The basis of this process is the embedding of an active ingredient in a melt from a carrier for
  • Example fatty substances or water-soluble, thermoplastic polymers The melt is produced by melting the mixture of active ingredient, polymer and optionally other auxiliaries, for example in an extruder, and shaping it as a melt in a downstream calender into tablets, which harden by cooling.
  • the molding calender comprises a pair of molding rollers rotating in opposite directions, the molding rollers having engravings (depressions) on their surface which correspond to the shape of half the desired tablet.
  • the tablets are formed in the contact area of the two rollers by connecting the tablet masses in the depressions of one roller with those in the opposite depressions of the other roller.
  • roller construction is very complex.
  • the depressions are milled into the rollers and in most cases have to be polished afterwards in order to get the tablet surface as smooth as possible.
  • the production of such rollers is very expensive because the recesses have to be made with great precision.
  • the rollers have to be adjusted so that always two recesses face each other as exactly as possible. This condition is particularly difficult to achieve if the depressions are very small.
  • Such a device is also inflexible because, for example, if you want to use the same device to produce different tablet shapes and / or sizes, this is only possible through a complete exchange of the rollers and a complex readjustment.
  • devices for tablet production are becoming large
  • the object of the present invention to provide a device for producing tablets which, on the one hand, is cheaper than the known devices and, on the other hand, offers greater flexibility.
  • the object of the invention is also to provide a simple and flexible method for tablet production.
  • a device for producing flat shapes from an active substance-containing product mass with at least one charging means for supplying the product mass, at least one pair of rollers, consisting of two counter-rotating calender rollers, the device being characterized in that it is a, preferably as Endless belt encircling forming belt, which is guided between the two rollers of a pair of rollers, the forming belt having recesses on its surface for receiving the product mass.
  • the rollers are arranged so that they have a gap-like passage between their lateral surfaces.
  • the smallest distance between the lateral surfaces of the pair of rollers essentially corresponds to the thickness of the forming strip.
  • the product mass preferably as a wide belt
  • the trough-like trough fed between the two rollers.
  • the forming belt and product ends are guided further into the area between the calender rolls, which is becoming ever narrower, the product mass being pressed into the recesses in the forming belt.
  • the distance between the rollers essentially determines the pressure that is exerted on the product mass and thus the density of the moldings thus produced.
  • Forming tapes made of plastic, in which the cutouts can be produced by molding are particularly inexpensive. Of course, care must be taken that the plastic is dimensionally stable at the temperatures that occur during tablet production.
  • the moldings formed in this way have a flat surface formed by the pressure roller, while the opposite surface is determined by the shape of the recess in the forming belt.
  • the cutouts are through openings in the forming band.
  • the openings are preferably produced by punching, any tablet shape being able to be produced depending on the punching tool used.
  • the product mass which is pressed into the molds during tablet production comes into contact with the two lateral surfaces of the pair of calender rolls, so that here Tablets are produced that have two flat surfaces.
  • cutouts or the openings in the forming belt are introduced in such a way that the product mass can be transferred into the product moldings with as little loss as possible.
  • Recesses or openings are preferred which have a round, oval or hexagonal shape when viewed from above.
  • the openings can also have webs on their circumferential surface, for example, which are produced by corresponding notches in the punching mold, so that tablets with broken notches can be produced.
  • the forming tape can be made from any material, but preferably from metal, particularly preferably from steel, plastic or rubber. If a molding tape made of a relatively rigid material is used, the thickness of the tape corresponds essentially to the desired thickness of the tablets. Thicker tablet forms therefore require a thicker belt, which can optionally be in the form of a link belt, so that it can be guided around the deflection rollers of the device more easily. However, it is also possible to use shaped tapes made of flexible material, which can then also be thicker than the desired thickness of the tablets. In this case, in particular, the forming belt is thicker than the gap between the calender rolls. When it is drawn in between the rollers, the forming belt is pressed ever further together, so that, depending on the distance between the calender rollers, a different pressure can be exerted on the tablet tablets.
  • the calender rolls preferably have smooth outer surfaces. If tablet moldings with an enlarged surface are required, then, for example, calender rolls are also conceivable, the surface of which has a certain roughness. Calender rolls which can be tempered are advantageously used. If a product mass is used that is plastic at high temperature and solidifies on cooling, it is preferred to work with cooled calender rolls. On the other hand, product masses are also known which are plastic in the moist state and solid in the dry state, so that in this case it is preferred to work with heatable calender rolls. The rollers therefore serve to cool or dry the product mass. Depending on the diameter of the rollers, the product mass has different lengths of thermal contact with these rollers.
  • the pressure rollers are universal tools that are preferably thermally conductive, stable under pressure and inert to the substances used. The distance between the rollers can be adjusted to generate different contact pressures.
  • the device has only one loading means for the product mass.
  • the product belts can be fed to a pair of rollers at the same time.
  • the distance between the pairs of rollers will preferably be set so that the contact pressure is lowest for the first pair of rollers and highest for the last pair of rollers.
  • the resulting tablets are then multi-layer tablets.
  • a thin protective film for example a diffusion-tight polymer in order to achieve a specific release of active ingredient.
  • Protective films can be produced that only dissolve under specific ambient conditions (for example with regard to pH or temperature) and release the active ingredient.
  • the coating can also serve as a taste or light protection. Should the entire tablet are covered with a protective film, this is generally carried out in a separate subsequent step using known coating processes.
  • the protective films on the top and bottom do not have to be identical. In the case of multilayer tablets, the protective films can, for example, lead to a different release of active ingredient.
  • Extruders and / or heatable filling wedges are used as preferred feed agents.
  • the device according to the invention tablets or pellet-like moldings can be produced continuously.
  • the device is extremely universal, since the basic roller device remains unchanged and only the forming belt has to be replaced. Depending on the ribbon used and the dimensions of the
  • the range of products that can be produced ranges from very small pellet-like products to tablet weights of 1 gram and more.
  • the moldings have edge angles of 90 ° or less, which, particularly in the case of brittle product masses, facilitates deburring of the tablets.
  • the openings in the forming belt are preferably spaced from one another, so that there is no twin formation of tablets during manufacture. A subsequent separation of the tablets is therefore not necessary.
  • the length of the forming belt can be varied within wide limits. It proves to be particularly advantageous that the residence time of the tablets in the molds can be extended as required, so that an ejection of not yet cooled (not yet cured) tablets is avoided.
  • the products can be removed from the forming belt in a simple manner by the roller deflection or, if appropriate, by using a spiked roller. This is particularly true in the case of shaped tapes with through openings, since here the tablets are accessible from the top and bottom and can be easily pushed out of the tape.
  • the flat moldings available with the forming calender are particularly suitable for use as tablets.
  • IR tablets in particular tablets that release the active ingredient quickly (instant release), SR tablets, i.e. Tablets with slow release of active ingredient (SJLow Release), prolonged-release tablets, i.e. Tablets with delayed release of active ingredients, sublingual tablets, the active ingredients of which are absorbed through the oral mucosa and which are therefore intended to dissolve "under the tongue", lozenges or dissolving tablets.
  • the tablets that can be produced in this way can of course not only be used in the pharmaceutical or food sector (e.g. in the form of vitamin tablets), but also applications in crop protection and in many areas of technology are conceivable.
  • the present invention also relates to a process for the production of flat moldings from an active substance-containing product mass, wherein a shaped strip provided with recesses is passed between the counter-rotating rollers of a pair of calender rollers, at least one product strand consisting of the active substance-containing mass, preferably as a wide strip, forms this Feeding the product strand to the pair of rollers, the product mass being pressed into the recesses between the rollers of the pair of rollers and the shaped articles being removed from the recesses after passing through the pair of rollers.
  • the desired contact pressure with which the product mass is compressed is set by the
  • the distance between the rollers ie the smallest distance between their lateral surfaces, should preferably not be greater than the thickness of the forming tape used.
  • the gap between the rollers can be selected to be significantly smaller than the thickness of the belt, so that a higher pressure can be exerted on the product mass.
  • the product strip is passed through several successive pairs of rollers. It is also possible to form a number of different product strands which are fed simultaneously to a pair of rollers or to a plurality of pairs of rollers in succession.
  • a multilayer melt can be produced by coextrusion, which already has the desired layer sequence of the later tablet in the melt.
  • the product mass is hot plastic or wet plastic.
  • the roller pairs will either be heated or cooled in order to obtain solid, dimensionally stable tablets.
  • the tablets are produced from a mixture which contains one or more active pharmaceutical ingredients and one or more customary auxiliaries and which, by melting or softening at least one component, becomes pasty to viscous and therefore extrudable.
  • mixtures which contain pharmacologically acceptable polymers for example polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol , Ethylene / vinyl acetate copolymers, polyhydroxyethyl methacrylate, copolymers of methyl methacrylate and acrylic acid, cellulose esters, cellulose ethers, polyethylene glycol or polyethylene.
  • PVP polyvinylpyrrolidone
  • NDP N-vinylpyrrolidone
  • VRP N-vinylpyrrolidone
  • vinyl acetate copolymers of vinyl acetate and crotonic acid
  • partially saponified polyvinyl acetate polyvinyl alcohol
  • Ethylene / vinyl acetate copolymers polyhydroxyethyl methacrylate
  • Fikentscher, Cellulose-Chemie 13 (1932), pages 58 to 64 and 71 and 74) of the polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, for PVP preferably at 12 to 35, especially at 12 to 17.
  • the polymeric binder must soften or melt in the total mixture of all components in the range from 50 to 180, preferably 60 to 130 ° C., so that the composition can be extruded.
  • the glass transition temperature of the mixture must therefore be below 180, preferably below 130 ° C.
  • plasticizing ancillary substances such as long chain alcohols, ethylene glycol, Propylen ⁇ , trimethylolpropane, triethylene glycol, butanediols, pentanols, hexanols, polyethylene glycols, silicones, aromatic Carbonsaureester (such as dialkyl phthalates, trimellitic esters, benzoic esters, terephthalic esters) or aliphatic dicarboxylic esters (eg Dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters) or fatty acid esters.
  • plasticizing ancillary substances such as long chain alcohols, ethylene glycol, Propylen ⁇ , trimethylolpropane, triethylene glycol, butanediols, pentanols, hexanols, polyethylene glycols, silicones, aromatic Carbonsaureester (such as dialkyl phthalates
  • Common pharmaceutical auxiliaries the total amount of which can be up to 100% by weight, based on the polymer, are e.g.
  • Extenders or fillers such as silicates or silica, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or their salts, e.g. the magnesium or calcium salt, methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose, corn 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, are preferred;
  • 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, are preferred; Dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin, 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;
  • 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 C 12 , C 14 , C 16 and C 18 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 those 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;
  • Stabilizers such as antioxidants, light stabilizers, hydroperoxide killers, 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 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 as well as citric and succinic acid, bile acids, sterols and others as for example given by JL Ford, Pharm. Acta Helv. 6_1, 69-88 (1986).
  • 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 requirement is that they are sufficient to achieve the desired effect.
  • the active substance concentration can 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, for example ibuprofen / caffeine 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, the B group, meaning next to B ⁇ B 2, B 6 and B 12 i e nicotinic acid and nicotinamide sow also compounds with vitamin B properties are understood, such as adenine, choline, Pantothenic acid, biotin, adenylic acid, folic acid, orotic acid,
  • Active substances in the sense of the invention also include peptide therapeutic agents.
  • the method according to the invention is for example for processing suitable for the following active ingredients:
  • Cisplatin clarithromycin, clavulanic acid, clomibramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycine acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextrroethporphoxipod, dextro doproethoxamine, dextro dia methoxane, dextro dia methane pod
  • ron dihydroergotoxin diltiazem, diphenhydramine, dipyridamole, Dipy-, disopyramide, domperidone, dopamine, Doxocyclin, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl , Flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoXetin, flurbiprofen, furosemide, gallopamil, gemfibrozil, gentamicin, ginkgo biloba, glibenclamide, glipizide, clozapine, gly
  • 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.
  • the term “solid solutions” is familiar to the person skilled in the art, for example from the literature cited at the beginning.
  • the active ingredient is molecularly dispersed in the polymer.
  • the pharmaceutical mixture is then melted in a conventional manner, preferably in an extruder, and fed to the forming belt calender, as is the case, for example, in US Pat. 4,880,585. If necessary, the tablets are cooled after calendering, for example in an air or cooling bath.
  • a mold release agent for example a silicone oil or a silicone varnish.
  • FIG. 1 shows a schematic view of the forming band calender according to the invention
  • FIG. 2 shows a detailed view in longitudinal section according to a first embodiment of the forming belt of the device from FIG. 1 carried out between the calender rolls,
  • Figure 3 is a view as in Figure 2 of a second embodiment of the forming belt.
  • FIG. 1 shows the forming belt calender 10 according to the invention, a forming belt 12 being guided between the calender rollers 14, 16 via deflection rollers 18.
  • An extruder 20 is used to produce the plastic product mass, which is preferably produced as a wide product band 22.
  • the width of the calender rolls 14, 16, the forming belt 12 and the product belt 22 are preferably essentially the same.
  • the direction of rotation of the forming belt 12 and the direction of rotation of the rollers 14 and 16 are indicated by arrows.
  • the product belt 22 is added parallel to the direction of movement of the forming belt 12 into the trough-like recess 26 between the rollers 14 and 16.
  • the forming tape 12 has depressions 24 or openings 30 on its surface, as in particular in FIGS. 2 and 3 is shown.
  • FIG. 2 shows a first embodiment of the device according to the invention, in which the forming belt 12 has depressions 24. Molding tape 12 and product mass 22 are carried in the increasingly narrow gap between the two rollers 14 and 16, the product mass 22 being pressed into the recesses 24 of the molding tape 12. If it is, for example, a product mass that is supplied in a hot, plastic state, at least one of the rollers 14, 16 can be cooled, so that the product mass cools down in the recesses 24 as it passes between the rollers, thereby producing solid moldings 28 which can then be removed from the recesses.
  • FIG. 3 shows the same detail as FIG. 2 of a forming band calender according to the invention according to FIG. 1, the forming band 12 in FIG. 3 according to another embodiment of the invention having through openings 30 into which the product mass 22 is pressed as it passes between the rollers 14 and 16 of the device becomes.
  • the moldings 28 produced in this case have two smooth surfaces.
  • the openings 30 in the forming band 12 are preferably created by punching out the forming band.
  • shaped articles 28 are formed, the edge angles of which are essentially 90 °. Any protruding product mass can be easily deburred with tablets shaped in this way.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Casting Or Compression Moulding Of Plastics Or The Like (AREA)
  • Processing And Handling Of Plastics And Other Materials For Molding In General (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)

Abstract

The invention concerns a method and device for producing flat blanks, in particular tablets, from a product mass containing an active substance by fusion calendering. To this end, a charging device delivers the product mass to at least one pair of rollers consisting of two calender rollers which can rotate in opposite senses. The device comprises a circulating moulding strip which is guided between the two rollers and comprises on its surface recesses for receiving the product mass.

Description

Formbandkalander Forming calender
Die vorliegende Erfindung betrifft eine Vorrichtung und ein Verfahren zur Herstellung von flächigen Formungen, insbesondere Tabletten, aus einer wirkstoffhaltigen Produktmasse.The present invention relates to a device and a method for producing flat shapes, in particular tablets, from a product mass containing active ingredients.
Ein bekanntes Verfahren zur Herstellung von Tabletten ist die sogenannte Schmelzkalandrierung. Ein derartiges Verfahren ist beispielsweise in der DE-A-17 66 546 und der US-A- 4,880,585 beschrieben. Grundlage dieses Verfahrens ist die Einbettung eines Wirkstoffes in eine Schmelze aus einem Träger, zumA known method for the production of tablets is the so-called melt calendering. Such a process is described, for example, in DE-A-17 66 546 and US-A-4,880,585 b . The basis of this process is the embedding of an active ingredient in a melt from a carrier for
Beispiel Fettsubstanzen oder wasserlösliche, thermoplastische Polymere. Die Schmelze wird dadurch erzeugt, daß die Mischung aus Wirkstoff, Polymer und gegebenenfalls weiteren Hilfsstoffen beispielsweise in einem Extruder aufgeschmolzen und als Schmelze in einem nachgeschalteten Formkalander zu Tabletten geformt wird, die durch Abkühlen aushärten. Der Formkalander umfaßt ein sich gegenläufig drehendes Formwalzenpaar, wobei die Formwalzen auf ihrer Oberfläche Gravuren (Vertiefungen) aufweisen, die der Form einer Hälfte der gewünschten Tablette entsprechen. Die Tablettenformung erfolgt im Berührungsbereich der beiden Walzen durch Verbinden der Tablettenmassen in den Vertiefungen einer Walze mit denjenigen in den gegenüberliegenden Vertiefungen der anderen Walze.Example fatty substances or water-soluble, thermoplastic polymers. The melt is produced by melting the mixture of active ingredient, polymer and optionally other auxiliaries, for example in an extruder, and shaping it as a melt in a downstream calender into tablets, which harden by cooling. The molding calender comprises a pair of molding rollers rotating in opposite directions, the molding rollers having engravings (depressions) on their surface which correspond to the shape of half the desired tablet. The tablets are formed in the contact area of the two rollers by connecting the tablet masses in the depressions of one roller with those in the opposite depressions of the other roller.
Dieses Herstellungsverfahren für Tabletten weist jedochHowever, this manufacturing process for tablets shows
Nachteile auf. So ist beispielsweise die Walzenkonstruktion sehr aufwendig. Die Vertiefungen werden in die Walzen eingefräst und müssen in den meisten Fällen nachträglich poliert werden, um eine möglichst glatte Tablettenoberfläche zu erhalten. Die Herstellung derartiger Walzen ist sehr teuer, da die Vertiefungen mit großer Präzision eingebracht werden müssen. Die Walzen müssen nämlich so justiert sein, daß immer zwei Vertiefungen möglichst exakt gegenüberliegen. Diese Bedingung wird vor allem dann schwer realisierbar, wenn die Vertiefungen sehr klein sind.Disadvantages. For example, the roller construction is very complex. The depressions are milled into the rollers and in most cases have to be polished afterwards in order to get the tablet surface as smooth as possible. The production of such rollers is very expensive because the recesses have to be made with great precision. The rollers have to be adjusted so that always two recesses face each other as exactly as possible. This condition is particularly difficult to achieve if the depressions are very small.
Eine derartige Vorrichtung ist zudem unflexibel, denn will man beispielsweise mit derselben Vorrichtung unterschiedliche Tablettenformen und/oder -großen herstellen, so ist dies nur durch einen kompletten Austausch der Walzen und eine aufwendige NeuJustierung möglich. Insbesondere im Pharmabereich wird aber von Vorrichtungen zur Tablettenherstellung eine großeSuch a device is also inflexible because, for example, if you want to use the same device to produce different tablet shapes and / or sizes, this is only possible through a complete exchange of the rollers and a complex readjustment. In the pharmaceutical sector in particular, however, devices for tablet production are becoming large
Flexibilität hinsichtlich unterschiedlicher Tablettengrößen und -formen verlangt.Flexibility with regard to different tablet sizes and shapes is required.
Es ist daher die Aufgabe der vorliegenden Erfindung, eine Vorrichtung zur Herstellung von Tabletten anzugeben, die einerseits preiswerter als die bekannten Vorrichtungen ist und andererseits eine größere Flexibilität bietet. Aufgabe der Erfindung ist außerdem die Bereitstellung eines einfachen und flexiblen Verfahrens zur Tablettenherstellung.It is therefore the object of the present invention to provide a device for producing tablets which, on the one hand, is cheaper than the known devices and, on the other hand, offers greater flexibility. The object of the invention is also to provide a simple and flexible method for tablet production.
Diese Aufgabe wird gelöst durch eine Vorrichtung zur Herstellung von flächigen Formungen aus einer wirkstoffhaltigen Produktmasse, mit mindestens einem Beschickungsmittel zur Zuführung der Produktmasse, mindestens einem Walzenpaar, bestehend aus zwei gegenläufig rotierbaren Kalanderwalzen, wobei die Vorrichtung dadurch gekennzeichnet ist, daß sie ein, bevorzugt als Endlosband umlaufendes Formband umfaßt, das zwischen den beiden Walzen eines Walzenpaares geführt ist, wobei das Formband Aussparungen auf seiner Oberfläche zur Aufnahme der Produktmasse aufweist.This object is achieved by a device for producing flat shapes from an active substance-containing product mass, with at least one charging means for supplying the product mass, at least one pair of rollers, consisting of two counter-rotating calender rollers, the device being characterized in that it is a, preferably as Endless belt encircling forming belt, which is guided between the two rollers of a pair of rollers, the forming belt having recesses on its surface for receiving the product mass.
Die Walzen sind so angeordnet, daß sie zwischen ihren Mantelflächen einen spaltartigen Durchlaß aufweisen. Dabei entspricht der geringste Abstand zwischen den Mantelflächen des Walzenpaares im wesentlichen der Dicke des Formbandes. Parallel zur Bewegungsrichtung des Formbandes wird die Produktmasse, bevorzugt als breites Produktband, der trogartigen Mulde zwischen den beiden Walzen zugeführt. Formband und Produktπiasse werden weiter in den immer enger werdenden Bereich zwischen den Kalanderwalzen geführt, wobei die Produktmasse in die Aussparungen des Formbandes gepreßt wird. Der Abstand der Walzen bestimmt dabei im wesentlichen den Druck, der auf die Produktmasse ausgeübt wird und damit die Dichte der so entstehenden Formlinge.The rollers are arranged so that they have a gap-like passage between their lateral surfaces. The smallest distance between the lateral surfaces of the pair of rollers essentially corresponds to the thickness of the forming strip. Parallel to the direction of movement of the forming belt, the product mass, preferably as a wide belt, is the trough-like trough fed between the two rollers. The forming belt and product ends are guided further into the area between the calender rolls, which is becoming ever narrower, the product mass being pressed into the recesses in the forming belt. The distance between the rollers essentially determines the pressure that is exerted on the product mass and thus the density of the moldings thus produced.
Die Verwendung eines Formbandes führt zu einer erheblich größeren Flexibilität bei der Herstellung von Tabletten.The use of a forming tape leads to a considerably greater flexibility in the manufacture of tablets.
Unterschiedliche Tablettenformen oder -großen können jetzt dadurch hergestellt werden, daß lediglich das Formband der Vorrichtung ausgewechselt wird, während dieselben Andruckwalzen für verschiedene Tablettengrößen verwendet werden können. Die Vorrichtung ist zudem preiswerter herstellbar, da die Aussparungen im Formband nicht mehr mit hoher Präzision eingebracht werden müssen, da pro Tablette jetzt lediglich eine Aussparung erforderlich ist. Eine aufwendige Justierung von gegeneinander beweglichen Teilen entfällt.Different tablet shapes or sizes can now be made simply by changing the forming belt of the device, while the same pressure rollers can be used for different tablet sizes. The device is also less expensive to produce because the cutouts in the forming belt no longer have to be made with high precision, since only one cutout is now required per tablet. A complex adjustment of parts that move against each other is not necessary.
Besonders kostengünstig sind Formbänder aus Kunststoff, bei denen die Aussparungen durch Formen erzeugt werden können. Selbstverständlich ist dabei darauf zu achten, daß der Kunststoff bei den während der Tablettenherstellung auftretenden Temperaturen formstabil ist. Die so entstehenden Formlinge weisen eine durch die Andruckwalze gebildete flache Oberfläche auf, während die gegenüberliegende Oberfläche von der Form der Aussparung im Formband bestimmt wird.Forming tapes made of plastic, in which the cutouts can be produced by molding, are particularly inexpensive. Of course, care must be taken that the plastic is dimensionally stable at the temperatures that occur during tablet production. The moldings formed in this way have a flat surface formed by the pressure roller, while the opposite surface is determined by the shape of the recess in the forming belt.
Bei einer besonders einfachen und kostengünstigenWith a particularly simple and inexpensive
Ausführungform sind die Aussparungen durchgehende Öffnungen im Formband. Bei dieser Ausführungsform werden die Öffnungen bevorzugt durch Stanzen erzeugt, wobei je nach verwendetem Stanzwerkzeug, beliebige Tablettenformen herstellbar sind. Die Produktmasse, die bei der Tablettenherstellung in die Formen gepreßt wird, kommt bei dieser Ausführungsform mit den beiden Mantelflächen des Kalanderwalzenpaars in Berührung, so daß hier Tabletten erzeugt werden, die zwei ebene Oberflächen aufweisen.The cutouts are through openings in the forming band. In this embodiment, the openings are preferably produced by punching, any tablet shape being able to be produced depending on the punching tool used. In this embodiment, the product mass which is pressed into the molds during tablet production comes into contact with the two lateral surfaces of the pair of calender rolls, so that here Tablets are produced that have two flat surfaces.
Es versteht sich, daß die Aussparungen bzw. die Öffnungen im Formband so eingebracht werden, daß die Produktmasse mit möglichst wenig Verlust in die Produktformlinge übergeführt werden kann.It goes without saying that the cutouts or the openings in the forming belt are introduced in such a way that the product mass can be transferred into the product moldings with as little loss as possible.
Bevorzugt werden Aussparungen oder Öffnungen verwendet, die in der Aufsicht eine runde, ovale oder sechseckige Form aufweisen.Recesses or openings are preferred which have a round, oval or hexagonal shape when viewed from above.
Die Öffnungen können auf ihrer Umfangsflache beispielsweise auch Stege aufweisen, die durch entsprechende Einkerbungen in der Stanzform erzeugt werden, so daß Tabletten mit Bruchkerben hergestellt werden können.The openings can also have webs on their circumferential surface, for example, which are produced by corresponding notches in the punching mold, so that tablets with broken notches can be produced.
Das Formband kann aus einem beliebigen Material, bevorzugt aber aus Metall, besonders bevorzugt aus Stahl, Kunststoff oder Gummi bestehen. Verwendet man ein Formband aus relativ starrem Material, so entspricht die Dicke des Bandes im wesentlichen der gewünschten Dicke der Tabletten. Dickere Tablettenformen erfordern somit ein dickeres Band, welches gegebenenfalls als Gliederband vorliegen kann, so daß es leichter um die Umlenkrollen der Vorrichtung führbar ist. Es ist aber auch möglich, Formbänder aus flexiblem Material zu verwenden, die dann auch dicker als die gewünschte Dicke der Tabletten sein können. Insbesondere ist das Formband in diesem Fall dicker als der Spalt zwischen den Kalanderwalzen. Beim Einzug zwischen die Walzen wird das Formband immer weiter zusammengepreßt, so daß, je nach Abstand der Kalanderwalzen voneinander, ein unterschiedlicher Druck auf die Tablettenformlinge ausgeübt werden kann.The forming tape can be made from any material, but preferably from metal, particularly preferably from steel, plastic or rubber. If a molding tape made of a relatively rigid material is used, the thickness of the tape corresponds essentially to the desired thickness of the tablets. Thicker tablet forms therefore require a thicker belt, which can optionally be in the form of a link belt, so that it can be guided around the deflection rollers of the device more easily. However, it is also possible to use shaped tapes made of flexible material, which can then also be thicker than the desired thickness of the tablets. In this case, in particular, the forming belt is thicker than the gap between the calender rolls. When it is drawn in between the rollers, the forming belt is pressed ever further together, so that, depending on the distance between the calender rollers, a different pressure can be exerted on the tablet tablets.
Bevorzugt weisen die Kalanderwalzen glatte Mantelflächen auf. Werden Tablettenformlinge mit vergrößerter Oberfläche benötigt, so sind aber auch beispielsweise Kalanderwalzen denkbar, deren Oberfläche eine gewisse Rauhigkeit aufweist. Vorteilhaft verwendet man Kalanderwalzen, die temperierbar sind. Wird nämlich eine Produktmasse verwendet, die bei hoher Temperatur plastisch ist und beim Erkalten fest wird, so wird man bevorzugt mit gekühlten Kalanderwalzen arbeiten. Andererseits sind auch Produktmaεsen bekannt, die im feuchten Zustand plastisch sind und im trockenen Zustand fest, so daß man in diesem Fall bevorzugt mit beheizbaren Kalanderwalzen arbeitet. Die Walzen dienen demnach zum Kühlen bzw. zum Trocknen der Produktmasse. Je nach Durchmesser der Walzen ist die Produktmasse unterschiedlich lang mit diesen Walzen in thermischem Kontakt. Die Andruckwalzen sind Universalwerkzeuge, die bevorzugt wärmeleitfähig, druckkraftstabil und inert gegen die verwendeten Substanzen sind. Der Abstand der Walzen ist zur Erzeugung unterschiedlicher Anpreßdrucke einstellbar.The calender rolls preferably have smooth outer surfaces. If tablet moldings with an enlarged surface are required, then, for example, calender rolls are also conceivable, the surface of which has a certain roughness. Calender rolls which can be tempered are advantageously used. If a product mass is used that is plastic at high temperature and solidifies on cooling, it is preferred to work with cooled calender rolls. On the other hand, product masses are also known which are plastic in the moist state and solid in the dry state, so that in this case it is preferred to work with heatable calender rolls. The rollers therefore serve to cool or dry the product mass. Depending on the diameter of the rollers, the product mass has different lengths of thermal contact with these rollers. The pressure rollers are universal tools that are preferably thermally conductive, stable under pressure and inert to the substances used. The distance between the rollers can be adjusted to generate different contact pressures.
Bei einer einfachen Ausführungsform weist die Vorrichtung lediglich ein Beschickungsmittel für die Produktmasse auf. Es kann aber auch erwünscht sein, beispielsweise Mehrschichttabletten herzustellen, so daß andere Ausführungsformen auch mehrere Beschickungsmittel aufweisen können, die mehrere Produktbänder erzeugen. Die Produktbänder können gleichzeitig einem Walzenpaar zugeführt werden. Es ist aber auch möglich, das Formband durch mehrere Walzenpaare zu führen, wobei die unterschiedlichen Produktbänder nacheinander bei den einzelnen Walzenpaaren zugeführt werden. In diesem Fall wird man bevorzugt den Abstand der Walzenpaare so einstellen, daß der Anpreßdruck beim ersten Walzenpaar am geringsten und beim letzten Walzenpaar am höchsten ist. Die so entstehenden Tabletten sind dann Mehrschichttabletten.In a simple embodiment, the device has only one loading means for the product mass. However, it may also be desirable to produce, for example, multi-layer tablets, so that other embodiments may also have multiple feed agents that produce multiple product tapes. The product belts can be fed to a pair of rollers at the same time. However, it is also possible to pass the forming belt through several pairs of rollers, the different product bands being fed in succession to the individual pairs of rollers. In this case, the distance between the pairs of rollers will preferably be set so that the contact pressure is lowest for the first pair of rollers and highest for the last pair of rollers. The resulting tablets are then multi-layer tablets.
Es ist aber auch denkbar, Tabletten mit einem dünnen Schutzfilm zu überziehen, beispielsweise einem diffusionsdichten Polymer zur Erzielung einer spezifischen Wirkstoff-Freisetzung. Es sind Schutzfilme herstellbar, die sich nur unter spezifischen Umgebungsbedingungen (beispielsweise hinsichtlich pH-Wert oder Temperatur) auflösen und den Wirkstoff freigeben. Das Coating kann auch als Geschmacks- oder Lichtschutz dienen. Soll die gesamte Tablette mit einem Schutzfilm überzogen werden, so wird dies im allgemeinen in einem seperaten Folgeschritt mit bekannten Coatingverfahren durchgeführt. Es ist erfindungsgemäß aber auch möglich, eine oder zwei Folienbahnen zusammen mit der Schmelze so in der Walzenanordnung einzuziehen, daß sich die Schmelze zwischen den beiden Folienbahnen befindet. Dadurch entstehen Tabletten, die auf ihrer Ober- und/oder Unterseite mit geeigneten Schutzfilmen versehen sind. Die Schutzfilme der Ober- und Unterseite müssen nicht identisch sein. Bei Mehrschichttabletten können die Schutzfilme beispielsweise zu einer unterschiedlichen Wirkstoff-Freisetzung führen.However, it is also conceivable to coat tablets with a thin protective film, for example a diffusion-tight polymer in order to achieve a specific release of active ingredient. Protective films can be produced that only dissolve under specific ambient conditions (for example with regard to pH or temperature) and release the active ingredient. The coating can also serve as a taste or light protection. Should the entire tablet are covered with a protective film, this is generally carried out in a separate subsequent step using known coating processes. However, it is also possible according to the invention to feed one or two film webs together with the melt into the roller arrangement in such a way that the melt is between the two film webs. This creates tablets that are provided on their top and / or bottom with suitable protective films. The protective films on the top and bottom do not have to be identical. In the case of multilayer tablets, the protective films can, for example, lead to a different release of active ingredient.
Als bevorzugte Beschickungsmittel verwendet man Extruder und/oder beheizbare Füllkeile.Extruders and / or heatable filling wedges are used as preferred feed agents.
Mit der erfindungsgemäßen Vorrichtung können Tabletten oder pelletähnliche Formlinge kontinuierlich hergestellt werden. Die Vorrichtung ist äußerst universell, da das Walzengrundgerät unverändert bleibt und nur das Formband ausgewechselt werden muß. Je nach verwendetem Formband und Abmessungen derWith the device according to the invention, tablets or pellet-like moldings can be produced continuously. The device is extremely universal, since the basic roller device remains unchanged and only the forming belt has to be replaced. Depending on the ribbon used and the dimensions of the
Aussparungen oder der Öffnungen reicht die herstellbare Produktpalette von sehr kleinen pelletähnlichen Produkten bis zu Tablettenmassen von 1 Gramm und mehr. Die Formlinge weisen Kantenwinkel von 90° oder weniger auf, was, insbesondere bei spröden Produktmassen, das Entgraten der Tabletten erleichtert. Die Öffnungen im Formband sind vorzugsweise voneinander beabstandet, so daß bei der Herstellung keine Zwillingsbildung von Tabletten auftritt. Eine nachträgliche Vereinzelung der Tabletten entfällt daher.The range of products that can be produced ranges from very small pellet-like products to tablet weights of 1 gram and more. The moldings have edge angles of 90 ° or less, which, particularly in the case of brittle product masses, facilitates deburring of the tablets. The openings in the forming belt are preferably spaced from one another, so that there is no twin formation of tablets during manufacture. A subsequent separation of the tablets is therefore not necessary.
Durch die Reibungskopplung mit dem Druckwalzenantrieb ist kein separater Antrieb des Formbandes erforderlich. Die Länge des Formbandes ist in weiten Grenzen variierbar. Als besonders vorteilhaft erweist sich, daß dadurch die Verweilzeit der Tabletten in den Formen je nach Bedarf verlängert werden kann, so daß ein Ausstoß von noch nicht erkalteten (noch nicht ausgehärteten) Tabletten vermieden wird. Nach dem Verlassen der Kalanderwalze ist eine Entfernung der Produkte aus dem Formband durch die Rollenumlenkung oder gegebenenfalls durch die Verwendung einer Stachelwalze auf einfache Weise möglich. Dies gilt insbesondere im Fall der Formbänder mit durchgehenden Öffnungen, da hier die Tabletten von der Ober- und Unterseite her zugänglich sind und leicht aus dem Band herausgedrückt werden können.Due to the friction coupling with the pressure roller drive, no separate drive of the forming belt is required. The length of the forming belt can be varied within wide limits. It proves to be particularly advantageous that the residence time of the tablets in the molds can be extended as required, so that an ejection of not yet cooled (not yet cured) tablets is avoided. After leaving the calender roller, the products can be removed from the forming belt in a simple manner by the roller deflection or, if appropriate, by using a spiked roller. This is particularly true in the case of shaped tapes with through openings, since here the tablets are accessible from the top and bottom and can be easily pushed out of the tape.
Die mit dem Formbandkalander erhältlichen flachen Formlinge sind vor allem für die Anwendung als Tabletten geeignet. In Frage kommen hier insbesondere IR-Tabletten, alεo Tabletten, die den Wirkstoff schnell freisetzen (Instant Release) , SR- Tabletten, d.h. Tabletten mit langsamer Wirkstoffabgäbe (SJLow Release) , Retardtabletten, d.h. Tabletten mit verzögerter Wirkstoffabgäbe, Sublingualtabletten, deren Wirkstoffe über die Mundschleimhaut resorbiert werden und die sich daher "unter der Zunge" auflösen sollen, Lutschtabletten oder Lösungstabletten.The flat moldings available with the forming calender are particularly suitable for use as tablets. IR tablets, in particular tablets that release the active ingredient quickly (instant release), SR tablets, i.e. Tablets with slow release of active ingredient (SJLow Release), prolonged-release tablets, i.e. Tablets with delayed release of active ingredients, sublingual tablets, the active ingredients of which are absorbed through the oral mucosa and which are therefore intended to dissolve "under the tongue", lozenges or dissolving tablets.
Die so herstellbaren Tabletten sind selbstverständlich nicht nur im Pharmabereich oder Lebensmittelbereich (z.B. in Form von Vitamintabletten) verwendbar, sondern es sind auch Anwendungen im Pflanzenschutz und in vielen Bereichen der Technik denkbar.The tablets that can be produced in this way can of course not only be used in the pharmaceutical or food sector (e.g. in the form of vitamin tablets), but also applications in crop protection and in many areas of technology are conceivable.
Die vorliegende Erfindung betrifft außerdem ein Verfahren zur Herstellung flächiger Formlinge aus einer wirkstoffhaltigen Produktmasse, wobei man ein mit Aussparungen versehenes Formband zwischen den gegenläufig rotierenden Walzen eines Kalanderwalzenpaares durchlaufen läßt, mindestens einen aus der wirkstoffhaltigen Masse bestehenden Produktstrang, bevorzugt als breites Band, bildet, diesen Produktstrang dem Walzenpaar zuführt, wobei die Produktmasse beim Einzug zwischen die Walzen des Walzenpaares in die Aussparungen gepreßt wird und man die Formlinge nach dem Durchlaufen durch das Walzenpaar aus den Aussparungen entfernt. Der gewünschte Anpreßdruck, mit dem die Produktmasse komprimiert wird, wird durch Einstellung desThe present invention also relates to a process for the production of flat moldings from an active substance-containing product mass, wherein a shaped strip provided with recesses is passed between the counter-rotating rollers of a pair of calender rollers, at least one product strand consisting of the active substance-containing mass, preferably as a wide strip, forms this Feeding the product strand to the pair of rollers, the product mass being pressed into the recesses between the rollers of the pair of rollers and the shaped articles being removed from the recesses after passing through the pair of rollers. The desired contact pressure with which the product mass is compressed is set by the
Abstandes der beiden Walzen voneinander vorgegeben. Der Abstand der Walzen voneinander, d.h. der geringste Abstand zwischen ihren Mantelflächen, sollte bevorzugt nicht größer als die Dicke des verwendeten Formbandes sein. Bei einem besonders elastischen Formband kann der Spalt zwischen den Walzen deutlich kleiner als die Dicke des Bandes gewählt werden, so daß ein höherer Druck auf die Produktmasse ausgeübt werden kann.Distance between the two rollers specified. The distance between the rollers, ie the smallest distance between their lateral surfaces, should preferably not be greater than the thickness of the forming tape used. In the case of a particularly elastic forming belt, the gap between the rollers can be selected to be significantly smaller than the thickness of the belt, so that a higher pressure can be exerted on the product mass.
Bei einer anderen Ausführungsform des erfindungsgemaßen Verfahrens führt man das Produktband durch mehrere aufeinanderfolgende Walzenpaare hindurch. Es können auch mehrere unterschiedliche Produktstränge gebildet werden, die gleichzeitig einem Walzenpaar oder nacheinander mehreren Walzenpaaren zugeführt werden. Als Variante dieser Ausführungsform kann durch Coextrusion eine Mehrschichtschmelze erzeugt werden, welche die gewünscht Schichtfolge der späteren Tablette bereits in der Schmelze aufweist.In another embodiment of the method according to the invention, the product strip is passed through several successive pairs of rollers. It is also possible to form a number of different product strands which are fed simultaneously to a pair of rollers or to a plurality of pairs of rollers in succession. As a variant of this embodiment, a multilayer melt can be produced by coextrusion, which already has the desired layer sequence of the later tablet in the melt.
Die Produktmasse ist je nach gewünschter Tablette heißplastisch oder feuchtplastisch. Je nach Herstellungsart wird man die Walzenpaare entweder aufheizen oder kühlen, um feste, formstabile Tabletten zu erhalten.Depending on the desired tablet, the product mass is hot plastic or wet plastic. Depending on the type of manufacture, the roller pairs will either be heated or cooled in order to obtain solid, dimensionally stable tablets.
Die Herstellung der Tabletten erfolgt ausgehend von einer Mischung, die einen oder mehrere pharmazeutische Wirkstoffe sowie einen oder mehrere übliche Hilfsstoffe enthält und die durch Schmelzen oder Erweichen mindestens einer Komponente teigig bis zähflüssig und daher extrudierbar wird.The tablets are produced from a mixture which contains one or more active pharmaceutical ingredients and one or more customary auxiliaries and which, by melting or softening at least one component, becomes pasty to viscous and therefore extrudable.
Das sind insbesondere Mischungen die pharmakologisch akzeptable Polymere enthalten (wobei die Glastemperatur der Mischung unter der Zersetzungstemperatur aller Mischungskomponenten liegt) , beispielsweise Polyvinylpyrrolidon (PVP) , Copolymerisate von N- Vinylpyrrolidon (NVP) und Vinylacetat, Copolymerisate von Vinylacetat und Crotonsäure, teilverseiftes Polyvinylacetat, Polyvinylalkohol, Ethylen/Vinylacetat-Copolymerisate, Polyhy- droxyethylmethacrylat, Copolymerisate von Methylmethacrylat und Acrylsäure, Celluloseester, Celluloseether, Polyethylenglykol oder Polyethylen. Die K-Werte (nach H. Fikentscher, Cellulose- Chemie 13 (1932), Seiten 58 bis 64 und 71 und 74) der Polymeren liegen im Bereich von 10 bis 100, vorzugsweise 12 bis 70, ins¬ besondere 12 bis 35, für PVP vorzugsweise bei 12 bis 35, ins- besondere bei 12 bis 17.These are, in particular, mixtures which contain pharmacologically acceptable polymers (the glass transition temperature of the mixture being below the decomposition temperature of all mixture components), for example polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol , Ethylene / vinyl acetate copolymers, polyhydroxyethyl methacrylate, copolymers of methyl methacrylate and acrylic acid, cellulose esters, cellulose ethers, polyethylene glycol or polyethylene. The K values (according to H. Fikentscher, Cellulose-Chemie 13 (1932), pages 58 to 64 and 71 and 74) of the polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, for PVP preferably at 12 to 35, especially at 12 to 17.
Das polymere Bindemittel muß in der Gesamtmischung aller Komponenten im Bereich von 50 bis 180, vorzugsweise 60 bis 130°C erweichen oder schmelzen, so daß die Masse extrudierbar ist. Die Glasubergangstemperatur der Mischung muß daher unter 180, vorzugsweise unter 130°C liegen. Erforderlichenfalls wird sie durch übliche pharmakologisch akzeptable weichmachende Hilfsstoffe wie langkettige Alkohole, Ethylenglykol, Propylen¬ glykol, Trimethylolpropan, Triethylenglykol, Butandiole, Pentanole, Hexanole, Polyethylenglykole, Silicone, aromatische Carbonsaureester (z.B. Dialkylphthalate, Trimellithsäureester, Benzoesäureester, Terephthalsäureester) oder aliphatische Dicarbonsäureester (z.B. Dialkyladipate, Sebacinsäureester, Azelainsäureester, Zitronen- und Weinsäureester) oder Fettsäureester herabgesetzt.The polymeric binder must soften or melt in the total mixture of all components in the range from 50 to 180, preferably 60 to 130 ° C., so that the composition can be extruded. The glass transition temperature of the mixture must therefore be below 180, preferably below 130 ° C. Where appropriate, it is glycol by conventional pharmacologically acceptable plasticizing ancillary substances such as long chain alcohols, ethylene glycol, Propylen¬, trimethylolpropane, triethylene glycol, butanediols, pentanols, hexanols, polyethylene glycols, silicones, aromatic Carbonsaureester (such as dialkyl phthalates, trimellitic esters, benzoic esters, terephthalic esters) or aliphatic dicarboxylic esters (eg Dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters) or fatty acid esters.
Übliche galenische Hilfsstoffe, deren Gesamtmenge bis zu 100 Gew.-% bezogen auf das Polymerisat, betragen kann, sind z.B.Common pharmaceutical auxiliaries, the total amount of which can be up to 100% by weight, based on the polymer, are e.g.
Streckmittel bzw. Füllstoffe, wie Silikate oder Kieselerde, Magnesiumoxid, Aluminiumoxid, Titanoxid, Stearinsäure oder deren Salze, z.B. das Magnesium- oder Kalziumsalz, Methyl¬ cellulose, Natrium-Carboxymethylcellulose, Talkum, Saccharose, Lactose, Getreide- oder Maisstärke, Kartoffelmehl, Polyviny- lalkohol, insbesondere in einer Konzentration von 0,02 bis 50, vorzugsweise 0,20 bis 20 Gew.-%, bezogen auf das Gesamtgewicht des Gemisches bevorzugt sind;Extenders or fillers, such as silicates or silica, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or their salts, e.g. the magnesium or calcium salt, methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose, corn 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, are preferred;
Schmiermittel, wie Aluminium- und Calciumstearat, Talcum und Silicone, in einer Konzentration von 0,1 bis 5, vorzugsweise 0,1 bis 3 Gew.-%, bezogen auf das Gesamtgewicht des Gemisches bevorzugt sind; 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;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, are preferred; Dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin, 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;
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 C12-, C14-, C16- und C18-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 erwähntenPlasticizers, 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 C 12 , C 14 , C 16 and C 18 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 those mentioned above
Fettsäuretypen ab. Die Gesamtmenge an Fetten, Wachsen, Mono-, Diglyceriden und/oder Lecithinen beträgt 0,1 bis 30, vorzugsweise 0,1 bis 5 Gew.-%, bezogen auf das Gesamtgewicht der Masse für die jeweilige Schicht;Types of fatty acids. 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;
Stabilisatoren, wie Antioxidanzien, Lichtstabilisatoren, Hydroperoxid-Vernichter, Radikalfänger, Stabilisatoren gegen mikrobiellen Befall.Stabilizers, such as antioxidants, light stabilizers, hydroperoxide killers, 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 Zitronen- und Bernsteinsäure, Gallensäuren, Sterine und andere wie z.B. bei J. L. Ford, Pharm. Acta Helv. 6_1, 69-88 (1986) 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 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 as well as citric and succinic acid, bile acids, sterols and others as for example given by JL Ford, Pharm. Acta Helv. 6_1, 69-88 (1986).
Als pharmazeutische Hilfsstoffe gelten auch Zusätze von Basen und Säuren zur Steuerung der Löslichkeit eines Wirkstoffes (siehe beispielsweise K. Thoma et al., Pharm. Ind. 5_1, 98-101 (1989) ) .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. 5_1, 98-101 (1989)).
Einzige Voraussetzung für die Eignung von Hilfsstoffen ist eine ausreichende TemperaturStabilität.The only requirement for the suitability of auxiliaries is sufficient 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 einzige Bedingung ist, daß sie zur Erzielung der gewünschten Wirkung ausreichen. So kann die Wirk¬ stoffkonzentration im Bereich von 0,1 bis 95, vorzugsweise von 20 bis 80, insbesondere 30 bis 70 Gew.-% liegen. Auch Wirkstoff-Kombinationen, z.B. Ibuprofen/Coffein, können einge¬ setzt werden. Wirkstoffe im Sinne der Erfindung sind auch Vit- amine und Mineralstoffe, sowie Pflanzenbehandlungsmittel und Insektizide. Zu den Vitaminen gehören die Vitamine der A- Gruppe, der B-Gruppe, worunter neben B^ B2, B6 und B12 sowie Nicotinsäure und Nicotinamid auch Verbindungen mit Vitamin B- Eigenschaften verstanden werden, wie z.B. Adenin, Cholin, Pan- tothensäure, Biotin, Adenylsäure, Folsäure, Orotsäure,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 requirement is that they are sufficient to achieve the desired effect. Thus, the active substance concentration can 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, for example ibuprofen / caffeine, 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, the B group, meaning next to B ^ B 2, B 6 and B 12 i e nicotinic acid and nicotinamide sow also compounds with vitamin B properties are understood, such as adenine, choline, Pantothenic acid, biotin, adenylic acid, folic acid, orotic acid,
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.Pangamic acid, carnitine, p-aminobenzoic 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 Verarbei- tung folgender Wirkstoffe geeignet:The method according to the invention is for example for processing suitable for the following active ingredients:
Acebutolol, Acetylcystein, Acetylsalicylsäure, Acyclovir, Al- brazolam, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikacin, Amilorid, Aminoessigsäure, Amiodaron, Amitriptylin, Amlodipin, Amoxicillin, Ampicillin, Ascorbinsaure, Aspartam, Astemizol, Atenolol, Beclomethason, Benserazid, Benzalkonium- Hydrochlorid, Benzocain, Benzoesäure, Betamethason, Bezafibrat, Biotin, Biperiden, Bisoprolol, Bromazepam, Bromhexin, Bromo- criptin, Budesonid, Bufexamac, Buflomedil, Buspiron, Coffein, Campher, Captopril, Carbamazepin, Carbidopa, Carboplatin, Cefachlor, Cefalexin, Cefatroxil, Cefazolin, Cefixim, Cefotaxi- m, Ceftazidim, Ceftriaxon, Cefuroxim, Celedilin, Chloramp- henicol, Chlorhexidin, Chlorpheniramin, Chlortalidon, Cholin, Cyclosporin, Cilastatin, Cimetidin, Ciprofloxacin, Cisapride,Acebutolol, Acetylcysteine, Acetylsalicylic Acid, Acyclovir, Albrazolam, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikacin, Amilorid, Amino Acid, Astitripoline, Bicarbonate, Bicarbonate, Bicarbonate Hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexin, bromocriptin, budesonid, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopaxachachin, carboplatin, carboplatinfx, carboplatin, carboplatin Cefazolin, Cefixim, Cefotaxim, Ceftazidim, Ceftriaxon, Cefuroxim, Celedilin, Chloramphenicol, Chlorhexidine, Chlorpheniramine, Chlortalidon, Choline, Cyclosporin, Cilastatin, Cimetidine, Ciprofloxacin, Cisapride,
Cisplatin, Clarithromycin, Clävulansäure, Clomibramin, Clonaze- pam, Clonidin, Clotrimazol, Codein, Cholestyramin, Cromoglycin- säure, Cyanocobalamin, Cyproteron, Desogestrel, Dexamethason, Dexpanthenol, Dextromethorphan, Dextropropoxiphen, Diazepam, Diclofenac, Digoxin, Dihydrocodein, Dihydroergotamin,Cisplatin, clarithromycin, clavulanic acid, clomibramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycine acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextrroethporphoxipod, dextro doproethoxamine, dextro dia methoxane, dextro dia methane pod
Dihydroergotoxin, Diltiazem, Diphenhydramin, Dipyridamol, Dipy- ron, Disopyramid, Domperidon, Dopamin, Doxocyclin, Enalapril, Ephedrin, Epinephrin, Ergocalciferol, Ergotamin, Erythromycin, Estradiol, Ethinylestradiol, Etoposid, Eucalyptus Globulus, Famotidin, Felodipin, Fenofibrat, Fenoterol, Fentanyl, Flavin- Mononucleotid, Fluconazol, Flunarizin, Fluorouracil, FluoXetin, Flurbiprofen, Furosemid, Gallopamil, Gemfibrozil, Gentamicin, Ginkgo Biloba, Glibenclamid, Glipizid, Clozapin, Glycyrrhiza glabra, Griseofulvin, Guaifenesin, Haloperidol, Heparin, Hyalu- ronsäure, Hydrochlorothiazid, Hydrocodon, Hydrocortison, Hydro- morphon, Ipratropium-Hydroxid, Ibuprofen, Imipenem, Indometha- cin, Iohexol, Iopamidol, Isosorbid-Dinitrat, Isosorbid-Mononi- trat, Isotretinoin, Ketotifen, Ketoconazol, Ketoprofen, Ketoro- lac, Labatalon, Lactulose, Lecithin, Levocarnitin, Levodopa, Levoglutamide, Levonorgestrel, Levothyroxin, Lidocain, Lipase, Lipramin, Lisinopril, Loperamid, Lorazepam, Lovastatin, Medrox- yprogesteron, Menthol, Methotrexat, Methyldopa, Methylpredniso- OZ 0480/01154 13ron dihydroergotoxin, diltiazem, diphenhydramine, dipyridamole, Dipy-, disopyramide, domperidone, dopamine, Doxocyclin, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl , Flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoXetin, flurbiprofen, furosemide, gallopamil, gemfibrozil, gentamicin, ginkgo biloba, glibenclamide, glipizide, clozapine, glycyrrhiza glabra, griseofulvin, hyoperfidoline, guaifenolidonid , Hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indomethamine, iohexol, iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketinolactulose, labatal , Levocarnitin, Levodopa, Levoglutamide, Levonorgestrel, Levothyroxine, Lidocaine, Lipase, Lipramin, Lisinopril, Loperamide, Lorazepam, Lovastatin, Me droxyprogesterone, menthol, methotrexate, methyldopa, methylpredniso- OZ 0480/01154 13
Ion, Metoclopramid, Metoprolol, Miconazol, Midazolam, Minocy- clin, Minoxidil, Misoprostol, Morphin, Multivitamin-Mischungen bzw. -kombinationen und Mineralsalze, N-Methylephedrin, Nafti- drofuryl, Naproxen, Neomycin, Nicardipin, Nicergolin, Nicotina- mid, Nicotin, Nicotinsäure, Nifedipin, Nimodipin, Nitrazepam, Nitrendipin, Nizatidin, Norethisteron, Norfloxacin, Norgestrel, Nortriptylin, Nystatin, Ofloxacin, Omeprazol, Ondansetron, Pan- creatin, Panthenol, Pantothensäure, Paracetamol, Penicillin G, Penicillin V, Phenobarbital, Phenoxifyllin, Phenoxymethy- lpenicillin, Phenylephrin, Phenylpropanolamin, Phenytoin, Piro- xicam, Polymyxin B, Povidon-Iod, Pravastatin, Prazepam, Prazosin, Prednisolon, Prednison, Promocriptin, Propafenon, Propranolol, Proxyphyllin, Pεeudoephedrin, Pyridoxin, Quinidin, Ramipril, Ranitidin, Reserpin, Retinol, Riboflavin, Rifampicin, Rutosid, Saccharin, Salbutamol, Salcatonin, Salicylεäure, Sim- vastatin, Somatropin, Sotalol, Spironolacton, Sucralfat, Sul- bactam, Sulfamethoxazol, Sulfasalazin, Sulpirid, Tamoxifen, Tegafur, Teprenon, Terazosin, Terbutalin, Terfenadin, Tetracyclin, Theophyllin, Thiamin, Ticlopidin, Timolol, Tran- examsäure, Tretinoin, Triamcinolon-Acetonid, Triamteren, Trime- thoprim, Troxerutin, Uracil, Valproinsäure, Vancomycin, Verapa- mil, Vitamin E, Volinsäure, Zidovudin.Ion, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, Nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pan-creatine, panthenol, pantothenic acid, penillinoxin, penillinoxin, penylinaminophenin, paracetaminophenin, paracetaminophenin Phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, promocriptine, propafenone, propranolol, proxyphidoxinid, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepyridine, quininepinepine , Retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, sim- vastatin, somatropin, sotalol, spironolactone, sucralfate, sul- bactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine, tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine, triamine acetide, Valproic acid, vancomycin, verapamil, vitamin E, volinic acid, 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 Lösungen 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 solid solutions of active pharmaceutical ingredients in polymers, the active ingredient is molecularly dispersed in the polymer.
Die pharmazeutische Mischung wird dann in üblicher Weise aufgeschmolzen, vorzugsweise in einem Extruder, und dem Formbandkalander zugeführt, wie das beispielsweise in der US-A- 4,880,585 beschrieben ist. Falls erforderlich werden die Tabletten nach der Kalandrierung gekühlt, z.B. in einem Luft¬ oder Kühlbad.The pharmaceutical mixture is then melted in a conventional manner, preferably in an extruder, and fed to the forming belt calender, as is the case, for example, in US Pat. 4,880,585. If necessary, the tablets are cooled after calendering, for example in an air or cooling bath.
Bei klebrigen oder hochviskosen Materialien, die sich nur schwer oder gar nicht von der Form lösen, ist die Anwendung eines Formentrennmittels, beispielsweise ein Silikonöl oder ein Silikonlack, zweckmäßig.In the case of sticky or highly viscous materials which are difficult or impossible to detach from the mold, it is advisable to use a mold release agent, for example a silicone oil or a silicone varnish.
Im folgenden werden bevorzugte Ausführungsformen der erfindungsgemäßen Vorrichtung anhand der beigefügten Zeichnung erläutert. Dabei zeigtPreferred embodiments of the device according to the invention are explained below with reference to the accompanying drawing. It shows
Figur 1 eine schematische Ansicht des erfindungsgemäßen Formbandkalanders,FIG. 1 shows a schematic view of the forming band calender according to the invention,
Figur 2 eine Detailansicht im Längsschnitt gemäß einer ersten Ausführungsform des zwischen den Kalanderwalzen durchgeführten Formbandes der Vorrichtung aus Figur 1,FIG. 2 shows a detailed view in longitudinal section according to a first embodiment of the forming belt of the device from FIG. 1 carried out between the calender rolls,
Figur 3 eine Ansicht wie in Figur 2 einer zweiten Ausführungsform des Formbandes.Figure 3 is a view as in Figure 2 of a second embodiment of the forming belt.
Figur 1 zeigt den erfindungsgemäßen Formbandkalander 10, wobei ein Formband 12 zwischen Kalanderwalzen 14,16 über Umlenkrollen 18 geführt ist. Ein Extruder 20 dient zur Herstellung der plastischen Produktmasse, die bevorzugt als breites Produktband 22 erzeugt wird. Die Breite der Kalanderwalzen 14,16, des Formbandes 12 und des Produktbandes 22 sind bevorzugt im wesentlichen gleich. Die Umlaufrichtung des Formbandes 12, und die Drehrichtung der Walzen 14 und 16 sind durch Pfeile angedeutet. Das Produktband 22 wird parallel zur Bewegungsrichtung des Formbandes 12 in die trogähnliche Vertiefung 26 zwischen den Walzen 14 und 16 zugegeben.FIG. 1 shows the forming belt calender 10 according to the invention, a forming belt 12 being guided between the calender rollers 14, 16 via deflection rollers 18. An extruder 20 is used to produce the plastic product mass, which is preferably produced as a wide product band 22. The width of the calender rolls 14, 16, the forming belt 12 and the product belt 22 are preferably essentially the same. The direction of rotation of the forming belt 12 and the direction of rotation of the rollers 14 and 16 are indicated by arrows. The product belt 22 is added parallel to the direction of movement of the forming belt 12 into the trough-like recess 26 between the rollers 14 and 16.
Das Formband 12 weist auf seiner Oberfläche Vertiefungen 24 oder Öffnungen 30 auf, wie insbesondere in den Figuren 2 und 3 dargestellt ist.The forming tape 12 has depressions 24 or openings 30 on its surface, as in particular in FIGS. 2 and 3 is shown.
Figur 2 zeigt eine erste Ausführungsform der erfindungsgemäßen Vorrichtung, bei der das Formband 12 Vertiefungen 24 aufweist. Formband 12 und Produktmasse 22 werden in den immer enger werdenden Spalt zwischen den beiden Walzen 14 und 16 mitgeführt, wobei die Produktmasse 22 in die Aussparungen 24 des Formbandes 12 gepreßt wird. Handelt es sich beispielsweise um eine Produktmasse, die in einem heißen, plastischen Zustand zugeführt wird, so kann mindestens eine der Walzen 14,16 gekühlt sein, so daß die Produktmasse beim Durchlaufen zwischen den Walzen in den Aussparungen 24 erkaltet, wodurch feste Formlinge 28 entstehen, die anschließend aus den Aussparungen entfernt werden können.FIG. 2 shows a first embodiment of the device according to the invention, in which the forming belt 12 has depressions 24. Molding tape 12 and product mass 22 are carried in the increasingly narrow gap between the two rollers 14 and 16, the product mass 22 being pressed into the recesses 24 of the molding tape 12. If it is, for example, a product mass that is supplied in a hot, plastic state, at least one of the rollers 14, 16 can be cooled, so that the product mass cools down in the recesses 24 as it passes between the rollers, thereby producing solid moldings 28 which can then be removed from the recesses.
Figur 3 zeigt den gleichen Ausschnitt wie Figur 2 eines erfindungsgemäßen Formbandkalanders gemäß Figur 1, wobei das Formband 12 in Figur 3 gemäß einer anderen Ausführungsform der Erfindung durchgehende Öffnungen 30 aufweist, in welche die Produktmasse 22 beim Durchlaufen zwischen den Walzen 14 und 16 der Vorrichtung gepreßt wird. Die in diesem Fall entstehenden Formlinge 28 weisen zwei glatte Oberflächen auf. Die Öffnungen 30 im Formband 12 werden bevorzugt durch Ausstanzen des Formbandes erzeugt. Wie aus Figur 3 ersichtlich, entstehen Formlinge 28, deren Kantenwinkel im wesentlichen 90° betragen. Eventuell überstehende Produktmasse läßt sich bei derartig geformten Tabletten leicht entgraten. FIG. 3 shows the same detail as FIG. 2 of a forming band calender according to the invention according to FIG. 1, the forming band 12 in FIG. 3 according to another embodiment of the invention having through openings 30 into which the product mass 22 is pressed as it passes between the rollers 14 and 16 of the device becomes. The moldings 28 produced in this case have two smooth surfaces. The openings 30 in the forming band 12 are preferably created by punching out the forming band. As can be seen from FIG. 3, shaped articles 28 are formed, the edge angles of which are essentially 90 °. Any protruding product mass can be easily deburred with tablets shaped in this way.

Claims

P a t e n t a n s p r ü c h e Patent claims
1. Vorrichtung zur Herstellung von flächigen Formungen (28) aus einer wirkstoffhaltigen Produktmasse (22) , mit mindestens einem Beschickungsmittel (20) zur Zuführung der1. Device for producing flat formations (28) from an active substance-containing product mass (22), with at least one loading means (20) for supplying the
Produktmasse, mindestens einem Walzenpaar (14,16), bestehend aus zwei gegenläufig rotierbaren Kalanderwalzen, dadurch gekennzeichnet, daß die Vorrichtung ein umlaufendes Formband (12) umfaßt, das zwischen den beiden Walzen (14,16) durchgeführt ist, wobei dasProduct mass, at least one pair of rollers (14, 16), consisting of two counter-rotating calender rollers, characterized in that the device comprises a rotating forming belt (12) which is carried out between the two rollers (14, 16), the
Formband auf seiner Oberfläche Aussparungen (24,30) zurForming tape on its surface with recesses (24,30)
Aufnahme der Produktmasse aufweist.Includes absorption of the product mass.
2. Vorrichtung gemäß Anspruch 1, dadurch gekennzeichnet, daß die Aussparungen durchgehende Öffnungen (30) in dem Formband (12) sind.2. Device according to claim 1, characterized in that the recesses are through openings (30) in the forming belt (12).
3. Vorrichtung gemäß Anspruch 2, dadurch gekennzeichnet, daß die Öffnungen (30) eine runde, ovale oder sechseckige Form aufweisen.3. Device according to claim 2, characterized in that the openings (30) have a round, oval or hexagonal shape.
4. Vorrichtung gemäß Anspruch 2 oder 3, dadurch gekennzeichnet, daß die Öffnungen (30) auf ihrem Umfang nach innen weisende Stege zur Bildung von Bruchkerben in den Formungen aufweisen.4. Apparatus according to claim 2 or 3, characterized in that the openings (30) on their circumference have inwardly pointing webs to form notches in the formations.
5. Vorrichtung gemäß einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß das Formband (12) aus Metall, Kunststoff oder einem Gummimaterial besteht. 5. Device according to one of claims 1 to 4, characterized in that the forming tape (12) consists of metal, plastic or a rubber material.
6. Vorrichtung gemäß einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß die Dicke des Formbandes (12) mindestens so groß wie die gewünschte Dicke der Formlinge (28) ist.6. Device according to one of claims 1 to 5, characterized in that the thickness of the forming belt (12) is at least as large as the desired thickness of the molded articles (28).
7. Vorrichtung gemäß einem der vorangegangenen Ansprüche, dadurch gekennzeichnet, daß die Kalanderwalzen (14,16) glatte Mantelflächen aufweisen.7. Device according to one of the preceding claims, characterized in that the calender rolls (14, 16) have smooth outer surfaces.
8. Vorrichtung gemäß einem der vorangegangen Ansprüche, dadurch gekennzeichnet, daß die Kalanderwalzen (14,16) temperierbar sind.8. Device according to one of the preceding claims, characterized in that the calender rolls (14, 16) can be tempered.
9. Vorrichtung gemäß einem der vorangegangenen Ansprüche, dadurch gekennzeichnet, daß der Abstand der Walzen (14,16) eines Walzenpaares veränderbar ist, so daß variabler Anpreßdruck erzeugt werden kann.9. Device according to one of the preceding claims, characterized in that the distance between the rollers (14, 16) of a pair of rollers is variable, so that variable contact pressure can be generated.
10. Vorrichtung nach einem der vorangegangenen Ansprüche, dadurch gekennzeichnet, daß die Vorrichtung (lo) mehrere Beschickungsmittel (20) für unterschiedliche Produktmassen aufweist.10. Device according to one of the preceding claims, characterized in that the device (lo) has a plurality of loading means (20) for different product masses.
11. Vorrichtung gemäß Anspruch 10, dadurch gekennzeichnet, daß aus unterschiedlichen Produktmassen bestehende Produktstränge (22) gleichzeitig einem Walzenpaar zugeführt werden.11. The device according to claim 10, characterized in that consisting of different product masses product strands (22) are simultaneously fed to a pair of rollers.
12. Vorrichtung gemäß Anspruch 10, dadurch gekennzeichnet, daß aus unterschiedlichen Produktmassen bestehende Produktstränge (22) aufeinanderfolgenden Walzenpaaren zugeführt werden.12. The apparatus according to claim 10, characterized in that existing product strands (22) of successive roller pairs are supplied from different product masses.
13. Vorrichtung gemäß einem der vorangegangenen Ansprüche, dadurch gekennzeichnet, daß die Beschickungsmittel (20) Extruder und/oder beheizbare Füllkeile sind. 13. Device according to one of the preceding claims, characterized in that the charging means (20) are extruders and / or heatable filling wedges.
14. Verfahren zur Herstellung flächiger Formlinge aus einer wirkstoffhaltigen Produktmasse, wobei man - zwischen den gegenläufig rotierenden Walzen eines Kalanderwalzenpaares ein Formband mit Aussparungen durchlaufen läßt, den gewünschten Anpreßdruck der beiden Walzen einstellt, mindestens einen aus der wirkstoffhaltigen Masse bestehenden Produktstrang bildet, diesen Produktstrang dem Walzenpaar zuführt, wobei die Produktmasse in die Aussparungen gepreßt wird, die Formlinge aus den Aussparungen entfernt.14. Process for the production of flat moldings from an active substance-containing product mass, whereby - between the oppositely rotating rollers of a pair of calender rollers, a forming strip with recesses is run through, the desired contact pressure of the two rollers is set, at least one product strand consisting of the active substance-containing mass is formed, this product strand Feeds pair of rollers, the product mass is pressed into the recesses, the moldings removed from the recesses.
15. Verfahren gemäß Anspruch 14, dadurch gekennzeichnet, daß man das Produktband zwischen mehreren Walzenpaaren hindurchführt.15. The method according to claim 14, characterized in that the product belt is passed between several pairs of rollers.
16. Verfahren gemäß einem der Ansprüche 14 oder 15, dadurch gekennzeichnet, daß man mehrere Produktstränge bildet, die gleichzeitig einem Walzenpaar oder nacheinander mehreren Walzenpaaren zugeführt werden.16. The method according to any one of claims 14 or 15, characterized in that several product strands are formed, which are fed simultaneously to a pair of rollers or successively several pairs of rollers.
17. Verfahren gemäß einem der Ansprüche 14 bis 16, dadurch gekennzeichnet, daß man eine heißplastische Produktmasse zuführt, die beim Erkalten fest wird.17. The method according to any one of claims 14 to 16, characterized in that one feeds a hot plastic product mass, which becomes solid on cooling.
18. Verfahren gemäß Anspruch 17, dadurch gekennzeichnet, daß man mindestens ein Walzenpaar kühlt.18. The method according to claim 17, characterized in that cooling at least one pair of rollers.
19. Verfahren gemäß einem der Ansprüche 14 bis 16, dadurch gekennzeichnet, daß man eine feuchtplastische Produktmasse verwendet, die beim Trocknen fest wird.19. The method according to any one of claims 14 to 16, characterized in that one uses a moist plastic product mass, which becomes solid during drying.
20. Verfahren gemäß Anspruch 19, dadurch gekennzeichnet, daß man mindestens ein Walzenpaar heizt. 20. The method according to claim 19, characterized in that heating at least one pair of rollers.
PCT/EP1996/004600 1995-10-23 1996-10-23 Moulding strip calender WO1997015268A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AU74911/96A AU705657B2 (en) 1995-10-23 1996-10-23 Molding belt calender
JP9516273A JPH11514275A (en) 1995-10-23 1996-10-23 Molded belt calender
KR1019980702910A KR19990066977A (en) 1995-10-23 1996-10-23 Molding strip calendar
EP96937213A EP0957884A1 (en) 1995-10-23 1996-10-23 Moulding strip calender
SI9620112A SI9620112A (en) 1995-10-23 1996-10-23 Moulding strip calender
SK506-98A SK50698A3 (en) 1995-10-23 1996-10-23 Moulding strip calender
BR9611239A BR9611239A (en) 1995-10-23 1996-10-23 Machine and process for producing flat molded parts from a product composition containing an active ingredient
NO981795A NO981795L (en) 1995-10-23 1998-04-22 Molding in a calender

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19539359A DE19539359A1 (en) 1995-10-23 1995-10-23 Forming calender
DE19539359.7 1995-10-23

Publications (2)

Publication Number Publication Date
WO1997015268A1 true WO1997015268A1 (en) 1997-05-01
WO1997015268B1 WO1997015268B1 (en) 1997-06-05

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Country Status (16)

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EP (1) EP0957884A1 (en)
JP (1) JPH11514275A (en)
KR (1) KR19990066977A (en)
CN (1) CN1200663A (en)
AU (1) AU705657B2 (en)
BR (1) BR9611239A (en)
CA (1) CA2232353A1 (en)
CZ (1) CZ109698A3 (en)
DE (1) DE19539359A1 (en)
HU (1) HUP9900734A3 (en)
NO (1) NO981795L (en)
SI (1) SI9620112A (en)
SK (1) SK50698A3 (en)
TW (1) TW343920B (en)
WO (1) WO1997015268A1 (en)
ZA (1) ZA968848B (en)

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WO2014139803A1 (en) * 2013-03-15 2014-09-18 AbbVie Deutschland GmbH & Co. KG Process and apparatus for metering a plasticized formulation

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DE19901383A1 (en) * 1999-01-15 2000-07-20 Knoll Ag Process for the preparation of different solid dosage forms
DE10007560C2 (en) * 1999-12-14 2002-09-26 Alexanderwerk Ag Device for compacting small amounts of powdery material
DE10038571A1 (en) * 2000-08-03 2002-02-14 Knoll Ag Compositions and dosage forms for use in the oral cavity in the treatment of mycoses
NL2002672C2 (en) * 2009-03-26 2010-09-28 Stork Titan Bv MASS DIVIDING DEVICE AND MOLDING DEVICE CONTAINING SUCH A MASS DIVIDING DEVICE.
EP2590615B1 (en) * 2010-07-09 2015-08-26 Research Center Pharmaceutical Engineering GmbH Multi-layer tablet formation by adhering tablet bodies together

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DE1766546A1 (en) * 1968-06-11 1971-09-30 Eriksson Karl Gunnar Process for the production of medicinal pills or tablets
CH530944A (en) * 1971-05-14 1972-11-30 Lonza Ag Semi isostatic pressing - using fine powders and continuous belt and drum press
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WO2014139803A1 (en) * 2013-03-15 2014-09-18 AbbVie Deutschland GmbH & Co. KG Process and apparatus for metering a plasticized formulation

Also Published As

Publication number Publication date
KR19990066977A (en) 1999-08-16
ZA968848B (en) 1998-04-22
JPH11514275A (en) 1999-12-07
CA2232353A1 (en) 1997-05-01
EP0957884A1 (en) 1999-11-24
HUP9900734A3 (en) 2000-07-28
HUP9900734A2 (en) 1999-10-28
NO981795L (en) 1998-04-23
SK50698A3 (en) 1999-01-11
NO981795D0 (en) 1998-04-22
MX9802985A (en) 1998-09-30
CN1200663A (en) 1998-12-02
AU705657B2 (en) 1999-05-27
CZ109698A3 (en) 1999-07-14
DE19539359A1 (en) 1997-04-24
BR9611239A (en) 1999-03-30
SI9620112A (en) 1998-08-31
AU7491196A (en) 1997-05-15
TW343920B (en) 1998-11-01

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