WO1997015292A1

WO1997015292A1 - Method of producing medicaments in solid form

Info

Publication number: WO1997015292A1
Application number: PCT/EP1996/004586
Authority: WO
Inventors: Jörg Breitenbach; Axel Paul HÄRTL; Werner Maier; Joerg Rosenberg; Michael Schiessl; Hans Dieter Zettler
Original assignee: Basf Aktiengesellschaft
Priority date: 1995-10-23
Filing date: 1996-10-22
Publication date: 1997-05-01
Also published as: DE19539362A1

Abstract

The invention concerns a method of producing medicaments in solid form by mixing and melting at least one pharmacologically acceptable polymer binder, at least one pharmaceutical active substance and optionally conventional pharmaceutical additives in the absence of a solvent to form a plastic mixture, and shaping this mixture to form the desired medicament, the mixing, melting and shaping steps being carried out continuously and separately. The method according to the invention enables high-quality medicaments to be produced in a simple and careful manner.

Description

METHOD FOR PRODUCING SOLID MEDICINAL FORMS

The present invention relates to a process for the production of solid pharmaceutical forms by mixing and melting at least one pharmacologically acceptable polymeric binder, at least one pharmaceutical active ingredient and, where appropriate, customary pharmaceutical additives in the absence of a solvent.

The classic processes for producing solid medicament formulations, in particular tablets, are carried out batchwise and comprise several stages. First, the components of the dosage form are conveyed into a suitable container and mixed there with the addition of a solvent to form a kneadable dough. The dough is then granulated, the granules are dried and shaped into the desired medicinal form, for example by compression into tablets. Such methods are described in relevant textbooks and for example in DE-A-41 41 268 and EP-A-590 963. The disadvantage of this process lies in the use of a solvent and in the large number of stages and equipment required.

For some time now, a much simpler continuous process for the production of solid medicinal forms has been known, in which an active substance-containing, solvent-free melt is extruded from a polymeric 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. A problem with this continuous process is the exact metering of all individual components required for the production of pharmaceuticals. It did not seem practicable to premix the components and feed this premix into the extruder because the risk of segregation of the components and thus the production of dosage forms of uneven composition increases

REPLACEMENT BLAπ (RULE 26) is great. In order to avoid this problem, EP-A-337 256 proposes to meter the individual components continuously into the hopper of an extruder. The dosing takes place with the aid of the very precisely working differential dosing scales. Dosing fluctuations can nevertheless not be completely avoided because the differential dosing scales have to be operated volumetrically during filling. As a result, at least some of the pharmaceutical forms obtained do not meet the requirements.

Another disadvantage of the process described in EP-A-337 256 is the high outlay for distributing the powdered active ingredient during the mixing process in the plastic zone of the extruder in order to be able to achieve the necessary axial backmixing. The coupling of the melting and mixing process in the extruder requires a relatively long residence time in a zone with high shear in order to achieve sufficient mixing. This can lead to local overheating and damage to the product, especially when using a shear and temperature-sensitive active ingredient.

WO-A-94/25008 describes the preparation of an active ingredient-containing solution based on polyvinylpyrrolidone with a low K value in combination with certain esters as plasticizers. The esters under consideration are clear, viscous liquids, with triethyl acetate and glycerol triacetate being preferred. The ester content in this combination is at least 50%. To produce the capsule contents, polyvinylpyrrolidone and the active ingredient are processed with heating to form a homogeneous solution. The high proportion of plasticizer in the combination mentioned leads to the so-called cold flow of the solidified solvent system, which is therefore not stable in storage. It is therefore necessary to fill the solution in soft gelatin capsules. The process therefore requires a further step and is not suitable for the production of solid medicament forms.

REPLACEMENT BLADE (RULE 26) The present invention is therefore based on the object of providing a simple and gentle process for the production of solid medicament forms, moreover the process should be inexpensive and finally it should allow the medicament forms to be produced reliably with a constant composition.

Surprisingly, it has now been found that this object is achieved if the mixing and melting of the components are carried out in a separate step, i.e. in a separate step. if the melting, mixing and shaping steps required for the production of the pharmaceutical forms are each carried out separately and in optimized apparatus.

The present invention therefore relates to a process for the production of solid pharmaceutical forms by mixing and melting at least one pharmacologically acceptable polymeric binder, at least one active pharmaceutical ingredient and, if appropriate, customary pharmaceutical additives in the absence of a solvent to give a plastic mixture and shaping the mixture desired dosage form, which is characterized in that the steps of mixing, melting and shaping are carried out continuously and separately from one another.

The process according to the invention is carried out continuously. In the present case, steps which are separate from one another are to be understood to mean that each step is carried out in the apparatus which is optimal for the step in question and the materials used. At least one device is provided for each step. The equipment used for mixing and melting can be the same, the same type or different types. For example, mixing with the aid of a solid mixer or an extruder and melting in a further extruder, which is an identical,

REPLACEMENT BLAπ (RULE 26) but extruder operated under different conditions, or be carried out in an extruder of a different type.

The components can first be mixed and then melted and homogenized. However, especially when using sensitive active ingredients, it has proven to be preferred to first melt and premix the polymeric binder, if appropriate together with customary pharmaceutical additives, the stirred tanks, stirrers, solid-state mixers etc. optionally being operated alternately and then to mix in (homogenize) the active ingredient or the active ingredients, which can be used in solid form or as a solution or dispersion.

The melting takes place in a device customary for this purpose. Extruders or heatable containers with stirrers, e.g. Kneader (like the type mentioned below). A very short and therefore inexpensive extruder is sufficient as the extruder.

Devices which are also used in plastics technology for mixing can be used as a mixing apparatus. Suitable devices are described, for example, in "Mixing during the manufacture and processing of plastics", H. Pahl, VDI-Verlag, 1986. Particularly suitable mixing apparatuses are extruders and dynamic and static mixers, as well as stirred tanks, single-shaft agitators with stripping devices, in particular So-called paste agitators, multi-shaft agitators, in particular PDSM mixers, solid matter mixers and preferably mixing-kneading reactors (eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei), double-bowl kneaders (trough mixers) and stamp kneaders (internal mixers) or Rotor / stator systems (eg Dispax from IKA).

In the case of sensitive active ingredients, the polymeric binder is first melted in an extruder and then the active ingredient is mixed in a mixing kneading reactor. at

REPLACEMENT BLAπ (RULE 26) By contrast, less sensitive active ingredients can be used to intensively disperse the active ingredient using a rotor / stator system.

The mixing device can be fed continuously or discontinuously in the usual manner. Powdered components can be fed in free, e.g. be introduced via a differential metering scale. Plastic masses can be fed in directly from an extruder or fed in via a gear pump, which is particularly advantageous at high viscosities and high pressures. Liquid media can be metered in using a suitable pump unit.

As already mentioned, all components can be added to the mixing device and then mixed and then passed as a mixture to a melting device. However, it is preferred to first melt the binder, if appropriate together with customary additives, and then to mix in at least one active ingredient in the mixing device. Depending on the consistency of the active ingredient, it can be added using one of the methods described above. The subsequent addition of the active ingredient (and / or other components) is particularly advantageous if the substances are sensitive to shear and temperature, because then the time during which they are subject to the high shear forces and are exposed to high temperatures, is considerably shorter.

Compared to the method according to EP-A-337 256, the outlay for metering the components is reduced in the method according to the invention. Fluctuations in the product quality are avoided, that is, the method according to the invention reliably delivers the desired dosage forms and with the desired specifications. In addition, the optimum device can be selected for each stage depending on the component used. A particularly effective mixing effect can therefore be achieved. In addition, the process can be carried out very gently. It therefore provides medicinal forms in particular

REPLACEMENT BLAπ (RULE 26) high product quality, even when using sensitive materials and active ingredients.

The mixture obtained by mixing and melting the binder, the active ingredient and optionally the additive or additives is pasty to viscous (thermoplastic) and therefore also extrudable. The glass transition temperature of the mixture is below the decomposition temperature of all components contained in the mixture. The binder should preferably be soluble or swellable in a physiological environment. Examples of suitable binders are:

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 polymethacrylates and polymethacrylates , Copolymers of methyl methacrylate and acrylic acid, cellulose esters, cellulose ethers, in particular methyl cellulose and ethyl cellulose, hydroxyalkyl celluloses, in particular hydroxypropyl cellulose, hydroxyalkyl alkyl celluloses, in particular hydroxypropyl ethyl cellulose, cellulose phthalates, in particular cellulose acetate phthalate and hydroxypropylene, methyl cellulose especially galactomannans. The K values (according to H. Fikentscher, Cellulose-Chemie 13 (1932), pages 58 to 64 and 71 and 74) of the polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, for PVP> 17, in particular 20 to 35.

Preferred polymeric binders are polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates, polymethacrylates, alkyl celluloses and hydroxyalkyl celluloses.

In the total mixture of all components, the polymeric binder must soften or melt in the range from 50 to 180 ° C., preferably 60 to 130 ° C. The glass transition temperature of the Mi

ERSATZBL _Ä TT (REGEL26) Schung 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 pharmaceutical forms are formed which show no cold flow. However, the mixture preferably 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 propylene glycols, silicones, aromatic carboxylic acid esters (eg dialkyl acid phthalates, terephthalic acid phthalates, trimesteric acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, and trimellitic acid phthalates, 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 diethylsulfosuccinate. The concentration of plasticizer is generally 0.5 to 15, preferably 0.5 to 5% by weight, based on the total weight of the mixture.

Common pharmaceutical auxiliaries, the total amount of which can be up to 100% by weight, based on the polymer, are e.g.

Extenders or fillers, such as silicates or silica, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or their salts, e.g. the magnesium or calcium salt, methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, polyvinyl alcohol, in particular in a concentration of 0.02 to 5.0, preferably 0.20 to 20% by weight. -%, 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

REPLACEMENT BLAπ (RULE 26) 0.1 to 3 wt .-%, based on the total weight of the mixture.

Plasticizers, such as animal or vegetable fats, especially in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50 ° C or higher. Triglycerides of C ₂ -, C _{| 4} -, C ₁₆ - and C2g 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, 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, being preferred ;

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

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

In the context of the invention, auxiliary substances are also to be understood as meaning substances for producing a solid solution with the active pharmaceutical ingredient. These auxiliaries are, for example, pentaerythritol and pentaerythritol tetraacetate, polymers such as e.g. Polyethylene or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers

REPLACEMENT BLAπ (RULE 26) of vinyl pyrrolidone, surfactants such as polyoxyethylene 40 stearate and citric and succinic acid, bile acids, sterols and others such as those from JL Ford, Pharm. Acta Helv. 6 _. 1: 69-88 (1986).

Additions of bases and acids to control the solubility of an active ingredient are also considered pharmaceutical auxiliaries

(See, for example, K. Thoma et al., Pharm. Ind. 5_1, 98-101

(1989)).

The only requirement for the suitability of auxiliaries is adequate temperature stability.

Pharmaceutical active substances in the sense of the invention are understood to mean all substances with a pharmaceutical effect and as few side effects as possible, provided that they do not decompose under the processing conditions. The amount of active ingredient per dose unit and the concentration can vary within wide limits depending on the effectiveness and rate of release. The only condition is that they are sufficient to achieve the desired effect. The active ingredient concentration can thus be in the range from 0.1 to 95, preferably from 20 to 80, in particular 30 to 70% by weight. Combinations of active substances can also be used. Active substances in the sense of the invention are also vitamins and minerals, as well as plant treatment agents and insecticides. The vitamins include the vitamins of the A group and the B group, which in addition to Bi, B ₂ , B ₆ and B _j 2 as well as nicotinic acid and nicotinamide also include compounds with vitamin B properties, such as 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 therapeutics.

The method according to the invention is for example for processing

SPARE BLADE (RULE 26) suitable for the following active ingredients:

Acebutolol, Acetylcysteine, Acetylsalicylic Acid, Acyclovir, Albrazolam, Alfacalcidol, Allantoin, Allopurinol, Ambroxol, Amikakin, Amilorid, Amino Acetic Acid, Amiodarone, Amitriptylin, Acyclic Acid, Asoxicinolonol, Asoxicinolonol Benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamaefa- carbin, chloratinopa Cefalexin, Cefatroxil, Cefazolin, Cefixim, Cefotaxim, Ceftazidim, Ceftriaxon, Cefuroxim, Celedilin, Chloramphenicol, Chlorhexidine, Chloropheniramine, Chlortalidon, Choline, Cyclosporin, Cilastatin, Cimetacin, Ciprofisin, Ciprofisin, Ciprofisin, Ciprofisin, Ciprofisin, Ciprofisin, Ciprofliscinol, Ciprofisin, Ciprofisin, Ciprofinicin, Ciprofisin, Ciprofinicin, Ciprofinicin, Ciprofinicin, Ciprofinicin, Ciprofinicin, Ciprofinicine, Ciprofinicin Clomibramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpan - thenol, dextromethorphan, Dextropropoxiphen, diazepam, Diclofe- nac, digoxin, dihydrocodeine, dihydroergotamine, Dihydroergoto- xin, diltiazem, mid diphenhydramine, dipyridamole, dipyrone, Disopyra-, domperidone, dopamine, doxocyclin, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine , Erythromycin, estradiol, ethinylestradiol, etoposide, eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin-mononucleotide, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbi- profen, furamilemibibin, furosemidibinomibibomidibinicibibomidibin, biloximidibin , Glibenclamide, glipizide, clozapine, glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, imipenem, indometholidolid, iodomololid, iodomololid, iodomololid, iodomololid, iodomololid, iodomololid, iodomololid, iodomololid, iodomololidophen Mononitrate, isotetrinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labatalon, lactulose, lecithin, levocarnitine, levodopa, levoglu tamid, levonorgestrel, levothyroxine, lidocaine, lipase, lipramin, lisinopril, loperamide, lorazepam, lovastatin, medroxyprogestone, menthol, methotrexate, methyldopa, methylprednisolone, meto-

REPLACEMENT BLAπ (RULE 26) clopramid, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotinamide, nicotinamide, nicotinamide nifedipine, nimodipine, nitrazepam, Ni trendipin, nicillin nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, Phenoxifyllin, Phenoxymethylpe-, Phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, promocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quininidine, quinidine , Rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfa methoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur, teprenone, terazosin, terbutaline, terfenadine, tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamoprene, triamoprene, triamterene, triamterene, Uracil, valproic acid, vancomycin, verapamil, vitamin E, volinic acid, zidovudine.

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

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

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

REPLACEMENT BLAπ (RULE 26) The mixture is shaped by customary methods. Common methods include:

Hot granulation leading to lenticular pellets with a diameter of 1 to 10 mm;

Cold granulation leading to cylindrical products with a length to diameter ratio of 1 to 10 and a diameter of 0.5 to 10 mm;

Calendering in a calender with two forming rolls, as described for example in EP-A-240 904;

Extrusion and deformation of the still plastic strand between a belt and a roller or between two belts or between two rollers, as described in EP-A-358 105.

Coextrusion of at least two strands and deformation into one of the above-mentioned methods to form an at least two-layer, open or closed dosage form. One of the layers contains an active ingredient, the other layer can be free of active ingredient or optionally contain another active ingredient. The layers generally contain different polymeric binders. You will e.g. produced with a slot die or a concentric, circular ring-shaped coextrusion die. Further information can be found in an application which was submitted by the applicant on the same day as the present application.

Solid pharmaceutical forms which can be produced by the process according to the invention are, in particular, coated tablets, pellets, granules and tablets. The forms obtained, in particular the granules, can then also be ground to powder and used in this form, for example in hard gelatin capsules. Granules can also be compressed into tablets in the usual way. Finally, the pharmaceutical forms obtained can also be provided in a conventional manner with film coatings, which the

REPLACEMENT BLAπ (RULE 26) Check active ingredient release or cover the taste. Suitable materials for such coatings are polyacrylates, such as the Eudragit types, cellulose esters, such as the hydroxypropyl methyl cellulose phthalates, and cellulose ethers, such as ethyl cellulose, hydroxypropyl methyl cellulose or hydroxypropyl cellulose.

The method according to the invention thus also allows the production of pharmaceutical forms by conventional methods, such as pressing granules into tablets, but without the disadvantages of these conventional methods.

The following examples illustrate the invention without limiting it.

example 1

In a co-rotating twin-screw extruder (type ZSK30, Werner & Fleiderer) was continuously 10 kg / h

Polyvinylpyrrolidone-vinyl acetate copolymer dosed and at one

Temperature of 110 ° C melted. The melt was metered in continuously in a mixing / kneading reactor (type API Conti, List), 2 kg / h captopril and the mixture was gently homogenized. The plastic mixture obtained was then discharged as a strand via a gear pump and a nozzle plate, pelletized by cold cutting and then continuously pelletized. Transparent drug forms were obtained in which the active ingredient is present as a solid solution. The pellets show a release of> 70% in 30 minutes, measured at pH 7.2, which corresponds to the requirements according to USP XXII.

Example 2

According to the process described in Example 1, in addition to 2 kg / h captopril, 2 kg / h methyl cellulose were also added.

REPLACEMENT BLAπ (RULE 26) siert. Pharmaceutical forms were obtained in which the active ingredient is present as a solid solution.

Example 3

150 l of polyvinylpyrrolidone-vinyl acetate copolymer were placed in a heated stirred tank (volume 200 l) and melted at a temperature of 110.degree. The melt was conveyed via a gear pump with a mass flow of 10 kg / h into a mixing-kneading reactor (type API Conti, company List). The melt was then continuously metered in 2 kg / h captopril and 2 kg / h methyl cellulose and it was gently homogenized. The plastic mixture was then pump via a gear and a nozzle plate discharged as a strand, by cold _"tee granulated and then continuously pelletized. This gave dosage forms in which the active ingredient is present as a solid solution.

Example 4

150 l of polyvinylpyrrolidone-vinyl acetate copolymer were placed in a heated stirred tank (volume 200 l) and melted at a temperature of 110.degree. The melt was continuously conveyed at a mass flow of 10 kg / h via a gear pump into a dynamic mixer with a rotor / stator system (type Dispax, company IKA). 4 kg / h acetylsalicylic acid and 2 kg / h isomaltose were metered into the melt and it was dispersed intensively. The plastic mixture was then discharged as a strand via a gear pump and a nozzle plate, granulated by cold cutting and then continuously pelletized.

REPLACEMENT BLAπ (RULE 26)

Claims

Patent claims

1. A process for the preparation of solid pharmaceutical forms by mixing and melting at least one pharmacologically acceptable polymeric binder, at least one pharmaceutical active ingredient and optionally conventional pharmaceutical additives in the absence of a solvent into a plastic mixture and shaping the mixture into the desired one Drug form,

characterized ,

that the steps of mixing, melting and shaping are carried out continuously and separately from one another.

2. The method according to claim 1, characterized in that the mixture mentioned contains no plasticizer.

3. The method according to claim 1 or 2, characterized in that a binder is used which is selected from polyvinylpyrrolidones with a K value of more than 17, polyacrylates, polymethacrylates, polyhydroxyacrylates, polyhydroxymethacrylates, alkyl celluloses and hydroxyalkyl celluloses.

4. The method according to any one of the preceding claims, characterized in that the mixing takes place in a continuously operated solid mixer.

5. The method according to any one of the preceding claims, characterized in that first all components are mixed and the mixture then melts.

6. The method according to any one of claims 1 to 4, characterized in that first of all the polymeric binder and optionally conventional pharmaceutical additives are melted and then the active pharmaceutical ingredient

REPLACEMENT BLAπ (RULE 26) mixes.

7. The method according to claim 6, characterized in that one carries out the melting in an extruder and the mixing in a mixing kneading reactor or a rotor / stator system.

8. The method according to claim 7, characterized in that captopril is used as the active ingredient and the mixing is carried out in a mixing-kneading reactor.

9. The method according to claim 7, characterized in that acetylsalicylic acid is used as the active ingredient and the mixing is carried out in a rotor / stator system.

REPLACEMENT BLAπ (RULE 26)