WO1999027909A1 - Method for producing solid dosing forms - Google Patents

Abstract

The invention relates to a method for producing solid dosing forms by mixing at least one polymeric binding agent, at least one optional active substance, and optional common additives while producing a plastic mixture. Homopolymers and/or copolymers of N-vinyl amides and/or N-vinyl amines with at least 5 wt. % units of formulae (I) and/or (II) in which R<1> and R<2> have meanings given in the description are utilized as polymeric binding agents.

Description

Process for the preparation of solid dosage forms

description

The invention relates to a process for the production of solid dosage forms by mixing at least one polymeric binder and optionally at least one active ingredient and optionally conventional additives to form a plastic mixture and shaping, in particular the invention relates to a process for the production of solid pharmaceutical forms.

The classic processes for producing solid pharmaceutical forms, in particular tablets, are carried out discontinuously and comprise several stages. Pharmaceutical granules represent an important intermediate product. B. from the book "Pharmaceutical Technology", author Prof. Bauer, Frömmig and Führer, Thieme Verlag, pages 292 ff., It can be seen that drug forms can be obtained from the melt by dry granulation. It is described that melt solidification granules can be produced either by melting and shock-freezing, by pouring and crushing, or by spray-solidifying in spray towers. One problem with these processes is the exact shape required for the manufacture of pharmaceuticals. Irregular particles or fragments are often generated, so that the shape obtained in no way corresponds to the usual dosage forms and therefore granules are of little importance as an independent dosage form. The production of the desired solid pharmaceutical forms requires the use of further process steps, such as, for example, compression with the aid of tableting machines. This is time and cost intensive.

For some time now, a much simpler continuous process for the production of solid pharmaceutical forms has been known, in which an active substance-containing, solvent-free melt is extruded from a polymeric, active substance-containing binder and the extruded strand is shaped into the desired medicinal form, for example in a calender with shaping rollers, see EP -A-240 904, EP-A-240 906 and EP-A-337 256 and EP-A-358105. This enables targeted shaping to be achieved. In particular, polymers of N-vinylpyrrolidone or copolymers thereof, eg. B. with vinyl acetate used.

The use of homopolymers and copolymers of N-vinylamides and N-vinylamines in various fields, such as as binders in pharmaceutical preparations, is known. DE-A-34 27 220 describes a process for the preparation of copolymers 10 to 90 parts by weight of acrylamide, 90 to 10 parts by weight of (meth) acrylic acid, 0 to 40 parts by weight of a copolymerizable monomer, which may be an N-vinylamide, and 0 to 5 parts by weight of a crosslinking agent with at least two olefinic double bonds and the use of the copolymers as thickeners for technical, cosmetic and pharmaceutical preparations.

EP-A-580 078 and EP-A-580 079 disclose polyvinylamine derivatives with hydrophilic centers, a process for their preparation from polyvinylamine and their use as medicaments, active substance carriers and food additives.

EP-A-295 614 and EP-A-295 615 disclose the production of polyvinylamides with an average molecular weight> 10 ⁶ by inverse emulsion polymerization, their conversion to polyvinylamines and their use in oil production and paper production. The utility for several other applications, including the manufacture of pharmaceuticals, food colors, herbicides and pesticides, is mentioned.

EP-A-452 758 discloses hydrocarbon-rich gels of surfactant, water, hydrocarbon and a water-soluble polymer, which are also a copolymer of 2-acrylamido-2-methyl-propanesulfonic acid, N-vinyl-N-methylacetamide and acrylic acid amide can, and their use as fracturing fluids and for medical and cosmetic preparations.

The use of crosslinked polyvinylformamides as thickeners in cosmetic and pharmaceutical preparations is also known, see EP-A-510 246.

The use of polyvinylamines in the manufacture of pharmaceutical formulations with certain release characteristics, such as. B. delayed, prolonged, evenly sustained or controlled release is also known. For example, EP-A-126 537 discloses microcapsules as an injectable administration system, the membranes of which consist of a polycationic salt bound to a polyanionic polymer. A polyvinylamine salt can also be used as the polycationic salt.

EP-A-199 362 and US-A-4 900 566 describe liposomes for the controlled release of biologically active substances which are shielded from the biological environment by a permeable polymer matrix. The permeable polymer matrix can also be produced using polyvinylamines. EP-A-207 655 describes methods for filling microcapsules with an active ingredient. The microcapsules are made of polyanionic polymers, e.g. B. acidic polysaccharides, and polycationic polymers, e.g. B. polyvinylamines, built and usable as an administration system for drugs or without filling as a release agent for high and low molecular weight substances.

DE-A-41 22 591 describes the solvent-free production of polymer microparticles or pellets with delayed release of active ingredient, the active ingredient being dissolved, dispersed or added in an aqueous polymer dispersion which contains one or more gellable auxiliaries, and this liquid phase is dripped or sprayed into a medium which causes gel formation. Polyvinylamines are also suitable as a gellable auxiliary.

However, the production of these dosage forms, such as microcapsules and microparticles, and the introduction of the active ingredient are very complex and therefore time-consuming and costly.

The object of the invention was therefore to provide a simple and inexpensive process for the production of solid dosage forms, in particular pharmaceutical forms.

Surprisingly, it has now been found that this object is achieved if the dosage forms are produced by melt extrusion and polyvinylamides and / or polyvinylamines are used as binders.

The present invention therefore relates to a process for the production of solid dosage forms by mixing at least one polymeric binder, optionally at least one active ingredient and optionally conventional additives to form a plastic mixture and shaping, characterized in that homopolymers and / or copolymers of N-vinylamides and / or N-vinylamines can be used as the polymeric binder.

The method according to the invention enables the production of solid dosage forms in a simple and inexpensive manner. The advantageous properties of the homo- and / or copolymers of vinyl amides and / or vinyl amines are not impaired by the conversion into the plastic state. In addition, the method according to the invention results in dosage forms with a very rapid release of active ingredient. Dosage forms are to be understood here to mean all forms which are suitable for use as medicaments, plant treatment agents, animal feeds and foods and for dispensing fragrance substances and perfume oils. These include, for example, tablets of any shape, pellets, granules, but also larger shapes, such as cubes, blocks (cuboids) or cylindrical shapes, which can be used in particular as feed or food.

The dosage forms obtainable according to the invention generally comprise:

a) 0 to 90% by weight, in particular 0.1 to 60% by weight (based on the total weight of the dosage form) of an active ingredient,

b) 10 to 100 wt .-%, in particular 40 to 99.9 wt .-% of a polymeric binder and

c) optionally additives.

If the dosage form is used for food or feed purposes, the active ingredient may be absent, i. H. the dosage form can comprise up to 100% of the polymeric binder. According to the invention, homopolymers and / or copolymers of vinylamides and vinylamines are used as the polymeric binder. The copolymers preferably contain at least 5% by weight, particularly preferably at least 10% by weight and in particular at least 20% by weight, of units of the formulas

(I) (II)

wherein R ¹ and R ² each independently represent H or Ci-C _ß alkyl groups such as methyl, ethyl, propyl, n-butyl and isobutyl. The polymers used as binders according to the invention are accessible in a manner known per se by radical polymerization. The preparation takes place, for example, by means of solution, precipitation, suspension or emulsion polymerization using compounds which form free radicals under the polymerization conditions. At least 5% by weight of monomers are used which form the units of the formulas I and / or II to lead. These are, for example, the following monomers: N-vinylformamide, N-vinyl-N-methylformamide, N-vinyl-N-methylacetamide, N-vinylacetamide, N-vinyl-N-ethylacetamide, N-vinylpropionamide, N-vinyl- N-methylpropionamide and N-vinylbutyramide. Of these, N-vinylformamide and N-vinyl-N-methylacetamide are particularly preferred. Suitable comonomers are, for example, monoethylenically unsaturated carboxylic acids having 3 to 8 carbon atoms, such as acrylic acid, methacrylic acid, dimethylacrylic acid, ethacrylic acid, maleic acid, citric acid, methylene malonic acid, allylacetic acid, vinyl acetic acid, crotonic acid, fumaric acid, mesaconic acid and itaconic acid and the half esters of mentioned dicarboxylic acids with Ci- to -C ₂ alkanols. Of these, preference is given to using acrylic acid, methacrylic acid, maleic acid or mixtures of the carboxylic acids mentioned. The monoethylenically unsaturated carboxylic acids can be used in the form of the free acid and, if present, the anhydrides or in partially or completely neutralized form in the copolymerization. Alkali metal or alkaline earth metal bases, ammonia or amines, e.g. B. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, magnesium oxide, calcium hydroxide, calcium oxide, gaseous or aqueous ammonia, triethylamine, ethanolamine, diethanolamine, morpholine, diethylene triamine or tetraethylene pentamine.

Furthermore, for example, the esters of the carboxylic acids mentioned above with Ci to Cχ suitable comonomers ₈ alkanols hydro xy-Cχ- to C ₄ -alkyl mono- and di-Ci to C ₄ alkylamino Cι- to C - alkyl esters, amides, mono- and di-Ci to C ₄ alkylamides and nitriles, e.g. As methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl acrylate, hydroxy ethyl methacrylate, hydroxypropyl methacrylate, lat Hydroxyisobutylacry-, Hydroxyisobutylmethacrylat, maleic acid monomethyl ester, ma- leinsäuredimethylester, maleic acid monoethyl ester, maleic acid diethyl ester, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, Stearyl acrylate, stearyl methacrylate, behenyl acrylate, behenyl methacrylate, octyl acrylate, octyl methacrylate, acrylamide, methacrylamide, N, N-dimethylacrylamide, N-tert-butylacrylamide, acrylonitrile, methacrylonitrile, dimethylaminoethylacrylate, diethylamethylacrylate, diethylamethylacrylate, diethylamethylacrylate, diethylaminoethyl acrylate, diethylaminoethyl acrylate, diethylaminoethyl acrylate, with carboxylic acids or mineral acids or the quaternized products.

Also suitable as copolymerizable monomers are acrylamidoglycolic acid, vinylsulfonic acid, allylsulfonic acid, methallylsulfonic acid, styrene sulfonic acid, acrylic acid (3-sulfopropyl) ester, methacrylic acid (3-sulfopropyl) ester and acrylamidomethylpropanesulfonic acid. acid and monomers containing phosphonic acid groups, such as vinylphosphonic acid, allylphosphonic acid and acrylamidomethylpropanephosphonic acid. Further suitable copolymerizable monomers are N-vinylpyrrolidone, N-vinylcaprolactam, N-vinylimidazole, N-vinyl-2-methylimidazole, N-vinyl-4-methylimidazole, diallylammonium chloride, vinyl esters, such as vinyl acetate and vinyl propionate, and vinyl aromatics, like styrene. Mixtures of the monomers mentioned can of course also be used. The copolymers contain at least 5, preferably at least 20 and in particular at least 50% by weight of polymerized N-vinylamides and / or N-vinylamines.

The polymerization temperatures are usually in the range from 30 to 200 ° C., preferably 40 to 110 ° C. Suitable initiators are, for example, azo and peroxy compounds and the customary redox initiator systems, such as combinations of hydrogen peroxide and reducing compounds, for example sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate and hydrazine.

The homopolymers and copolymers generally have K values of at least 7, preferably 10 to 250. The polymers can have K values of up to 300. The K values are determined according to H. Fikentscher, Cellulosechemie, Vol. 13, 58-64 and 71-74 (1932), in aqueous solution or in an organic solvent at 25 ° C and at concentrations that depend on the K value - range between 0.1% and 5%.

From the polymers of formula I described above, partial or complete cleavage of the amide bonds from the polymerized N-vinylamides to form amine or ammonium groups gives the polymers according to the invention to be used as polymers with the units of formula II. Such polymers are from EP 071 050 is known as a means for accelerating dewatering and increasing retention in the manufacture of paper. There, linear, basic polymers with vinyl laminate and vinyl formamide units are described, which are produced by homopolymerization of N-vinyl formamide and subsequent partial cleavage of formyl groups by the action of acids or bases.

Copolymers of N-vinylcarboxamides and other monoethylenically unsaturated compounds, such as acrylic acid, acrylic acid esters, vinyl acetate, N-vinylpyrrolidone or acrylonitrile, are also described in the literature, as are the modified copolymers obtainable therefrom by the action of acids or bases. In these, the carboxamide groups can entirely or partially eliminated from the copolymerized N-vinylcarboxamides and the copolymerized comonomers may be hydrolyzed, see e.g. B. EP 216 387, EP 251 182, EP 528 409, WO 82/02073, JP 84/033312, JP 84/039399, EP 337 310 and DE 43 22 854.

Depending on the reaction conditions chosen for the hydrolysis, either partial or complete hydrolysis of the units according to formula I is obtained. If copolymers of N-vinylamides are used, the comonomers used can also be chemically changed, depending on the hydrolysis conditions chosen . So arise. B. from vinyl acetate units, vinyl alcohol units, from acrylic acid methyl ester units, acrylic acid units and from acrylonitrile units, acrylamide or acrylic acid units.

Mineral acids, such as hydrogen halides, which can be used in gaseous form or in aqueous solution, are suitable for the hydrolysis. Hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid and organic acids such as, for. B.

C ₅ -C ₅ carboxylic acids and aliphatic or aromatic sulfonic acids. 0.05 to 2, preferably 1 to 1.5 molar equivalents of an acid are required per formyl group equivalent which is to be split off from the copolymerized units I.

The hydrolysis of the polymerized units of structure I can also be carried out with the aid of bases, e.g. B. with metal hydroxides, especially with alkali metal and alkaline earth metal hydroxide. Sodium hydroxide or potassium hydroxide is preferably used. The hydrolysis can optionally also be carried out in the presence of ammonia or amines.

In addition to the polymeric binders described above, in particular up to 30% by weight, based on the total weight of the binder, of other binders such as polymers, copolymers, cellulose derivatives, starch and starch derivatives can be used. For example:

Polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl esters, in particular vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol, polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates and polymethacrylate acrylates (E , Polyacrylic amides, polyethylene glycols, cellulose esters, cellulose ethers, in particular methyl cellulose and ethyl cellulose, hydroxyalkyl celluloses, in particular hydroxypropyl cellulose, hydroxyalkyl alkyl cellulose Loose, especially hydroxypropyl ethyl cellulose, cellulose phthalates, especially cellulose acetate phthalate and hydroxypropyl methyl cellulose phthalate, and mannans, especially galactomannans. Of these, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates, polymethacrylates, alkyl celluloses and hydroxyalkyl celluloses are particularly preferred.

The polymeric binder must soften or melt in the total mixture of all components in the range from 50 to 180 ° C., preferably 60 to 130 ° C. The glass transition temperature of the mixture must therefore be below 180 ° C, preferably below 130 ° C. If necessary, it is reduced by conventional, pharmacologically acceptable plasticizing auxiliaries. The amount of plasticizer is at most 30% by weight, based on the total weight of binder and plasticizer, so that storage-stable drug forms are formed which do not show a cold flow. However, the mixture preferably contains no plasticizer.

Examples of such plasticizers are:

(Eg. Dialkyl phthalates, trimellitic esters, benzoic esters, terephthalic esters) long chain alcohols, ethylene glycol, propylene glycol, glycerol, trimethylolpropane, triethylene glycol, butanediols, pentanols, such as pentaerythritol, hexanols, polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, silicones, aromatic Carbonsäureester or aliphatic dicarboxylic acid esters (eg dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters), fatty acid esters such as glycerol mono-, glycerol di- or glycerol triacetate or sodium diethyl sulfosuccinate. The concentration of plasticizer is generally 0.5 to 15, preferably 0.5 to 5 wt .-%, based on the total weight of the mixture.

Common pharmaceutical auxiliaries, the total amount of which is up to

100 wt .-%, based on the polymer, can be, for. B. extenders or fillers, such as silicates or silica, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or salts thereof, for. B. the magnesium or calcium salt, methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose, corn or corn starch, potato flour, polyvinyl alcohol, especially in a concentration of 0.02 to 50, preferably 0.20 to 20 wt .-% , based on the total weight of the mixture. Lubricants, such as aluminum and calcium stearate, talc and silicones, in a concentration of 0.1 to 5, preferably 0.1 to 3% by weight, based on the total weight of the mixture.

Plasticizers, such as animal or vegetable fats, especially in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50 ° C or higher. Triglycerides of Cχ ₂ , Cι, Cι ₆ and Ci ₈ fatty acids are preferred. Waxes such as carnauba wax can also be used. These fats and waxes can advantageously be admixed alone or together with mono- and / or diglycerides or phosphatides, in particular lecithin. The mono- and diglycerides are preferably derived from the fatty acid types mentioned above. The total amount of fats, waxes, mono-, diglycerides and / or lecithins is 0.1 to 30, preferably 0.1 to 5% by weight, based on the total weight of the mass for the respective layer;

Dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin, preference being given to inorganic pigments in a concentration of 0.001 to 10, preferably 0.5 to 3% by weight, based on the total weight of the mixture;

Stabilizers, such as antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.

Wetting agents, preservatives, disintegrants, adsorbents, mold release agents and blowing agents can also be added (see, for example, H. Sucker et al., Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978).

In the context of the invention, auxiliary substances are also to be understood as meaning substances for producing a solid solution of the active substance. These auxiliaries are, for example, pentaerythritol and pentaerythritol tetraacetate, polymers such as, for. B. polyethylene or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinyl pyrrolidone, surfactants such as polyoxyethylene 40 stearate and citric and succinic acid, bile acids, sterols and others such. B. J. L. Ford, Pharm. Acta Helv. 61, 69-88 (1986).

Additives of bases and acids to control the solubility of an active ingredient are also considered auxiliary substances (see, for example, K. Thoma et al., Pharm. Ind. 5.1, 98-101 (1989)). The only requirement for the suitability of auxiliaries is adequate temperature stability.

Active substances in the sense of the invention are understood to mean all substances with a physiological effect, provided they do not decompose under the processing conditions. In particular, they are active pharmaceutical ingredients (for humans and animals), active ingredients for plant treatment, insecticides, feed and food ingredients, fragrances and perfume oils. The amount of active substance per dose unit and the concentration can vary within wide limits depending on the effectiveness and the 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 can also be used. Active substances in the sense of the invention are also vitamins and minerals. The vitamins include the vitamins of the A group and the B group, which in addition to Bi, B ₂ , B ₆ and Bι ₂ as well as nicotinic acid and nicotinamide also include compounds with vitamin B properties, such as. B. adenine, choline, pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, 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. Plant treatment agents include e.g. B. Vinclozolin, Epiconazol and Quinmerac.

The method according to the invention is suitable, for example, for processing the following active ingredients:

Acebutolol, Acetylcysteine, Acetylsalicylic Acid, Aciclovir, Alprazolam, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikacin, Amilorid, Amino Acetic Acid, Amiodarone, Amitriptylin, Amlodipin, Amoxicillololol, Acidic Acid Asolonol, Acid Ascone, Acid Ascone, Acid Ascone, Acid Ascone, Acid Ascone Benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexin, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbidopazepine, carbamapazepine cefaclor, cefalexin, Cefadro- xil, cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone, Cefu- roxim, selegiline, chloramphenicol, chlorhexidine, chlor-phenir- amine, chlortalidone, choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, Clarithromycin, clavulanic acid, clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone, de-soestrel, dexamethaso n, dexpanthenol, dextromethorphan, dextro propoxiphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamol, dipyrone, disopyramide, domperidone, dopamine, doxycycline, enalapril, ephedrine, ergoline, epinephrine, ergoline, epinephrine, ergoline, epinephrine, ergoline, epinephrine, ergoline, epinephrine, ergoline, epinephrine, ergoline, epinephrine, ergoline, epinephrine, ergoline, epinephrine, ergoline, epinephrine, epinephrine, epinephrine; Ethinylestradiol, etoposide, eucalyptus globus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibobox, gibfibrozil, gentfibrozil, gent Glipizide, clozapine, glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, ipratropium hydroxide, ibuprofen, imipenem, indomethacin, dinorbitol, iohexitol, iodobraton , Isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, lactalol, lactulose, lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, levothy roxin, lidocaine, lipase, imipramine, lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam, minocycline, minoxidol, mi- minopin, mixtures, mi- sopin . Combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitritrazepam, nitrendipine, nizatidine, norethisterone, norgesyltrinacin, norgesyltrinacin, norfloxacin, norfloxacin Ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, prinoxidamin, piroxicamodin, piroxicamodin, piroxidamam, piroxidamin, piroxidamin, piroxidamid , Prazosin, prednisolone, prednisone, bromocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retino l, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegaferbin, tegaferbazine, te Theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, trimethomprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, folinic acid, zidovudine.

Preferred active substances are ibuprofen (as racemate, enantiomer or enriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid, verapamil, paracetamol, nifedipine or captopril. To produce the solid dosage forms, a plastic mixture of the components (melt) is provided, which is then subjected to a shaping cut. The components can be mixed and the melt can be formed in various ways. Mixing can take place before, during and / or after the formation of the melt. For example, the components can be mixed first and then melted or mixed and melted simultaneously. The plastic mixture is often also homogenized in order to obtain a highly dispersed distribution of the active ingredient.

In particular when using sensitive active ingredients, it has proven to be preferred to first melt and premix the polymeric binder, optionally together with conventional pharmaceutical additives, and then to add the sensitive active ingredient (s) in "intensive mixers" in the plastic phase to mix in very short dwell times (homogenization). The active ingredient (s) can be used in solid form or as a solution or dispersion.

Generally, the components are used as such in the manufacturing process. However, they can also be in liquid form, i.e. H. are used as a solution, suspension or dispersion.

Suitable solvents for the liquid form of the components are primarily water or a water-miscible organic solvent or a mixture thereof with water. However, usable solvents are also water-immiscible or miscible, organic solvents. Suitable water-miscible solvents are, in particular, -C -alkanols, such as ethanol, isopropanol or n-propanol, polyols, such as ethylene glycol, glycerol and polyethylene glycols. Suitable water-immiscible solvents are alkanes such as pentane or hexane, esters such as ethyl acetate or butyl acetate, chlorinated hydrocarbons such as methylene chloride and aromatic hydrocarbons such as toluene and xylene. Another usable solvent is liquid CO ₂ .

Which solvent is used in an individual case depends on the component to be absorbed and its properties. For example, active pharmaceutical ingredients are often used in the form of a salt, which is generally water-soluble. Water-soluble active ingredients can therefore be used as an aqueous solution or preferably incorporated into the aqueous solution or dispersion of the binder. The same applies to active ingredients that are soluble in one of the solvents mentioned are when the liquid form of the components used is based on an organic solvent.

If necessary, instead of melting, dissolving, suspending or dispersing in the abovementioned solvents, if desired and / or required with the addition of suitable auxiliaries, such as, for. B. emulsifiers. The solvent is then generally melted in a suitable apparatus, e.g. B. an extruder removed. In the following, this is to be encompassed by the term mixing.

The melting and / or mixing takes place in a device which is customary for this purpose. Extruders or optionally heated containers with stirrers, e.g. B. kneader, (like the type mentioned below).

Devices which are used in plastics technology for mixing are particularly useful as mixing apparatus. Suitable devices are described, for example, in "Mixing in the Production and Processing of Plastics", H. Pahl, VDI-Verlag, 1986. Particularly suitable mixing devices are extruders and dynamic and static mixers, and stirred kettles, single-shaft stirrers with stripping devices, in particular so-called paste stirrers, multi-shaft Agitators, in particular PDSM mixers, solids mixers and preferably mixing / kneading reactors (eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei or Ko-Kneaders from Buss), double bowl kneaders (Trough mixer) and stamp kneader (internal mixer) or rotor / stator systems (e.g. Dispax from IKA).

In the case of sensitive active substances, the polymer binder is preferably first melted in an extruder and then the active substance is mixed in in a kneading reactor. In the case of less sensitive active ingredients, on the other hand, a rotor / stator system can be used for intensive dispersion of the active ingredient.

Depending on the design, the mixing device is loaded continuously or discontinuously in the usual way. Powdery components can be fed freely, e.g. B. be introduced via a differential weigher. Plastic masses can be fed in directly from an extruder or fed in via a gear pump, which is particularly advantageous for high viscosities and high pressures. Liquid media can be metered in using a suitable pump unit. The mixture obtained by mixing and / or melting the binder, the active ingredient and optionally the additive or additives is pasty to viscous (thermoplastic) or liquid and therefore extrudable. The glass transition temperature of the mixture is below the decomposition temperature of all components contained in the mixture. The binder should preferably be soluble or swellable in a physiological environment.

The mixing and melting process steps can be carried out in the same apparatus or in two or more separate devices. The preparation of a premix can be carried out in one of the conventional mixing devices described above. Such a premix can then directly, for. B. fed into an extruder and then optionally extruded with the addition of other components.

The method according to the invention makes it possible to use single-screw machines, intermeshing screw machines or multi-screw extruders, in particular twin-screw extruders, rotating in the same direction or in opposite directions and optionally equipped with kneading disks, as extruders. If a solvent has to be evaporated during the extrusion, the extruders are generally equipped with an evaporation part. Extruders of the ZKS series from Werner u. Pfleiderer.

According to the invention, multilayer pharmaceutical forms can also be produced by coextrusion, several mixtures of the components described above being combined in one tool during the extrusion in such a way that the desired layer structure of the multilayer pharmaceutical form is obtained. Different binders are preferably used for different layers.

Multilayer dosage forms preferably comprise two or three layers. They can be in open or closed form, especially as open or closed multi-layer tablets.

At least one of the layers contains at least one active pharmaceutical ingredient. It is also possible to include another active ingredient in another layer. This has the advantage that two mutually incompatible active substances can be processed or that the release characteristics of the active substance can be controlled. The molding is carried out by coextrusion, the mixtures from the individual extruders or other units being fed and discharged into a common coextrusion tool. The shape of the coextrusion tools depends on the desired pharmaceutical form. For example, tools with a flat exit gap, so-called wide-slot tools, and tools with an annular cross-section-shaped exit cross section are suitable. The nozzle design depends on the polymeric binder used and the desired pharmaceutical form.

The mixture obtained is preferably solvent-free, i.e. it contains neither water nor an organic solvent.

The plastic mixture is usually subjected to a final shaping. A variety of shapes can be created, depending on the tool and the type of shaping. For example, when using an extruder, the extruded strand can be between a belt and a roll, between two belts or between two rolls, as described in EP-A-358 105, or by calendering in a calender with two forming rolls, see for example EP- A-240 904, mold. Additional shapes can be obtained by extrusion and hot or cold cutting of the strand, for example small-sized and uniformly shaped granules. Hot granulation generally leads to lenticular dosage forms (tablets) with a diameter of 1 to 10 mm, while cold granulation normally leads to cylindrical products with a length to diameter ratio of 1 to 10 and a diameter of 0.5 to 10 mm leads. In this way, single-layer dosage forms can be produced, but when using coextrusion, open or closed, multi-layer dosage forms, for example oblong tablets, dragees, pastilles and pellets. The granules obtained can then also be ground to powder and compressed into tablets in the customary manner. Micropastilles can be made by the Rotoform-Sandvik process. These dosage forms can be rounded off and / or provided with a coating in a subsequent process step using customary methods. Suitable materials for film coatings are e.g. B. polyacrylates, such as the Eudragit types, cellulose esters, such as the hydroxypropyl cellulose phthalates, and cellulose ethers, such as ethyl cellulose, hydroxypropyl methyl cellulose or hydroxypropyl cellulose.

In particular, solid solutions can be formed. The term “solid solutions” is familiar to the person skilled in the art, for example from the literature cited at the beginning. In fixed solutions Solutions of active ingredients in polymers, the active ingredient is molecularly dispersed in the polymer.

The following examples are intended to illustrate the process according to the invention, but without restricting it.

Examples

example 1

520 g of a copolymer of 50% by weight vinylformamide and 50% by weight vinylpyrrolidone (K value 45.0; 0.1% in N-methylpyrrolidone) are mixed with 480 g verapamil hydrochloride under the conditions specified below extruded and calendered to 500 mg oblong tablets according to the method described in EP-A-240 904.

Shot 1 60 ° C

Shot 2 95 ° C

Shot 3 133 ° C

Shot 4 112 ° C

Shot 5 94 ° C

Nozzle: 86 ° C The release after 1 hour was 72%, after 2 hours 100% [paddle model according to USP (pH change)].

Example 2

520 g copolymer of 50 wt .-% vinylamine and 50 wt .-% vinylpyrrolidone are extruded with 480 g verapamil hydrochloride to 500 mg oblong tablets under the conditions specified below and calendered as above.

Shot 1 55 ° C

Shot 2 85 ° C

Shot 3: 134 ° C

Shot 4: 113 ° C

Shot 5: 102 ° C

Nozzle: 99 ° C

The release after 1 hour was 100 [paddle model according to USP (pH change)]. 500 g copolymer of 50 wt .-% vinylformamide and 50 wt .-% vinyl pyrrolidone (K value 45.0; 0.1% in N-methylpyrrolidone) are extruded with 500 g vinclozoline, cooled and granulated.

Shot 1 63 ° C

Shot 2 98 ° C

Shot 3 141 ° C

Shot 4 152 ° C

Shot 5 127 ° C

Nozzle: 101 ° C

Transparent, X-ray amorphous, water-dispersible granules were obtained.

Claims

claims Process for the preparation of solid dosage forms by mixing at least one polymeric binder, optionally at least one active ingredient and optionally conventional additives to form a plastic mixture and shaping, characterized in that the polymeric binder used is homo- and / or copolymers of N-vinylamides and / or N-vinyl amines used. 2. The method according to claim 1, characterized in that the binder at least 5 wt .-% units of the formulas

(I) (II) wherein R ¹ and R ² each independently represent H or C to C ₆ alkyl groups. A method according to claim 2, characterized in that R ¹ and R ^{2 are} independently selected from H, methyl, ethyl, propyl, n-butyl and isobutyl. 4. The method according to claim 3, characterized in that the polymeric binder used is poly (vinylformamide) or a copolymer thereof with vinylpyrrolidone. 5. The method according to any one of the preceding claims, characterized in that the formation of the plastic mixture takes place by mixing and / or melting the components in an extruder. Method according to one of claims 1 to 5 for the production of pharmaceutical dosage forms containing pharmaceuticals. Method according to one of claims 1 to 5 for the production of plant treatment agents. 8. The method according to any one of claims 1 to 5 for the production of feed additives and additives. 9. The method according to any one of claims 1 to 5 for the production of food additives. 10. Solid dosage forms obtainable by a process according to any one of claims 1 to 9.