Solid dosage form with copolymeric binder

The invention relates to solid dosage forms comprising at least one polymeric binder and at least one active ingredient and optionally conventional additives and a process for the preparation of the solid dosage form.

Solid dosage forms containing physiologically acceptable polymers as binders are becoming increasingly important, especially for sustained-release drug dosage forms. Thus, EP-A-609 961 describes solid dosage forms based on physiologically compatible copolymers which have a core / shell structure of different copolymers in order to achieve a uniform release of active ingredient.

WO 89/06957 describes controlled-release pharmaceutical formulations in which the N-vinylpyrrolidone / alkyl (meth) acrylate copolymer used as the binder permits sustained release of active ingredient due to its high swelling capacity of 50% to 250%.

US-A-3,900,559 discloses sustained-release drug compositions based on crosslinked copolymers containing, inter alia, N-vinyllactams and (meth) acrylates, especially (meth) acrylates of di- and polyols, as comonomers. The introduction of the active ingredient is preferably carried out by impregnating the polymer with a solution of the active ingredient or by polymerization of the monomers in the presence of the dissolved active ingredient.

In order to achieve a delayed release of active ingredient, the polymers containing acid groups used as binders are dissolved in US-A-4,248,855 and mixed with a solution of a salt-forming agent and formulated the active ingredient / polymer salt for pharmaceutical use. In order to achieve sufficient solubility, the binder contains at least 75% by weight of hydrophilic monomers; of these, in turn, at least 10 wt .-% of acid group-containing monomers to allow binding of the active ingredient in the form of its salt.

The abovementioned solid dosage forms of the prior art have the disadvantage that the introduction of the active ingredient and / or its release take place by diffusion. The release is coupled to the high swelling capacity of the binder and thus dependent on the diffusion behavior of the respective active ingredient in the respective binder. The incorporation of the active ingredient and / or the preparation of the solid dosage form requires elaborate or multi-step procedures to achieve the desired sustained release. In addition, the classical processes for preparing solid pharmaceutical dosage forms, in particular tablets, are carried out discontinuously and comprise several stages.

A much simpler continuous process for preparing solid pharmaceutical dosage forms comprising extruding a drug-containing, solvent-free melt from a polymeric drug-containing binder and forming the extruded strand into the desired dosage form, for example in a calender with forming rolls, is disclosed in EP-A-240 904, EP-A-240 906, EP-A-337 256 and EP-A-358 105 (melt extrusion).

In EP-A-240 904 are as polymeric binder polyvinylpyrrolidone or copolymers of N-vinylpyrrolidone with, inter alia, vinyl esters, unsaturated carboxylic acids, including acrylic acid and methacrylic acid, their amides and their esters with C₁-C₁₂Called alkanols. In the examples vinylpyrrolidone / vinyl acetate copolymers are used. The N-vinylpyrrolidone / vinyl acetate copolymers, as well as the N-vinylcaprolactam polymers and copolymers disclosed in DE 197 53 300.0, have a very favorable property profile as binders for the production of solid dosage forms by pressing under pressure and temperature and in particular by melt extrusion However, they have the disadvantage that they release the drug relatively quickly.

The present invention is therefore based on the object to provide solid dosage forms that allow a slow release of the drug and can be easily and inexpensively, for example by melt extrusion produce.

Surprisingly, it has now been found that this object is achieved if the binder used is a polymer of at least one N-vinyllactam, methyl methacrylate, at least one further copolymerizable monomer and optionally up to 9.9 wt .-% of at least one copolymerizable carboxylic acid.

The present invention therefore relates to a solid dosage form comprising at least one polymeric binder and at least one active ingredient and optionally conventional additives, which is characterized in that the polymeric binder<ul id="ul0001" list-style="none"><li>a) from 15 to 83% by weight of at least one N-vinyllactam of the formula I,<chemistry id="chem0001" num="0001"><img file="EP0998918A2_D0001.tif" /></chemistry> where n is 1, 2 or 3,</li><li>b) 15 to 83% by weight of methyl methacrylate,</li><li>c) 2 to 70 wt .-% of at least one other monomer selected from vinyl esters of aliphatic C.₁-C₂₂-Carboxylic acids, esters of α, β-ethylenically unsaturated C₃-C_8thMono- and dicarboxylic acids with C₁-C_8thAlkanols, C₁-C₄Diols or di (C₁-C₄) Alkylamino-C₁-C₄alkanols, amides, nitriles and cyclic anhydrides of these carboxylic acids, and</li><li>d) 0 to 9.9 wt .-% of at least one α, β-ethylenically unsaturated acid, selected from C₃- to C_8thMono- and dicarboxylic acids, noncyclic anhydrides of these carboxylic acids, half esters of C₃- to C_8thDicarboxylic acids, α, β-ethylenically unsaturated sulfonic acids and the salts or quaternized products thereof,</li></ul> contains copolymerized, wherein the amounts of the monomers add up to 100 wt .-%.

The polymer used as a binder preferably contains from 25 to 75% by weight and more preferably from 30 to 65% by weight of at least one N-vinyllactam of the formula I in copolymerized form. The binder may contain in copolymerized form a mixture of N-vinyllactams of the formula I, the binder preferably comprising one copolymerized N-vinyllactam. The N-vinyllactams of the formula I are preferably N-vinylpyrrolidone, N-vinylpiperidone and N-vinylcaprolactam; particularly preferred is N-vinylpyrrolidone. As a comonomer, the binder preferably contains 20 to 70% by weight and more preferably 20 to 55% by weight of methyl methacrylate in copolymerized form.

In addition, the polymeric binder contains at least one further copolymerizable monomer (further monomer c)) in an amount of 2 to 70 wt .-%, preferably 5 to 55 wt .-% and particularly preferably 15 to 50 wt .-%, based on the total weight of the monomers, copolymerized. Suitable as a further monomer c) are in particular vinyl esters of aliphatic C.₁-C₂₂Carboxylic acids such as vinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl valerate, vinyl capronate, vinyl octanoate, vinyl caprate, vinyl laurate, vinyl myristate and vinyl palmitate, with vinyl acetate being particularly preferred. Also suitable as further monomer c) are, for example, the esters of monoethylenically unsaturated carboxylic acids having 3 to 8 carbon atoms, such as acrylic acid, methacrylic acid, dimethacrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, allylacetic acid, vinylacetic acid, crotonic acid, fumaric acid, mesaconic acid and itaconic acid, with C.₁- to C_8thAlkanols, except methyl methacrylate, with C₁- to C₄-Iols, with mono- and di-C₁- to C₄alkylamino-C₁- to C₄alkanols, as well as the amides, mono- and di-C₁- to C₄alkylamides and nitriles of these arbon acids, eg methyl acrylate, ethyl acrylate, propyl acrylate, Acrylic acid-n-butyl ester, 2-ethylhexyl acrylate, methacrylate, propyl methacrylate, Methacrylic acid-n-butyl ester, 2-ethylhexyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxybutyl, Hydroxyisobutylacrylat, hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxybutyl, Hydroxyisobutylmethacrylat, dimethyl maleate, maleate, maleate, acrylamide, methacrylamide, N, N-dimethyl acrylamide, N-tert-butylacrylamide, acrylonitrile, methacrylonitrile, dimethylaminoethyl diethylaminoethyl, Diethylaminoethylmethacrylat and the salts of the latter monomers with carboxylic acids or mineral acids or the quaternized products. Of course, it is also possible to use mixtures of the monomers mentioned.

In addition, the polymeric binder may additionally contain from 0 to 9.9% by weight, in particular 0 to 7% by weight, preferably 0 to 5% by weight of at least one α, β-ethylenically unsaturated acid, in particular monoethylenically unsaturated carboxylic acid having 3 to 8 carbon atoms, like acrylic acid, methacrylic acid, dimethacrylate, ethacrylic, maleic acid, citraconic, methylenemalonic allylacetic Vinyl acetic acid, crotonic, fumaric acid, Mesaconic acid and itaconic acid, and the half esters of the dicarboxylic acids mentioned with C₁- to C_8thAlkanols, such as Monomethyl maleate, monoethyl maleate, monobutyl maleate. Preference is given to 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, the anhydrides or in partially or completely neutralized form. For neutralization, preference is given to using alkali metal or alkaline earth metal bases, ammonia or amines, for example Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, magnesium oxide, calcium hydroxide, calcium oxide, gaseous or aqueous ammonia, triethylamine, ethanolamine, diethanolamine, morpholine, diethylenetriamine or tetraethylenepentamine. In addition, is suitable as a copolymerizable α, β-ethylenically unsaturated acid acrylamidoglycolic acid, vinylsulfonic acid, allylsulfonic acid, Methallylsulfonsäure, Styrolsulf onsäure, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylates and acrylamidomethylpropanesulfonic and phosphonic acid containing monomers such as vinylphosphonic acid, allylphosphonic and acrylamidomethylpropanephosphonic acid. Of course, it is also possible to use mixtures of the monomers mentioned. When present, generally at least 0.1% by weight, preferably at least 0.5% by weight of at least one acid group-containing monomer is copolymerized.

In preferred embodiments of the present invention, the polymeric binders contain no acid group-containing monomer in copolymerized form.

In addition, the polymeric binder may optionally additionally contain from 0.1 to 10% by weight of at least one further copolymerizable monomer e), such as N-vinylimidazole, N-vinyl-2-methylimidazole, N-vinyl-4-methylimidazole, and vinylaromatics, such as eg styrene.

Optionally, the polymeric binder may additionally contain in copolymerized form 0.1 to 2.0% by weight of at least one crosslinking monomer. Crosslinking monomers are understood here essentially di-, tri- and polyolefinic monomers and Macromere. Suitable crosslinking monomers include, for example the di-, tri- or polyester ethylenically unsaturated carboxylic acids with low molecular weight, di-, trihydric or polyhydric alcohols, preferably the acrylic and methacrylic esters of dihydric, trihydric and polyhydric alcohols, such as ethylene glycol, propylene glycol and their higher condensed representatives, eg Diethylene glycol, triethylene glycol, dipropylene glycol and tripropylene glycol, and butanediol, pentanediol, hexanediol, propanetriol and trimethylolpropane. Likewise suitable are polyether (meth) acrylates, polyester (meth) acrylates and polyurethane (meth) acrylates which carry two or more α, β-ethylenically unsaturated groups. Also suitable are the di-, tri- and polyethers of said di- and polyfunctional alcohols with vinyl alcohol, and vinyl aromatics, such as Di- and trivinylbenzene, divinylureas, eg Divinylmethyleneurea and diallylamines such as diallylamine and diallylammonium chloride. Further crosslinking monomers and macromers are known to the person skilled in the art and are described, for example, in P. K. T. Oldring (ed.), Chemistry and Technology of UV and EB Formulations for Coatings and Paints, Vol. II, SITA Technology, London 1991.

In particularly preferred embodiments of the present invention, the polymeric binders comprise substantially 30 to 65% by weight of N-vinylpyrrolidone, 20 to 60% by weight of methyl methacrylate and 15 to 50% by weight of vinyl acetate in copolymerized form.

As a rule, the binders according to the invention have a water absorption by swelling of less than 150%, preferably less than 100%, based on the weight of the binder. The water absorption in percent is defined according to the following formula:<maths id="math0001" num=""><math display="block"><mrow><mfrac><mrow><mtext>Weight of hydrated binder - Weight of dry binder</mtext></mrow><mrow><mtext>Wt. Dry binder</mtext></mrow></mfrac><mtext> · 100%</mtext></mrow></math><img file="EP0998918A2_D0002.tif" /></maths>

The water absorption on thin films of the respective binder is determined after 24 hours of swelling in water at room temperature and removal of superficially adhering water droplets.

The copolymers are prepared by known processes, for example solution, precipitation, suspension or reverse suspension polymerization, or emulsion or reverse emulsion polymerization using compounds which form radicals under polymerization conditions.

The polymerization temperatures are usually in the range of 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 sulfoxilate and hydrazine.

The copolymers have K values ​​of at least 7, preferably 10 to 100, particularly preferably 10 to 50. The K values ​​are determined by H. Fikentscher, Cellulose-Chemie, Volume 13, (1932) 58-64 and 71-74, in aqueous solution or in an organic solvent at 25 ° C, at concentrations ranging from 0.1% to 5%, depending on the K value range.

In addition to the polymeric binders described above, it is possible to use up to 95% by weight, in particular up to 85% by weight and preferably up to 75% by weight, of further binders, based on the total weight of the binder. When present, at least 0.1% by weight, preferably at least 0.5% by weight, of the further binder is generally used. Suitable polymers, copolymers, cellulose derivatives, starch and starch derivatives, for example:

Polyvinylpyrrolidone (PVP), Copolymers of N-vinylpyrrolidone (NVP) and vinyl acetate or vinyl propionate, Copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol, polyhydroxyalkyl, polyhydroxyalkyl, Polyacrylates and polymethacrylates (Eudragit types), Copolymers of methyl methacrylate and acrylic acid, Polyacrylami-us, Polyethylene glycols, Polyvinylformamide (optionally partially or completely hydrolyzed), Celluloseester, cellulose ethers, especially methylcellulose and ethylcellulose, Hydroxy-alkylcelluloses, especially hydroxypropyl cellulose, Hydroxyalkylalkylcelluloses, especially hydroxypropyl-ethylcellulose, Cellulose phthalates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, and mannans, in particular galactomannans. Of these, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates, polymethacrylates, alkylcelluloses and hydroxyalkylcelluloses are particularly preferred.

Likewise provided by the present invention are solid dosage forms as described above in the form of pharmaceutical dosage forms, plant treatment agents, feed additives and food additives.

The binders according to the invention are suitable for all customary processes for producing solid dosage forms, such as granulation, milling, pressing, molding, tableting under pressure, tableting under pressure and heat and, in particular, for extrusion or melt extrusion.

Another object of the invention is a process for the preparation of the above-described solid dosage form, which is characterized in that the components, if desired, first melts or mixed directly and forms the resulting plastic mixture to the desired dosage form.

For use in melt extrusion, the polymeric binder must soften or melt in the total mixture of all components in the range from 50 to 180.degree. C., preferably 60 to 130.degree. 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 excipients. The amount of plasticizer is at most 30 wt .-%, based on the total weight of binder and plasticizer, so that storage-stable drug forms are formed, which show no cold flow. Preferably, however, the mixture contains no plasticizer.

Examples of such plasticizers are:

long-chain alcohols, ethylene glycol, propylene glycol, glycerol, trimethylolpropane, triethylene glycol, butanediols, pentanols, such as pentaerythritol, hexanols, polyethylene glycols, polypropylene glycols, polyethylene glycols, silicones, aromatic carboxylic esters (eg Dialkyl phthalates, trimellitic acid esters, benzoic acid esters, terephthalic acid esters) 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 from 0.5 to 15, preferably 0.5 to 5 wt .-%, based on the total weight of the mixture.

Usual galenic auxiliaries whose total amount can be up to 100 wt .-%, based on the polymer, are, for example Extender or Fillers such as silicates or silica, magnesia, alumina, titania, stearic acid or their salts, eg 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 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 wt .-%, based on the total weight of the mixture;

Flow agents, such as animal or vegetable fats, in particular in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50 ° C or higher. Preferred are triglycerides of the C₁₂-, C₁₄-, C₁₆- and C₁₈Fatty acids. Even waxes, such as carnauba wax, are useful. These fats and waxes may 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 wt .-%, based on the total weight of the mass for each layer;

Dyes, such as azo dyes, organic or inorganic pigments or dyes of natural origin, with inorganic pigments in a concentration of 0.001 to 10, preferably 0.5 to 3 wt .-%, based on the total weight of the mixture are preferred;

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

It is also possible to add wetting agents, preservatives, disintegrants, adsorption agents, mold release agents and propellants (cf., for example, H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978).

In the context of the invention, auxiliaries 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 Polyethylene or Polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of vinylpyrrolidone, surfactants such as polyoxyethylene-40-stearate and citric and succinic acids, bile acids, sterols and others such as at J. L. Ford, Pharm. Acta Helv. <u>61</u>, 69-88 (1986).

Adjuncts also include additions of bases and acids for controlling the solubility of an active ingredient (see, for example, K. Thoma et al., Pharm. Ind. <u>51</u>, 98-101 (1989)).

The only prerequisite for the suitability of excipients for melt extrusion is sufficient temperature stability.

Active substances within the meaning of the invention are to be understood as meaning all substances having a physiological action, provided that they do not decompose under the processing conditions. These are, in particular, 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 ingredient per unit dose and the concentration can vary within wide limits depending on the efficacy and rate of release. The only condition is that they are sufficient to achieve the desired effect. Thus, the concentration of active ingredient in the range of 0.1 to 95, preferably from 20 to 80, in particular 30 to 70 wt .-% are. Also drug combinations can be used. Active substances within the meaning of the invention are also vitamins and minerals. The Vitainines include the vitamins of the A group, the B group, below which B₁, B₂, B₆ and B₁₂ as well as nicotinic acid and nicotinamide also compounds with vitamin B properties are understood, such as eg 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 D group, E group, F group, H group, I and J group, K group and P group. Active substances within the meaning of the invention also include peptide therapeutics. To plant treatment agents include, for example Vinclozolin, epoxiconazole and quinmerac.

The binder according to the invention is suitable, for example, for processing with the following active substances:

acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam, Alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, aminoacetic amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol, beclomethasone, benserazide Benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, Budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, Carboplatin, cefaclor, cephalexin, cefadroxil, cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, selegiline, chloramphenicol, chlorhexidine, Chloro-pheniramine chlorthalidone, choline, cyclosporine, cilastatin cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, Clävulansäure, clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromolyn sodium, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, Dextropropoxiphen, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxine, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone dopamine, doxycycline, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, ethinyl estradiol, etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, Flavin mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, gallopamil, gemfibrozil, Gentamicin, Gingko biloba, glyburide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, Hydrocortisone, hydromorphone, Ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol, iopamidol, Isosorbide dinitrate, Isosorbide mononitrate, isotretinoin, itraconazole, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitine, levodopa, Levoglutamid, levonorgestrel, levothyroxine, lidocaine, lipase imipramine, lisinopril, loperamide, lorazepam, lovastatin, medroxyprogesterone, Menthol, methotrexate, methyldopa, methylprednisolone, 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, norethindrone, norfloxacin, Norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, Penicillin G, Penicillin V, Phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, Polymyxin B, Povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, bromocriptine, propafenone, propranolol, proxyphylline, Pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone terazosin, terbutaline, terfenadine, tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, Triamcinolone acetonide, triamterene, trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, Vitamin E, folinic acid, Zidovudine.

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

To prepare the solid dosage forms, a plastic mixture of the components (melt) is provided, which is then subjected to a shaping step. The mixing of the components and the formation of the melt can take place in different ways. The mixing can take place before, during and / or after the formation of the melt. For example, the components may first be mixed and then melted or simultaneously mixed and melted. Frequently, a homogenization of the plastic mixture is still carried out to obtain a highly dispersed distribution of the active ingredient.

However, especially when using sensitive active ingredients, it has proved to be preferable to first melt and premix the polymeric binder, optionally together with customary pharmaceutical additives, and then (the) sensitive active ingredient (s) in "intensive mixers" in the plastic phase with very short residence times to mix in (homogenize). The active ingredient (s) may be used in solid form or as a solution or dispersion.

In general, the components are used as such in the manufacturing process. However, they can also be used in liquid form, ie as a solution, suspension or dispersion.

The solvent used for the liquid form of the components is primarily water or a water-miscible organic solvent or a mixture thereof with water. However, useful solvents are also water-immiscible or miscible organic solvents. Suitable water-miscible solvents are in particular C₁-C₄Alkanols, 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 useful solvent is liquid CO₂,

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

Optionally, instead of reflowing, dissolving, suspending or dispersing in the abovementioned solvents, if desired and / or required, may occur with the addition of suitable auxiliaries, for example emulsifiers. The solvent is then generally removed to form the melt in a suitable apparatus, for example an extruder. In the following, this is to be encompassed by the term mixing.

The melting and / or mixing takes place in a device customary for this purpose. Particularly suitable extruders or optionally heated container with agitator, eg kneader, (as the type mentioned below).

As a mixing apparatus in particular those devices are useful, which are used in the plastic technology for mixing. Suitable devices are described, for example, in "Blending in the Manufacture and Processing of Plastics", H. Pahl, VDI-Verlag, 1986. Particularly suitable mixing apparatuses are extruders and dynamic and static mixers, and stirred tanks, single-shaft agitators with stripping devices, in particular so-called paste agitators, multi-shaft agitators, in particular PDSM mixers, solid mixers and preferably mixing kneading reactors (eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei or Ko-Kneader from Fa. Buss), Doppelmuldenkneter (tray mixer) and Stempelkneter (internal mixer) or rotor / stator systems (eg Dispax of the company IKA).

In the case of sensitive active ingredients, the melting of the polymeric binder in an extruder is preferably carried out first, and then the admixing of the active ingredient in a mixing / kneading reactor. In contrast, with less sensitive active ingredients, a rotor / stator system can be used to intensively disperse the active ingredient.

The charging of the mixing device takes place depending on their design continuously or discontinuously in the usual way. Powdered components can be introduced in the free inlet, eg via a differential dosing scale. Plastic compositions can be fed directly from an extruder or via a gear pump, which is particularly advantageous at high viscosities and high pressures advantageous. Liquid media can be added via a suitable pump set.

The mixture obtained by mixing and / or melting the binder, the active ingredient and optionally the additive or the additives is doughy 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 process steps mixing and melting can be carried out in the same apparatus or in two or more separately operating devices. The preparation of a premix can be carried out in one of the usual mixing devices described above. Such a premix can then be fed directly, for example into an extruder, and then optionally extruded with the addition of further components.

The process according to the invention makes it possible to use single-screw machines, intermeshing screw machines or even multi-shaft extruders, in particular twin-screw extruders, rotating in the same direction or in opposite directions and optionally equipped with kneading disks as extruders. When a solvent needs to be evaporated during extrusion, the extruders are generally equipped with an evaporation section. Particular preference is given to extruders of the ZKS series by Werner u. Pfleiderer.

According to the invention, multilayer pharmaceutical forms can also be produced by co-extrusion, in which case several mixtures of the components described above are combined during extrusion in a tool in such a way that the desired layer structure of the multilayered pharmaceutical form results. Preferably, different binders are used for different layers.

Multilayer dosage forms preferably comprise two or three layers. They may be in open or closed form, especially as open or closed multilayer tablets.

At least one of the layers contains at least one pharmaceutical agent. It is also possible to incorporate another active ingredient in another layer. This has the advantage that two incompatible active ingredients can be processed or that the release characteristics of the active ingredient can be controlled.

The molding is carried out by coextrusion, wherein the mixtures are led out of the individual extruders or other aggregates in a common co-extrusion tool and discharged. The shape of the coextrusion tools depends on the desired pharmaceutical form. For example, tools with a flat outlet gap, so-called slot dies, and tools with kreisringspaltförmigem outlet cross section are suitable. The nozzle design is carried out depending on the polymeric binder used and the desired pharmaceutical form.

The resulting mixture is preferably solvent-free, ie it contains neither water nor an organic solvent.

The plastic mixture is usually subjected to a final shaping. In this case, a variety of shapes, depending on the tool and type of molding, can be generated. For example, when using an extruder, the extruded strand can be between a strip and a roll, between two strips or between two rolls, as described in EP-A-358 105, or by calendering in a calender with two forming rolls, see for example A-240 904, forming. By extrusion and hot or cold deduction of the strand other forms can be obtained, for example, small-sized and uniformly shaped granules. Hot granulation typically results in lenticular dosage forms (tablets) having a diameter of 1 to 10 mm, while cold granulation normally results in cylindrical products having a length to diameter ratio of 1 to 10 and a diameter of 0.5 to 10 mm , Thus, single-layered, when using coextrusion but also open or closed, multilayer dosage forms can be prepared, for example, oblong tablets, dragees, lozenges and pellets. The granules obtained can then also be ground to powder and compressed in the usual way to tablets. Micropastils can be made by the Rotoform-Sandvik process. These dosage forms can be rounded in a subsequent process step by conventional methods and / or provided with a coating. Suitable materials for film coatings are, for example Polyacrylates, such as the Eudragit types, cellulose esters, such as the Hydroxypropylcellulosephthalate, and cellulose ethers, such as ethyl cellulose, hydroxypropylmethyl cellulose or hydroxypropyl cellulose.

In particular, it can come to the formation of fixed solutions. The term "solid solutions" is familiar to the expert, for example from the literature cited above. In solid solutions of active ingredients in polymers, the active ingredient is molecularly dispersed in the polymer.

The following examples are intended to illustrate the process of the invention without, however, limiting it. The calendering of the extruded melt was carried out as described in EP-A-240,904.

Examples

The extrusion was carried out in each case with a twin-screw extruder ZKS 30 from. Werner and Pfleiderer with 5 shots under the conditions given in the respective example.

example 1

520 g copolymer of 50% by weight of vinylpyrrolidone, 20% by weight of methyl methacrylate and 30% by weight of vinyl acetate (K value 31.4, 1% strength in acetone) were extruded with 480 g of verapamil hydrochloride and added to 500 mg Calendar tablets calendered.

The extrusion took place under the following conditions: <tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Shot 1</entry><entry namest="col2" nameend="col2" align="center">53 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 2</entry><entry namest="col2" nameend="col2" align="center">89 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 3</entry><entry namest="col2" nameend="col2" align="center">134 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 4</entry><entry namest="col2" nameend="col2" align="center">117 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 5</entry><entry namest="col2" nameend="col2" align="center">109 ° C</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">jet</entry><entry namest="col2" nameend="col2" align="center">100 ° C</entry></row></tbody></tgroup></table></tables>

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH change). It was 22% after 1 hour, 31% after 2 hours and 57% after 8 hours.

Example 2

520 g copolymer of 50% by weight of vinylpyrrolidone, 30% by weight of methyl methacrylate and 20% by weight of vinyl acetate (K value 32.4, 1% strength in acetone) were extruded and calendered with 480 g of verapamil hydrochloride.

The extrusion took place under the following conditions: <tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Shot 1</entry><entry namest="col2" nameend="col2" align="center">49 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 2</entry><entry namest="col2" nameend="col2" align="center">88 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 3</entry><entry namest="col2" nameend="col2" align="center">133 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 4</entry><entry namest="col2" nameend="col2" align="center">116 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 5</entry><entry namest="col2" nameend="col2" align="center">107 ° C</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">jet</entry><entry namest="col2" nameend="col2" align="center">101 ° C</entry></row></tbody></tgroup></table></tables>

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH change). It was 25% after 1 hour, 39% after 2 hours and 73% after 8 hours.

Example 3

252 g copolymer of 50% by weight of vinylpyrrolidone, 20% by weight of methyl methacrylate and 30% by weight of vinyl acetate (K value 31.4, 1% strength in acetone) were mixed with 60 g of Kollidon 30 (polyvinylpyrrolidone) and 288 g Verapamil hydrochloride is extruded and calendered into 500 mg oblong tablets.

The extrusion took place under the following conditions: <tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Shot 1</entry><entry namest="col2" nameend="col2" align="center">23 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 2</entry><entry namest="col2" nameend="col2" align="center">60 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 3</entry><entry namest="col2" nameend="col2" align="center">93 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 4</entry><entry namest="col2" nameend="col2" align="center">133 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 5</entry><entry namest="col2" nameend="col2" align="center">114 ° C</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">jet</entry><entry namest="col2" nameend="col2" align="center">93 ° C</entry></row></tbody></tgroup></table></tables>

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH change). It was 25% after 1 hour, 37% after 2 hours and 63% after 8 hours.

Example 4

252 g copolymer of 50% by weight of vinylpyrrolidone, 25% by weight of methyl methacrylate and 25% by weight of vinyl acetate (K value 31.5, 1% strength in acetone) were mixed with 60 g of Kollidon VA 64 (polyvinylpyrrolidone) and 288 g verapamil hydrochloride extruded and calendered into 500 mg oblong tablets.

The extrusion took place under the following conditions: <tables id="tabl0004" num="0004"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Shot 1</entry><entry namest="col2" nameend="col2" align="center">23 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 2</entry><entry namest="col2" nameend="col2" align="center">42 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 3</entry><entry namest="col2" nameend="col2" align="center">83 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 4</entry><entry namest="col2" nameend="col2" align="center">131 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 5</entry><entry namest="col2" nameend="col2" align="center">100 ° C</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">jet</entry><entry namest="col2" nameend="col2" align="center">95 ° C</entry></row></tbody></tgroup></table></tables>

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH change). It was 7% after 1 hour, 41% after 2 hours and 74% after 8 hours.

Example 5

282 g copolymer of 50% by weight of vinylpyrrolidone, 30% by weight of methyl methacrylate and 20% by weight of vinyl acetate (K value 32.4, 1% strength in acetone) were mixed with 30 g of Klucel EF (hydroxypropylcellulose) and 288 g Verapamil hydrochloride is extruded and calendered into 500 mg oblong tablets.

The extrusion took place under the following conditions: <tables id="tabl0005" num="0005"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Shot 1</entry><entry namest="col2" nameend="col2" align="center">23 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 2</entry><entry namest="col2" nameend="col2" align="center">47 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 3</entry><entry namest="col2" nameend="col2" align="center">90 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 4</entry><entry namest="col2" nameend="col2" align="center">131 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 5</entry><entry namest="col2" nameend="col2" align="center">113 ° C</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">jet</entry><entry namest="col2" nameend="col2" align="center">96 ° C</entry></row></tbody></tgroup></table></tables>

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH change). It was 26% after 1 hour, 38% after 2 hours and 65% after 8 hours.

Example 6

252 g copolymer of 50% by weight of vinylpyrrolidone, 30% by weight of methyl methacrylate and 20% by weight of vinyl acetate (K value 32.4, 1% in acetone) were mixed with 60 g of Klucel EF (hydroxypropylcellulose) and 288 g Verapamil hydrochloride is extruded and calendered into 500 mg oblong tablets.

The extrusion took place under the following conditions: <tables id="tabl0006" num="0006"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Shot 1</entry><entry namest="col2" nameend="col2" align="center">23 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 2</entry><entry namest="col2" nameend="col2" align="center">55 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 3</entry><entry namest="col2" nameend="col2" align="center">94 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 4</entry><entry namest="col2" nameend="col2" align="center">132 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 5</entry><entry namest="col2" nameend="col2" align="center">114 ° C</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">jet</entry><entry namest="col2" nameend="col2" align="center">95 ° C</entry></row></tbody></tgroup></table></tables>

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH change). It was 43% after 1 hour, 67% after 2 hours and 92% after 8 hours.

Example 7

160 g copolymer of 50% by weight of vinylpyrrolidone, 30% by weight of methyl methacrylate and 20% by weight of vinyl acetate (K value 51.5, 1% in acetone) were mixed with 3.4 mg of Aerosil 200, 1.6 mg of magnesium stearate and 160 mg of propranolol hydrochloride directly tableted to a faceted 10 mm tablet at a force of 18 kN.

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH 7.4). It was 16% after 1 hour, 25% after 2 hours, 61% after 8 hours and 95% after 16 hours.

Example 8

160 The copolymer of 40% by weight of vinylpyrrolidone, 40% by weight of methyl methacrylate and 20% by weight of vinyl acetate (K value 40.1, 1% strength in acetone) was mixed with 3.4 mg of Aerosil 200, 1.6 mg of magnesium stearate and 160 mg of propranolol hydrochloride directly tableted to a faceted 10 mm tablet at a force of 18 kN.

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH 7.4). It was 41% after 1 hour, after 2 hours 50%, after 8 hours 71% and after 16 hours 95%.

Comparative Example 1

500 g copolymer of 60 wt .-% N-vinylpyrrolidone and 40 wt .-% vinyl acetate are extruded with 500 g of verapamil hydrochloride under the conditions given below and calendered to 500 mg oblong tablets.

The extrusion took place under the following conditions: <tables id="tabl0007" num="0007"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Shot 1</entry><entry namest="col2" nameend="col2" align="center">90 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 2</entry><entry namest="col2" nameend="col2" align="center">100 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 3</entry><entry namest="col2" nameend="col2" align="center">110 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 4</entry><entry namest="col2" nameend="col2" align="center">120 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 5</entry><entry namest="col2" nameend="col2" align="center">130 ° C</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">jet</entry><entry namest="col2" nameend="col2" align="center">135 ° C</entry></row></tbody></tgroup></table></tables>

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH change). It was 100% after 3 hours.

Comparative Example 2

500 g copolymer of 30 wt .-% vinyl pyrrolidone and 70 wt .-% vinyl acetate are extruded with 500 g of verapamil hydrochloride under the conditions given below and calendered to 500 mg oblong tablets.

The extrusion took place under the following conditions: <tables id="tabl0008" num="0008"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Shot 1</entry><entry namest="col2" nameend="col2" align="center">30 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 2</entry><entry namest="col2" nameend="col2" align="center">60 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 3</entry><entry namest="col2" nameend="col2" align="center">100 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 4</entry><entry namest="col2" nameend="col2" align="center">100 ° C</entry></row><row><entry namest="col1" nameend="col1" align="left">Shot 5</entry><entry namest="col2" nameend="col2" align="center">120 ° C</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">jet</entry><entry namest="col2" nameend="col2" align="center">120 ° C</entry></row></tbody></tgroup></table></tables>

The release of the active ingredient from the tablets was investigated according to the paddle model (USP, pH change). It was 100% after 8 hours.