EP1133271A1

EP1133271A1 - Method of producing solid dosage forms

Info

Publication number: EP1133271A1
Application number: EP99959299A
Authority: EP
Inventors: Jörg Rosenberg; Werner Maier
Original assignee: Knoll GmbH
Current assignee: Abbott GmbH and Co KG
Priority date: 1998-11-23
Filing date: 1999-11-22
Publication date: 2001-09-19
Anticipated expiration: 2019-11-22
Also published as: EP1133271B1; DE59910408D1; JP4488143B2; ATE274896T1; ES2226469T3; CA2351484A1; JP2002530155A; DE19853985A1; US6737005B1; CA2351484C; WO2000030586A1

Abstract

A process for producing solid dosage forms by a) producing a plastic mixture which comprises at least one active ingredient and at least one polymeric binder, and b) shaping the plastic mixture to the solid dosage forms in a molding calender with two counterrotating molding rolls, wherein one molding roll has at least one annular groove running along its periphery and the other molding roll has at least one ring, running along its periphery, of teeth extending radially outward and able to engage in the annular groove is described.

Description

Process for the preparation of solid dosage forms

description

The present invention relates to a method for producing solid dosage forms by producing a plastic mixture which contains at least one active ingredient and at least one polymeric binder, and molding the plastic mixture into the solid dosage forms in a mold calender with two counter-rotating molding rolls.

Such a method is e.g. known from US-A-4,880,585. In this process, an active substance and binder-containing mass is plasticized with an extruder, and the resultant

Melt is subjected to shaping in a form calender. The form rollers of the form calender have depressions with corresponding contour lines on their surface. The depressions on the surfaces of the shaping rollers briefly meet at the contact line of the shaping rollers to form molds for the active substance-containing melt and then strive apart again as the shaping rollers continue to rotate, the molded dosage forms being released. This method has certain disadvantages. For example, the recesses on the surface of the shaping rollers with their outlines must lie exactly one above the other when shaping the plastic mixture in order to achieve a complete positive fit. Even the smallest displacements of the wells against each other, for example in the range of a few micrometers, immediately lead to a recognizable offset of the top and bottom of the dosage form. On the one hand, this requires a high degree of precision in the production of the forming rolls, on the other hand, the forming rolls in the calender have to be moved exactly in synchronization with each other. This is only possible with complex machine designs. The production of the forming rolls is complex and cost intensive because cavities with a three-dimensional structure have to be provided in the roll surfaces. This applies in particular if more complicated geometries, for example dividable tablets with a score line, are aimed for. Because of the necessity of the exact alignment of the two forming rolls in the known form calendering processes, segmentation of the forming rolls into individual roll disks, which each contain only one or a few traces of depressions and can be combined in any way to form a multi-track roll, is impossible because the pressing forces occurring during calendering are easily "twisted" the individual segments. However, this twisting means that the upper and lower halves of the tablet shapes do not lie exactly one above the other during rotation. The segmentation of the form rollers is However, it is desirable, for example, if only one roller disc and not the entire roller has to be replaced if individual cavities are damaged, or in order to be able to combine different shapes in one roller as desired.

It has already been proposed to combine a shaping roller which has depressions on its surface with a second roller which does not contain any depressions (smooth roller). This eliminates the need for exact alignment of the two rollers with each other. The disadvantage here, however, is that at least one of the two rollers still has to be manufactured in a complex manner. In addition, the possibilities of designing the tablet shapes with this combination are very limited.

The present invention is therefore based on the object of providing a simple and inexpensive method for producing solid dosage forms, in which no problems arise with respect to an offset of the top and bottom halves of the dosage forms.

Surprisingly, it was found that this object is achieved if the surface of the shaping rollers is designed in such a way that they can interlock.

The present invention therefore relates to a process for the production of solid dosage forms

a) producing a plastic mixture which contains at least one active ingredient and at least one polymeric binder, and

b) shaping the plastic mixture into the solid dosage forms in a molding calender with two counter-rotating molding rolls, characterized in that one molding roll has at least one circumferential annular groove and the other shaping roll has at least one circumferential rim of radially outwardly extending teeth has, which can engage in the annular groove. The teeth are shaped in such a way that they fully fill the cross-section of the ring groove with maximum engagement in the ring groove, i.e. the cross-sectional profile of the ring groove and the teeth are essentially complementary.

The "interlocking" of the form rollers eliminates the need for exact alignment of the two individual rollers to one another, since only one roller of the pair of rollers has an angle-dependent surface structure. It is therefore possible to Chere machine constructions for the forming rollers

Calender to choose.

Molding rolls to be used according to the invention are known as “prism rolls” from compacting technology. Reference is made to B. Pietsch, Aufaufungs-Technik 3 (1970) pp. 128-138. The use of such rollers for solidifying free-flowing bulk goods into granules is described there. Problems of a possible misalignment between the upper and lower half of the compresses formed are not addressed in this context.

Despite the simple roller construction, pairs of rollers to be used according to the invention enable a considerable variety of shapes of the solid dosage forms thus produced. The possible variations relate primarily to the formation of the annular groove and the formation of the space between successive teeth of a ring. For example, the ring groove can have a number of different cross-sectional profiles (projection onto a plane that contains the roller axis). The ring groove can have a rectangular, triangular, rounded or other cross section. In general, it is preferred that the annular groove has a rounded cross-sectional profile for easier demolding of the shaped dosage forms.

The longitudinal profile of the spaces between successive teeth of a ring (i.e. the projection of the space on a plane perpendicular to the roller axis) is also subject to variation. The gaps can have a triangular, parallelogram-shaped, rounded or other longitudinal profile. In general, however, it is preferred that the spaces between successive teeth of a ring have a rounded longitudinal profile.

The dosage forms obtained can be e.g. Have prism shape, prism shape, tetrahedral shape or saddle body shape, the saddle body shape being preferred.

In a preferred embodiment of the method according to the invention there is a circumferential web at the bottom of the annular groove and the teeth have a corresponding recess. In this way it is possible to produce divisible tablets which have a notch on one side of their surface. Between successive teeth of a ring there can also be a web that does not extend to the outer surface of the roller. In this way it is also possible to produce dividable tablets with a notch.

In order to facilitate the demolding of the dosage forms formed from the annular groove or the interdental spaces, it is possible to keep the contact pressure between the two shaping rollers low or to keep a small distance between the shaping rollers, e.g. 0.1-1 mm to be provided. In this way, a "tablet belt" is obtained in which the individual dosage forms are still connected to one another via narrow ridges. The individual dosage forms can be easily separated from one another, in particular if the plastic mixture shows greater brittleness after it has cooled completely. It may be advisable to subsequently deburr the dosage forms obtained.

After the molding process, the dosage forms are allowed to cool and solidify, e.g. on a cooling belt.

The present method of making solid dosage forms involves making a plastic mixture. This is usually done 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 presence or absence of a solvent. These process steps can be carried out in a known manner.

The components can first be mixed and then melted and homogenized. However, especially when using sensitive active ingredients, it has proven to be preferable to first melt and premix the polymeric binder, optionally together with customary pharmaceutical additives, the stirred kettles, agitators, solid-state mixers etc. optionally being operated alternately, and then the Mix in (the) sensitive active ingredient (s) in "intensive mixers" in the plastic phase with very short residence times (homogenization). The active ingredient (s) can be used in solid form or as a solution or dispersion.

The melting and mixing takes place in a device which is customary for this purpose. Extruders or heatable containers with stirrers, such as kneaders, (such as those mentioned below) are particularly suitable. Devices which are used in plastics technology for mixing can also be used as a mixing apparatus. Suitable devices are described, for example, in "Mixing in the manufacture 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 mixers) and stamp kneaders (Internal mixer) or rotor / stator systems (eg 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. Powdered components can be fed in free, e.g. be introduced via a differential dosing scale. 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 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 polymethacrylate methacrylate (E) acrylate and polymethacrylate methacrylates (E) acrylate and polymethacrylate methacrylate types (E) , Cellulose esters, cellulose ethers, especially methyl cellulose and ethyl cellulose, hydroxyalkyl celluloses, especially hydroxypropyl cellulose loose, hydroxyalkyl-alkyl celluloses, in particular hydroxypropyl ethyl cellulose, cellulose phthalates, in particular cellulose tritphthalate and hydroxypropyl methyl cellulose phthalate, and mannans, in particular galactomannans. The K values (according to H. Fikentscher, Cellulose-Chemie 13 (1932), pages 58-64, 71, 74) of the polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, for PVP> 17, especially 20 to 35.

Preferred polymeric binders are polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates, polyacrylates, alkyl celluloses and hydroxyalkyl celluloses. 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 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 (for example dialkyl phthalate, benzoate phthalate ester acid) 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 wt .-%, based on the total weight of the mixture.

Typical pharmaceutical auxiliaries, the total amount of which can be up to 100% by weight, based on the polymer, are, for example, extenders or fillers, such as silicates or silica, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or their salts, for example 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 50, preferably 0.20 to 20% by weight, based on the total weight of the mixture. Lubricants, such as aluminum and calcium stearate, talc and silicone, in a concentration of 0.1 to 5, preferably 0.1 to 3% by weight, based on the total weight of the mixture.

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 Cj _.2 -, C ₁₄ -, Cι ₆ - and Ciβ 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 (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 of vinyl pyrrolidone, surfactants such as polyoxyethylene 40 stearate and citric and succinic acid, bile acids, sterols and others such as e.g. in J.L. Ford, Pharm. Acta Helv. 61 (1986) pp. 69-88.

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. 51 (1989) 98-101). 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 substance 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 _ß and B ₁₂ and nicotinic acid and nicotimide also include compounds with vitamin B properties, such as adenine, choline, Pantothenic acid, biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-amine-topzoic 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.

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

Acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alfacalcidol, allantoin, allopurinol, alprazolam, ambroxol, amikacin, amilorid, aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillartin, astaminsolonol, astorbicoleminol, azorbicoleminol, azorbicoleminol, azorbicoleminol, azorbicoleminol, azorbic acid Benzalkonium hydrochloride, benzocaine, benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbidopazepine, carbamapazepine Cefachlor, Cefadroxil, Cefalexin, Cefazolin, Cefixim, Cefotaxim, Ceftazidim, Ceftriaxon, Cefuroxim, Chloramphenicol, Chlorhexidine, Chloropheniramine, Chloractidone, Choline, Cyclosporin, Cilastatin, Cimetacin, Ciprofinitoxin, Ciprofinitoxin, Ciprofinitoxin, Ciprofinicidine, Ciprofinidicine, Ciprofinidicine, Ciprofinicidine, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofinicid, Ciprofin, Ciprofin, Ciprofin, Ciprofin Clomipramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpantheno l, dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine, dipyridamol, dipyron, disopyramid, domperidon, dopamine, enphedrin, epoxyrilin, doxocryclin nephrin, ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide, eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol, fentanyl, flavin-mononucleotide, fluconazole, flunarizine, folouracid, gallophenic acid, furoxiliprofen, furolemosilicate, furoxemic acid, furoxiliprofinic acid, fluoxaciliprofinic acid, furoxemic acid, furoxiliprofinic acid, fluoxaciliprofinic acid, furoxiliprofluoric acid, fluoxaciliprofluoric acid Gentamicin

Gingko biloba, glibenclamide, glipizide, clozapine, glycyrrhiza gla- bra, griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen, indiphenol, imopen Isosorbide dinitrate, isosorbide mononitrate, isotretinoin, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, lecithin, levocarnitin, levodopa, levoglutamide, levonorgestrel, levothyroxine, lidocain, lipidastam, lipopa, lupidastin, lopatin, lipopa, lopodin, lipopa Medroxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramid, metoprolol, miconazole, midazolam, minocycline, minoxidil, miisoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephrofuryl, naftide mycin, nicardipine, nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin, norge strel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, pentoxifylline, phenobarbital, phenoxymethylpenicillin, phenylephrine, phenoxinoxymin, phenoxinoxinol, polynoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxynoxinoxinoxinoxinoxinoxinoxynoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxinoxin, -Iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, propafone, propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharol, salcharin, salcatol , Salicylic acid, selegiline, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifene, tegafur, teprenone, terazosine, terbutaline, terfenadine, tetracyclolidine, tranoline , Tretinoin, triamcinolone acetonide, triamterene, trimethomprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E, zidovudine.

Preferred active substances 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 fixed solutions Solutions of active pharmaceutical ingredients in polymers, the active ingredient is molecularly dispersed in the polymer.

The mixture obtained is preferably solvent-free, i.e. it contains neither water nor an organic solvent. The resulting mixture is then introduced into a mold calender discussed above.

Finally, the solid pharmaceutical forms which can be produced by the process according to the invention can also be provided in a conventional manner with film coatings which control the release of active ingredient or cover the taste. Suitable materials for coatings of this type are polyacrylates, such as the Eurogitit types, cellulose esters, such as the hydroxypropylmethylcellulose sephates, and cellulose ethers, such as ethylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose.

With the method according to the invention it is thus possible to produce particularly precisely dimensioned dosage forms. Surprisingly, this process is inexpensive, allows very large quantities to be achieved per unit of time and avoids any waste.

The figures explain the invention without limiting it. Figures 1 to 3 are briefly described below.

In the drawings:

Figure 1: Different designs of the annular groove present in a roller according to the invention; FIG. 2: Different designs of the spaces between successive teeth of a ring of teeth present on a roller according to the invention and the dosage forms obtainable therewith; FIG. 3: The construction principle of a pair of rollers to be used according to the invention using a concrete example.

In Figure 1, different versions of the annular groove are shown in cross section. The ring groove can have a rectangular (a), triangular (b) or rounded (c) cross-sectional profile. At the bottom of the annular groove there can be a circumferential ridge (d) which leads to solid dosage forms which have a notch on one side of their surface. According to FIG. 2, the dosage forms with prism shape (a), prism shape (b) or saddle body shape (c) are shown, depending on the design of the spaces between successive teeth of a ring.

FIG. 3 illustrates the construction principle of a pair of rollers with two tracks, one roller having two circumferential ring grooves with a rounded cross-sectional profile and the other roller having two circumferential rings of radially outwardly extending teeth, the spaces between successive teeth having a rounded longitudinal profile. FIG. 3 shows a cross section of the roller pair through the roller axes at the top. Figure 3 shows a cross section of the roller pair perpendicular to the roller axes below.

Claims

claims

1. Process for the preparation of solid dosage forms

b) shaping the plastic mixture into the solid dosage forms in a molding calender with two counter-rotating molding rolls, characterized in that one molding roll has at least one circumferential annular groove and the other shaping roll has at least one circumferential rim of radially outwardly extending teeth has, which can engage in the annular groove.

2. The method according to claim 1, characterized in that the annular groove has a rounded cross-sectional profile.

3. The method according to claim 1 or 2, characterized in that the spaces between successive teeth of a ring have a rounded longitudinal profile.

4. The method according to any one of the preceding claims, characterized in that there is a circumferential web at the bottom of the annular groove and the teeth have a corresponding recess.

5. The method according to any one of the preceding claims, characterized in that the dosage forms obtained are deburred.

6. Solid dosage forms, obtainable by the process according to one of claims 1 to 5.