SK50698A3 - Moulding strip calender - Google Patents

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

Calender with forming belt

Technical field

BACKGROUND OF THE INVENTION The present invention relates to machinery and a process for the production of flat compacts, in particular tablets, from a product mixture containing active ingredients.

BACKGROUND OF THE INVENTION

A known process for producing tablets is melt calendering. A manufacturing process of this type is described e.g. in DE-A 17 66 546 and in US-A 4,880,585. The principle of this procedure is to disperse the active ingredient into the melt of the carrier, e.g. fatty acids or water-soluble thermoplastic polymers. After mixing the active ingredient, the polymer and, if necessary, other auxiliaries, the melt is obtained by melting e.g. in an extrusion press and then molded in a molding calender into tablets that solidify upon cooling. The molding calender comprises a pair of counter-rotating rollers having cavities (depressions) on their surface, the shape of which corresponds to the shape of half of the tablet produced. The tablet formation takes place at the point of contact of the two rollers by joining the mixture into tablets pressed into the recesses in the opposite roller.

However, the tablet manufacturing process has its drawbacks. So eg. is a very complicated cylinder design. These rollers have to have recesses in their manufacture, which in most cases still need to be polished in order to obtain a maximum smooth tablet surface. The manufacture of these rollers is very costly since the depressions must be adjusted very precisely. The rollers must be adjusted so that the two opposing recesses are always aligned as precisely as possible. Compliance with this condition is particularly difficult in cases where these recesses are very small.

Moreover, these machines do not allow their flexible use, because if, for example, the production of tablets of different shapes and / or sizes on the same machine is desired, this means that the rollers can be completely replaced and laboriously aligned. However, great flexibility is required in the pharmaceutical industry for tableting machines to produce different tablet sizes and shapes.

CH-A 530 944 discloses a flat stamping machine, equipped with at least one feed device for feeding the product mixture, with at least one pair of rollers formed by two counter-rotating calender rolls, the machine also comprising a forming belt which passes between the two rolls forming pairs, the molding belt having depressions on its surface into which the product mixture is pressed. This known machine is used to produce relatively large moldings.

SUMMARY OF THE INVENTION

It is an object of the present invention to produce a flat molding machine from a product mixture containing the active ingredient which is cheaper than known conventional machines and which allows greater flexibility in use. It is also an object of the present invention to provide a simple and flexible method of making tablets.

It has been found that the present invention provides a machine for producing flat compacts in a product blend containing the active ingredient having at least one dispensing device for feeding the product blend, at least one pair of rollers formed by two counter-rotating calender rolls, a web, preferably a continuous web, which passes between two calender rolls and has depressions on its surface for injecting the product mixture, characterized in that the depressions are cut openings in the forming belt.

The rollers are arranged so that there is a gap between their outer surfaces. That is, the smallest distance between the outer surfaces of the pair of rollers essentially corresponds to the thickness of the treadmill. The product mixture is fed, in particular in the form of a wide strip of product, parallel to the direction of movement of the forming strip into the groove space between the two rolls. The molding belt and the product mixture are fed into a continuously tapered space between the calender rolls, the product mixture being forced into the recesses in the forming belt. The gap between the rollers essentially determines the pressure applied to the product mixture, thereby determining the thickness of the moldings obtained in this way.

The use of a molding belt makes it possible to substantially increase the flexibility of use of the tablet machine. Different tablet shapes or sizes can be produced in this process by simply replacing the molding belt in a machine, the same press rolls being used for different tablet sizes. The manufacturing cost of this machine is lower, since the recesses in the molding belt do not need to be positioned with such high precision, as only one recess is required per tablet in this case. At the same time, there is no laborious alignment of machine parts which move against each other.

Molding strips made of plastic are particularly economical since the recesses can be made by pressing. It goes without saying that in this case it must be ensured that the plastic used is dimensionally stable at the temperatures used in the manufacture of the tablets.

The apertures in the molding belt are preferably made by shearing, i.e. any shape of tablet can be produced depending on the shearing tool. In this arrangement, the molded product molded into the tablets comes into contact with the two outer surfaces of the pair of calender rolls, so that in this case the tablets produced have two flat surfaces.

It goes without saying that the recesses or holes in the molding belt pass so that the product mixture can be processed into moldings with minimal loss.

The preferred shape of the depressions or openings is circular, oval or hexagonal when viewed from above.

The openings may have circumferentially e.g. as well as various stripes which are made by notches in the punching preparation so that it is possible to obtain scored tablets.

The molding belt may be made of any suitable material, but preferred materials are metals, especially steel, and further plastics or rubber. If the molding belt is made of a relatively rigid material, the thickness of the belt corresponds essentially to the desired thickness of the tablets. This means that thicker tablet shapes require a belt of greater thickness, so that the belt may, if necessary, be composed of individual links that more easily pass through the machine roll. It is also possible to use molding strips of flexible material, which may then be thicker than the desired tablet thickness. In this case, the forming belt is slightly thicker than the gap between the calender rolls. In the process between rollers, this molding belt is increasingly compressed so that the tablet moldings can be subjected to different pressures depending on the gap between the rolls of the calender.

The calender rolls typically have smooth outer surfaces. However, if the compressed tablets have an enlarged surface, it is possible to use calender rolls e.g. with a surface of some roughness.

It is preferred to use a calender roller with temperature control. When using a product mixture that is plastic at high temperature and solidifies upon cooling, it is preferred to use chilled calender rolls. In contrast, when the product mixture is plastic in the wet state and dry in the dry state, it is preferable to use a calender with heating rollers in this case. That is, the calender rolls are accordingly used to cool or dry the product mixture. The product mixture is in thermal contact with these rollers for different periods of time depending on the diameter of the rollers. The pressure rollers are universal tools, which are generally thermally conductive, always resistant to compressive forces and inert to the material being processed.

The gap between the rollers can be adjusted to create different contact pressures.

In a simple arrangement, the machine has only one dispensing device for delivering the product mixture. However, it may be necessary to produce e.g. multilayer tablets, so that, in another arrangement, the machine may consist of multiple dispensing devices supplying several product bands. These individual product strips can be fed simultaneously to one pair of rollers. It is also possible to guide the molding belt through several pairs of rollers so that the strips of different products are fed successively to individual pairs of rollers. In this case, the gap between the roller pairs is adjusted such that the contact pressure is the lowest for the first pair of rollers and that for the last pair of rollers, this pressure is highest. The tablets produced in this way are then composed of several layers.

It is also possible to coat the tablets with a thin protective film to achieve specific release of the active ingredient. a diffusion-preventing polymer. Thus, it is possible to obtain protective films which dissolve and release the active ingredient only under specific environmental conditions (e.g., pH or temperature). These coatings may also serve as a taste mask or as a light stabilizer. If the entire tablet is to be coated with the protective film, this operation is generally required to be carried out in the next separate step using conventional coating techniques. However, it is also possible according to the invention to feed one or two film strips together with the melt strip between the rolls so that the molten product is placed between the two protective film strips. Tablets are obtained which are provided on their upper and / or lower side with a suitable protective film. These protective films on the top and bottom may not be identical. For tablets that consist of several layers, e.g. these films provide different release of the active ingredient.

Preferred dosing and feeding devices are extruders and / or heated kneaders.

The machine of the present invention can be used to produce tablets or the like in a continuous manner. The machine is extremely versatile because its basic equipment remains unchanged and only the forming belt is replaced. Depending on the molding belt used and the dimensions of the recesses or holes, the range of products produced is wide, ranging from very small pelletized products to tablets weighing 1 g and above. These moldings have an edge angle of 90 or less, which facilitates the removal of overlaps from the tablets, particularly with fragile product mixtures. The arrangement of the apertures in the molding belt is generally such that their distance is sufficient to prevent the formation of duplicate tablets and the need to separate them.

The friction coupling connection with the pressure roller drive ensures that it is not necessary to use a separate belt drive. The length of this molding belt can vary widely. This has proven to be particularly advantageous since it allows for an extended tablet residence time in the mold, so that it is not necessary to eject tablets that have not yet cooled (solidified).

After passing through the calender rolls, it is easy to remove the product from the forming belt by bending it over the roller or, if necessary, using a nail roller. This method is used in particular for molded strips with cut openings, since in this case the tablets are accessible from both the top and the bottom and can be extruded from the molding belt.

The flat stampings which can be produced on this calender with a forming belt are particularly suitable for use as tablets. They are particularly suitable for use as IR tablets, i. tablets that release the active ingredient rapidly (Instant Release), such as SR tablets, i. tablets that release the active ingredient slowly (slow release), such as delayed action tablets, i. tablets which release the active ingredient with delay, sublingual tablets whose active ingredient is absorbed through the oral mucosa and which are therefore intended to be dissolved under the tongue, as lozenges or as soluble tablets.

Tablets produced by this method can be used in the pharmaceutical or food industry (e.g. in the form of vitamin tablets), but this method can be used e.g. also in the protection of agricultural crops and in a number of other industries.

The present invention also relates to a process for producing flat moldings from a product mixture containing the active ingredient, wherein the molding belt provided with depressions passes between a pair of calender rolls that rotate against each other, forming at least one product strand consisting of the mixture containing the active ingredient, generally as wide the product belt is fed to a pair of rollers, the product mixture being pressed into the depressions when passing between the pair of rollers, and the moldings are removed from the depressions after passing through the pair of calender rolls. The desired contact pressure by which the product mixture is compressed is pre-adjusted by adjusting the gap between the pair of rollers. The gap between these rollers, i. the minimum distance between their outer surfaces should generally not be greater than the thickness of the forming belt used. In the case of using elastic molding belts, it is possible to adjust the gap between the rolls slightly less than the thickness of the molding belt so that a higher pressure can be applied to the product mixture.

In another embodiment of the process of the present invention, the product web passes through several pairs of rollers in series. It is also possible to provide a series of different product strips, which are then fed simultaneously to one roller pair or sequentially to a series of roller pairs. As a variant of this arrangement, coextrusion of a multilayer melt with the desired layer order in tablets can be used.

The product mixture is plastic in the hot or wet state depending on the desired tablet. Depending on the method of manufacture, the pair of calender rolls can be either heated or cooled to obtain solid and dimensionally stable tablets.

Tablets are made from a mixture comprising one or more pharmacologically active ingredients and one or more conventional excipients and which, by melting or softening at least one ingredient, becomes pasty or viscous so that it can be extruded.

In particular, the invention encompasses compositions comprising pharmacologically acceptable polymers (with a bonding temperature lower than the decomposition temperature of all components of the composition), e.g. polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, ethylene / vinyl acetate copolymers, polyhydroxyethyl methacrylate, cellulose esters of acrylic acid; . The K-values (as reported by H. Fikentscher, Cellulose-Chemie 13 (1932), 58-64 and 71-74) of these polymers are in the range of 10 to 100, preferably 12 to 70, in particular 12 to 35, and for PVP preferably 12, to 35, in particular 12 to 17.

The polymeric binder must soften or melt to a complete mixture of all components within a temperature range of 50 to 180 ° C so that the mixture obtained can be extruded. The bonding temperature of the mixture must therefore be less than 180, preferably less than 130 ° C. If desired, this temperature can be lowered by the use of pharmacologically acceptable plasticizers such as long chain alcohols, ethylene glycol, propylene glycol, trimethylpropane, triethylene glycol, butanediols, pentanols, hexanols, polyethylene glycols, silicones, esters of aromatic dialkyl acids, esters, e.g. benzoic acid esters, terephthalic acid esters or aliphatic dicarboxylic acid esters (e.g. dialkyl adipates, sebacic esters, azelaic esters, citric and tartaric esters) or fatty acid esters.

Examples of conventional pharmaceutical excipients which may be up to 100% by weight of the polymer include:

fillers such as silicates or diatomaceous earth, magnesium oxide, alumina, titanium dioxide, stearic acid or salts thereof, e.g. magnesium or calcium salt, methylcellulose, sodium carboxymethylcellulose, talc, sucrose, lactose, corn or corn starch, potato flour, polyvinyl alcohol preferably at a concentration of 0.02 to 50, in particular 0.020 to 20% based on the total weight of the composition;

lubricants such as aluminum and calcium stearate, talc and silicones in concentrations of from 0.1 to 5, preferably 0.1 to 3%, based on the total weight of the composition;

coloring agents such as azo dyes, organic or inorganic pigments or dyes of natural origin, wherein the inorganic pigments are present in concentrations of from 0.001 to 10, preferably from 0.5 to 3% of the total weight of the composition;

flow promoters such as animal or vegetable fats, especially in the hydrogenated state, and fats that are solid at room temperature. The melting point of these fats should preferably be 50 ° C or higher. Preference is given to fatty acid triglycerides of C _{12 to} ^C 14 to ^C 16 'to ^C 18' Waxes such as e.g. carnauba wax. These fats and waxes may advantageously be mixed alone or together with mono- and / or diglycerides or phosphatides, in particular lecithin. Mono and / or diglycerides derived from the above-mentioned types of fatty acids are preferred. The total amount of fats, waxes, mono- and diglycerides and / or lecithin ranges from 0.1 to 30, preferably 0.1 to 5% of the total weight of the composition for each layer;

stabilizers such as antioxidants, photostabilizers, hydroperoxide degrading agents, radical scavengers and microorganism stabilizers.

Wetting agents, preservatives, adsorbents, separators for easier mold removal and propellants can also be added (see, e.g., H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978).

The excipients of the present invention also include solid solution formers with a pharmacologically active ingredient. Examples of such excipients are pentaerythritol and pentaerythritol tetraacetate, polymers such as polyethylene and polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone, surfactants such as polyoxyethylene-40-stearate. citric and succinic, bile acids, sterols, and others, as exemplified by e.g. in J. L. Ford, Pharm. Acta Helv. 61 (1986) 69-88.

Pharmaceutical excipients also include the addition of bases and acids to adjust the solubility of the active ingredient (see, e.g., K. Thoma et al., Pharm. Ind. 51 (1989) 98-101).

The only prerequisite for the suitability of the excipients is their corresponding thermal stability.

The pharmaceutical active ingredients according to the invention include all substances which have a pharmaceutical effect and minimal side effects and do not decompose under processing conditions. The amount of active ingredient per unit dose and the concentration of the active ingredient may vary within wide ranges depending upon the efficacy of the ingredient and the rate of release. The only condition is that these values are sufficient to achieve the desired effect. That is, the concentration of active ingredient may range from 0.1 to 95, preferably from 20 to 80, in particular 30 to 70% by weight. It is also possible to use a combination of active ingredients, e.g. ibuprofen / caffeine. The active ingredients according to the invention are also vitamins and minerals, as well as crop protection agents and insecticides. Vitamins include vitamins of group A, group B, i.e., in addition to B _in B ₂ , B ₆ and B ₁₂ , nicotinic acid and nicotinamide, also substances which possess vitamin B properties such as adenines, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myoinositol and lipoic acid, vitamin C, vitamins of group D, group E, group F, group H, groups I and J, group K and group P. Active ingredients according to the invention also include peptide and therapeutic preparations.

The process of the invention is suitable for processing the following active ingredients, such as:

acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, aspicemoline, ampicillol, aspicillol, ampicillol, ampicillol , benzocaine, benzoic acid, betamethazone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexin, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, caproprile, carbamazepine, carbidopa, carboplatin, cefat cefat, cefat cefat, cefat cefat, cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, selegiline, chloramphenicol, chlorhexidine, chlorpheniramide, chlortalidone, choline, cyclosporin, cilastatin, cimetidene, ciprofloxacin, cisapride, cisplatin, clarinone, clarinone, clarinromine, clarithromycin, , cromoglycic acid, cyanocobalamin, cyproterone, desogestrel, de xamethazone, dexpanthenol, dextromethorphan, dextropropoxifen, diazepam, diclofenac, digoxin, dihydrocodein, dihydroergotamine, dihydroergotoxin, diltiazem, diphenidamine, dipyridamole, dipyron, disopyramide, epperrinone, epamine, β-epinoline, doxycinine ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, phenoterol, fentanyl, flavin-mononucleotide, fluconazole, flunaricin, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibrocillin, gemfibrocid, gentamicin, gentamicin, gentamicin , griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol, isosorbide dinitrate, isosorbide, isosorbide, labetalol, lactulose, lecithin, levocamitin, levodopa, lion oglutamide, levonorgestrel, levothyroxine, lidocaine, lipase, imipramine, lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, meoprolol, miconazole, midazoin, minilboline, minilboline, minilboline, minilbamine, minilboline, minilbamine, mineral salts, N-methylephedrine, naphthidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, ontydin, nofloxacin, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine, pravastatin, prosinone, prazennis, prazepnis, prazepnis, prazepnis, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salkantonin, salicylic acid, simvastatin, somatotropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, terenosine, sulpirfen, sulpirfen, sulpirfen, sulpirfen , theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, folinic acid, zidovudine.

Preferred active ingredients are ibuprofen (such as racemate, enantiomer or enriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid, verapamil, paracetamol, nifeldipine or captopril.

In some cases, solid solutions may be formed. The term solid solution is known to those skilled in the art, e.g. from the literature mentioned in the introduction. In solid solutions in polymers, the pharmaceutical active ingredients are present in the form of a molecular dispersion in the polymer.

The pharmaceutical mixture is then melted in a conventional manner, typically in an extruder, and transferred to a calender with a forming belt as described e.g. in US-A 4,880,585. If desired, the tablets are cooled after calendering, e.g. in air or in a cooling bath.

For sticky or highly viscous materials which are difficult to remove from the mold or which cannot be removed from the mold, it is recommended to use separators for easier removal of the moldings, e.g. silicone oil or silicone lacquer.

Overview of the drawings

A preferred embodiment of the machine according to the invention is shown below in the attached figures. Where

FIG. 1 shows a schematic view of a calender with a forming belt according to the invention,

FIG. 2 shows a detail of a longitudinal section of a molding belt known in the art which passes between the calender rolls of the machine of FIG. 1

FIG. 3 shows the same view as in FIG. 2 in a molding belt arrangement according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In FIG. 1 shows a calender with a forming belt 10 according to the present invention wherein the forming belt 12 passes between the rolls of the calender 14, 16 through the tension deflection rollers 18. An extruder is used to prepare a plastic product mixture, preferably fed in the form of a wide product belt. 20. The calender rolls 14, 16, the forming belt 12 of the product 22 generally have approximately the same width. 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 web 22 is fed in parallel to the direction of movement of the mold web 12 into the groove space 26 between the rollers 14 and 16.

The forming belt 12 has depressions 24 or openings 30 on its surface as shown in FIG. 2 and 3.

In FIG. 2, the molding belt 12 in the previous embodiment with depressions 24 is shown. The molding belt 12 and the product mixture 22 come together into a continuously tapered gap between the two rollers 14 and 16, the product mixture 22 being pressed into the recesses 24 of the forming belt 12. . the product mixture is supplied in a hot plastic state, at least one of the rollers 14, 16 can be cooled so that the product mixture is cooled when passing between the rollers in the recesses 24 to obtain solid moldings 28 which can then be removed from the recesses .

In FIG. 3 shows the same detail as FIG. 2 showing a calender with a forming belt according to the invention as shown in FIG. 1, wherein the forming belt 12 in FIG. 3, according to another embodiment of the present invention, the apertures 30 have been completely cut into which the product mixture 22 is pressed as it passes between the rolls 14 and 16 of the machine, the moldings 28 having two smooth surfaces in this method. The apertures 30 in the forming belt 12 are preferably made by shearing the forming belt. As shown in FIG. 3, the obtained moldings 28 have an edge angle substantially 90 °. When pressing tablets in this way, any overlaps can easily be removed.

Claims (15)

PATENT CLAIMS A machine for producing flat compacts (28) from a product mixture (22) comprising an active ingredient, characterized in that it is equipped with at least one metering device (20) which feeds the product mixture to at least one pair of rollers (14, 16) comprising from two opposing rotating calender rolls and a circulating forming belt (12) that passes between the two rolls (14, 16), the forming belt having recesses on its surface into which the product mixture is pressed, and these recesses are completely cut openings (30). Machine according to claim 1, characterized in that the openings (30) have stripes on their periphery which are pressed so that grooves are formed on the moldings. Machine according to claim 1, characterized in that the thickness of the forming strip (12) is at least as large as the desired thickness of the moldings (28). * Machine according to claim 1, characterized in that the calender rolls (14, 16) have smooth outer surfaces. W The machine according to claim 1, characterized in that the temperature of the calender rolls (14, 16) can be controlled. A machine according to claim 1, characterized in that it is possible to vary the size of the gap between the rolls of the calender (14, 16). Machine according to claim 1, characterized in that the machine (10) is equipped with several feeding devices (20) for feeding different product mixtures. Machine according to claim 1, characterized in that extruders and / or heated mixers are used as the feeding devices (20). 9. A process for the production of flat compacts from a product mixture containing the active ingredient, characterized in that: - a forming belt with recesses in the form of cut openings passes between opposing calender rolls, - the necessary contact pressure on the two cylinders is set, - ³ and at least one web formed product consisting of a mixture comprising an active ingredient, - this product belt is fed to a pair of rollers and the product mixture is injected into the holes, - the moldings are removed from the holes. Process according to claim 9, characterized in that the strip of product passes between several pairs of rollers. Method according to claim 9, characterized in that several product strips are formed and these product strips are fed simultaneously to either one pair of rollers or successively to several roll pairs. Process according to claim 9, characterized in that the product mixture is hot plastic and solidifies upon cooling. Process according to claim 12, characterized in that at least one pair of rollers is cooled. Process according to claim 9, characterized in that the product mixture is plastic in the wet state and solidifies after drying. Process according to claim 14, characterized in that at least one pair of rollers is heated.