EP1133271B1 - Method of producing solid dosage forms - Google Patents

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

The present invention relates to a process for the preparation of solid dosage forms by making a plastic Mixture containing at least one active ingredient and at least one polymeric Contains binder, and forms of the plastic mixture to the solid dosage forms in a two-way mold calender rotating forming rollers.

Such a method is e.g. from US-A-4,880,585. In this process, a drug and binder-containing Mass plasticized with an extruder, and the resulting Melt is subjected to shaping in a mold calender. The forming rollers of the mold calender have depressions on their surface with mutually corresponding outlines. The wells on the surfaces of the forming rollers occur at the contact line the forming rollers for a short time to forms for the active ingredient Melt together and strive in the further rotation of the Forming rollers then apart again, with the molded Dosage forms are released. This procedure has certain Disadvantages. So the pits on the surface need the forming rollers with their outline in the formation of the plastic mixture exactly on top of each other to a complete To reach positive engagement. Even the smallest shifts the depressions against each other, e.g. in the range of a few Micrometers, immediately lead to a noticeable offset of Oberund Bottom of the dosage form. This requires one hand high precision in the production of molding rolls, on the other hand The forming rollers in the calender must be exactly synchronized with each other to be moved. This is only with elaborate machine designs possible. The production of the forming rollers is complicated and expensive, because in the roll surfaces cavities with three-dimensional Structure are provided. This is especially true if more complicated geometries, e.g. divisible tablets with a Score, are sought. Due to the need of accurate Alignment of the two forming rollers in the known Formkalandrierungs method is a segmentation of the forming rollers in single roller discs, each with only one or a few tracks of pits and arbitrary to a multi-lane Roller can be combined, impossible because of calendering occurring pressing forces the individual segments easily be "twisted". However, this twisting causes the Upper and lower halves of tablet forms at rotation not exactly above each other. The segmentation of the forming rolls is however, desirable, e.g. in case of damage to individual Cavities only one roller disc and not the entire roller replace to have or to arbitrary shapes in a roller to be able to combine.

It has already been proposed, a molding roll, on its Surface depressions contributes, with a second roller to combine, which contains no depressions (smooth roller). Here eliminates the need for the exact alignment of the two Rolling each other. The disadvantage here, however, that at least one of the two rolls still be made consuming got to. In addition, the possibilities of designing the tablet forms restricted in this combination.

DE4446470A discloses a process for producing divisible Tablets by melt calendering, wherein two molding rolls combined, of which at least one well Has at least one bridge, extending to the generatrix the forming roll extends and the formation of a breaking groove causes. A mold calender with two counter-rotating molding rolls, along their circumference extending annular grooves and along Wraparound rings from radially outward having extending teeth which engage in the annular grooves is known from WO97 / 36722A for briquette production.

The present invention is therefore based on the object simple and inexpensive process for the production of solid To provide dosage forms with no problems with respect to an offset of upper and lower half of the dosage forms occur.

Surprisingly, it has been found that this object is achieved is when the forming rollers are designed on their surface, that they can mesh.

a) Herstellen eines plastischen Gemisches, das wenigstens einen Wirkstoff und wenigstens ein polymeres Bindemittel enthält, und

b) Formen des plastischen Gemisches zu den festen Dosierungsformen in einem Formkalander mit zwei gegenläufig rotierenden Formwalzen, dadurch gekennzeichnet, dass eine Formwalze wenigstens eine entlang ihres Umfangs verlaufende Ringnut und die andere Formwalze wenigstens einen entlang ihres Umfangs verlaufenden Kranz von radial sich nach außen erstreckenden Zähnen aufweist, die in die Ringnut eingreifen können. Die Zähne sind so geformt, dass sie bei maximalem Eingriff in die Ringnut den Querschnitt der Ringnut im Wesentlichen vollständig ausfüllen, d.h. das Querschnittsprofil der Ringnut und der Zähne sind im wesentlichen komplementär.

The present invention therefore provides a process for the preparation of solid dosage forms

a) preparing a plastic mixture containing at least one active ingredient and at least one polymeric binder, and

b) forming the plastic mixture into the solid dosage forms in a mold calender with two counter-rotating mold rolls, characterized in that one mold roll has at least one annular groove running along its circumference and the other mold roll at least one ring extending along its circumference of radially outwardly extending teeth has, which can engage in the annular groove. The teeth are shaped to substantially completely fill the cross-section of the annular groove at maximum engagement with the annular groove, ie the cross-sectional profile of the annular groove and the teeth are substantially complementary.

Due to the "meshing" of the forming rollers eliminates the need the exact alignment of the two single rollers to each other, because only one roller of the roller pair has an angle-dependent surface structure having. It is therefore possible, much simpler Machine constructions for receiving the forming rollers Calender to choose.

Form rolls to be used according to the invention are known as "prism rolls" known from compacting technology. It will be on B. Pietsch, Processing Technique 3 (1970) pp. 128-138. There, the use of such rolls for solidifying flowable Bulk goods to granules described. Problems of a possible offset between the upper and lower half of the formed Comprimate are not addressed in this context.

Roller pairs to be used according to the invention allow, in spite of simple roll construction a considerable variety of shapes the solid dosage forms so prepared. The variations concern primarily the formation of the annular groove and the formation of the gap between successive ones Teeth of a wreath. So the ring groove can be a number of different Cross-sectional profiles (projection onto a plane, the the roll axis contains). The annular groove can be a rectangular, triangular, rounded or any other cross-section respectively. In general, it is preferred that the annular groove for easier to demould the shaped dosage forms into a rounded one Has cross-sectional profile.

The longitudinal profile of the spaces between successive Teeth of a wreath (i.e., the projection of the gap on a plane perpendicular to the roll axis) is also subject to one Variation. Thus, the spaces between triangular, parallelogram, have rounded or another longitudinal profile. In general, however, it is preferred that the spaces between successive teeth of a wreath a rounded one Have longitudinal profile.

The resulting dosage forms can be prepared in this way e.g. Prism shape, Prismatic stump shape, tetrahedral shape or caliper shape have, wherein the caliper shape is preferred.

In a preferred embodiment of the method according to the invention is located at the bottom of the annular groove a circumferential ridge and the teeth have a corresponding recess. To this Way is the production of divisible tablets on one Side of their surface have a breaking notch, possible.

Between successive teeth of a wreath may be also a bridge are located, not to the outer surface the roller extends. In this way is also the production divisible tablets with a break notch possible.

In order to remove the formed dosage forms from the annular groove, or the interdental spaces, it is possible, the To keep low contact pressure between the two forming rollers or a small distance between the forming rolls, e.g. 0.1-1 mm, provided. In this way, a "tablet band" is obtained, in the individual dosage forms still over narrow ridges with each other are connected. The individual dosage forms can, especially when the plastic mixture after the complete Cooling shows a higher brittleness, slightly separated from each other become. It may be appropriate to the dosage forms obtained then deburr.

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

The present process for the preparation of solid dosage forms involves the production of a plastic mixture. This is usually done by mixing and melting of at least a pharmacologically acceptable polymeric binder, at least one pharmaceutical agent and, where appropriate customary pharmaceutical additives in the presence or absence of a solvent. These process steps can be based on known Way to be done.

The components can first be mixed and then melted and homogenized. Especially when using sensitive However, active ingredients have proven to be preferred First, the polymeric binder, optionally together with conventional pharmaceutical additives, melt and premix, wherein the stirred tank, stirrers, solid mixers, etc. optionally be operated alternately, and then the (the) sensitive Active substance (s) in "intensive mixers" in plastic Phase at very small residence times (homogenize). The active ingredient (s) may be in solid form or be used as a solution or dispersion.

The melting and mixing takes place in one for this purpose usual device. Particularly suitable extruders or heated Container with stirrer, e.g. Kneader, (like the one below mentioned kind).

As a mixing apparatus, such devices are useful, the used in plastic technology for mixing. suitable Devices are for example described in "Mixing in the production and processing of plastics ", H. Pahl, VDI-Verlag, 1986. Particularly suitable mixing apparatuses are extruders and dynamic and static mixers, as well as stirred tank, single-shaft Stirrers with stripping devices, in particular so-called Paste agitators, multi-shaft agitators, in particular PDSM mixers, Solid mixers and preferably mixing kneading reactors (e.g., ORP, CRP, AP, DTB from List or Reactotherm Company) Krauss-Maffei or Ko-Kneader Fa. Buss), Doppelmuldenkneter (Trough mixer) and stamp mixer (internal mixer) or rotor / stator systems (e.g., Dispax from IKA).

For sensitive drugs, the first is preferably the first Melting of the polymeric binder in an extruder and then admixing the active ingredient in a mixing-kneading reactor. For less sensitive drugs, on the other hand, you can Intensive dispersion of the active ingredient a rotor / stator system use.

The charging of the mixing device takes place depending on their design continuously or discontinuously in the usual way. Powdered components may be in free feed, e.g. over a Differential dosing be introduced. Plastic masses can fed directly from an extruder or via a gear pump, especially at high viscosities and high pressures is beneficial to be fed. Liquid media can over a suitable pump unit are metered.

By mixing and melting the binder, the active ingredient and optionally the additive or additives Mixture is doughy to viscous (thermoplastic) and therefore also extrudable. The glass transition temperature of the mixture is below the decomposition temperature of all contained in the mixture Components. The binder should preferably be in physiological Environment be soluble or swellable. examples for 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 (Eudragit types), Copolymers of methyl methacrylate and acrylic acid, cellulose esters, Cellulose ethers, in particular methylcellulose and ethylcellulose, Hydroxyalkylcelluloses, in particular hydroxypropylcellulose, Hydroxyalkyl-alkylcelluloses, in particular hydroxypropyl-ethylcellulose, Cellulose phthalates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, and mannans, in particular galactomannans. The K values (after H. Fikentscher, Cellulose Chemistry 13 (1932), pages 58-64, 71, 74) of the polymers are in the range of 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, Alkylcelluloses and hydroxyalkylcelluloses. The polymeric Binder must be in the total mixture of all components in the Range from 50 to 180 ° C, preferably 60 to 130 ° C soften or melt. The glass transition temperature of the mixture must therefore below 180 ° C, preferably below 130 ° C. if necessary It is made by usual, pharmacologically acceptable softening Reduced excipients. The amount of plasticizer is at most 30 wt .-%, based on the total weight of binder and plasticizers to form storage-stable dosage forms, that 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 propylene glycols, silicones, aromatic carboxylic acid esters (e.g., dialkyl phthalates, trimellitic acid esters, benzoic acid esters, Terephthalic acid ester) or aliphatic dicarboxylic acid esters (e.g., dialkyl adipates, sebacic acid esters, azelaic acid esters, citric acid). and tartaric acid esters), fatty acid esters, such as glycerol mono-, Glycerine di- or Glycerintriacetat or Natriumdiethylsulfosuccinat. The concentration of plasticizer is generally 0.5 to 15, preferably 0.5 to 5 wt .-%, based on the total weight of the mixture.

Usual galenic adjuvants, their total amount up to 100 % By weight, based on the polymer, are e.g. Extenders or fillers, such as silicates or silica, magnesium oxide, Alumina, titania, 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 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.

Plasticizers, 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 C ₁₂ , C ₁₄ , C ₁₆ and C ₁₈ fatty 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 is preferred are;

Stabilizers, such as antioxidants, light stabilizers, hydroperoxide destroyers, Radical scavengers, stabilizers against microbial Infestation.

Furthermore, wetting, preserving, blasting, adsorption, mold-separating and blowing agents are added (see, e.g., H. Sucker et al. Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978).

Among excipients according to the invention are also substances for preparing a solid solution with the pharmaceutical To understand the active substance. These adjuvants are for example Pentaerythritol and pentaerythritol tetracaetate, polymers such as e.g. Polyethylene or polypropylene oxides and their block copolymers (Poloxamers), phosphatides such as lecithin, homo- and copolymers of Vinylpyrrolidones, surfactants such as polyoxyethylene-40-stearate and citric and succinic acid, bile acids, sterols and others like e.g. in J.L. Ford, Pharm. Acta Helv. 61 (1986) pp. 69-88.

As pharmaceutical auxiliaries also additives of bases and Acids to control the solubility of an active agent (see for example, K. Thoma et al., Pharm. Ind. 51 (1989) 98-101).

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

Pharmaceutical active substances in the context of the invention are to be understood as meaning all substances having a pharmaceutical action and the lowest possible side effects, provided that they do not decompose under the processing conditions. 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, as well as plant treatment agents and insecticides. The vitamins include the vitamins of the A group, the B group, which in addition to B ₁ , B ₂ , B ₆ and B ₁₂ and nicotinic acid and nicotinamide compounds with vitamin B properties are understood, 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 within the meaning of the invention also include peptide therapeutics.

The inventive method is for example for processing suitable for the following active substances:

Acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alfacalcidol, Allantoin, allopurinol, alprazolam, ambroxol, amikacin, Amiloride, aminoacetic acid, 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, cefachlor, cefadroxil, cefalexin, Cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, Chloramphenicol, chlorhexidine, chloropheniramine, chlortalidone, Choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, Cisapride, cisplatin, clarithromycin, clavulanic acid, clomipramine, Clonazepam, clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid, Cyanocobalamin, cyproterone, desogestrel, dexamethasone, Dexpanthenol, dextromethorphan, dextropropoxiphene, diazepam, Diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxine, Diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramide, Domperidone, dopamine, doxocycline, enalapril, ephedrine, epinephrine, Ergocalciferol, ergotamine, erythromycin, estradiol, Ethinyl estradiol, etoposide, eucalyptus globulus, famotidine, felodipine, Fenofibrate, fenoterol, fentanyl, flavin mononucleotide, Fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, Folinic acid, furosemide, gallopamil, gemfibrozil, gentamicin, Gingko biloba, glibenclamide, 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, Ketotifen, Ketoconazole, Ketoprofen, Ketorolac, Labetalol, Lactulose, lecithin, levocarnitine, levodopa, levoglutamide, 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, Norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, Ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, Paracetamol, penicillin G, penicillin V, pentoxifylline, Phenobarbital, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, Phenytoin, piroxicam, polymyxin B, povidone-iodine, Pravastatin, prazepam, prazosin, prednisolone, prednisone, propafenone, Propranolol, proxyphylline, pseudoephedrine, pyridoxine, quinidine, Ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, Rutoside, saccharin, salbutamol, salcatonin, salicylic acid, Selegiline, simvastatin, somatropin, sotalol, spironolactone, sucralfate, Sulbactam, sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, Tegafur, Teprenon, Terazosin, Terbutaline, Terfenadine, Tetracycline, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, Tretinoin, triamcinolone acetonide, triamterene, trimethoprim, Troxerutin, uracil, valproic acid, vancomycin, verapamil, Vitamin E, zidovudine.

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

In particular, it can lead to the formation of solid solutions. The term "solid solutions" is familiar to the person skilled in the art, for example from the literature cited above. In solid solutions of pharmaceutical active ingredients in polymers is the Active ingredient molecular dispersion in the polymer before.

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

The solid obtainable by the process according to the invention Finally, pharmaceutical forms can also be used in conventional Be provided with film coatings, which the drug release control or cover the taste. suitable Materials for such coatings are polyacrylates, such as the Eudragit types, Cellulose esters, such as the hydroxypropylmethylcellulose phthalates, and cellulose ethers such as ethyl cellulose, hydroxypropylmethyl cellulose or hydroxypropylcellulose.

With the method according to the invention it is thus possible, especially produce exactly sized dosage forms. Surprisingly This method is cheap, leaves very large quantities achieve per unit time and avoids any waste.

The figures illustrate the invention without limiting it. The Figures 1 to 3 will be briefly described below.

Figur 1: Verschiedene Ausführungen der erfindungsgemäß in einer Walze vorhandenen Ringnut;

Figur 2: Verschiedene Ausführungen der Zwischenräume zwischen aufeinanderfolgenden Zähnen eines erfindungsgemäß auf einer Walze vorhandenen Kranzes von Zähnen und die damit erhältlichen Dosierungsformen;

Figur 3: Das Konstruktionsprinzip eines erfindungsgemäß zu verwendenden Walzenpaars an einem konkreten Beispiel.

In the drawings shows:

Figure 1: Various embodiments of the invention present in a roll annular groove;

Figure 2: Different embodiments of the spaces between successive teeth of a present invention on a roller ring of teeth and the dosage forms available therewith;

FIG. 3: The construction principle of a roller pair to be used according to the invention on a concrete example.

In Figure 1, various embodiments of the annular groove in cross section shown. The ring groove can be rectangular (a), triangular (b) or rounded (c) have cross-sectional profile. On the ground the annular groove may be a circumferential web (d), the leads to solid dosage forms on one side of their surface have a breaking notch.

According to Figure 2, depending on the design of the spaces between successive teeth of a ring available dosage forms with prismatic shape (a), prismatic stump shape (b) or Saddle body shape (c) shown.

FIG. 3 illustrates the design principle of a pair of rollers with two tracks, one roller having two circumferential annular grooves having rounded cross-sectional profile and the other roller two circumferential rings extending radially outward Having teeth, wherein the spaces between successive Teeth have a rounded longitudinal profile. Figure 3 shows above a cross section of the roller pair through the roller axes. Figure 3 shows below a cross section of the roller pair perpendicular to the roll axes.

Claims (5)

1. 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.
2. A process as claimed in claim 1, wherein the annular groove has a rounded cross-section profile.
3. A process as claimed in claim 1 or 2, wherein the interstices between consecutive teeth in a ring have a rounded longitudinal profile.
4. A process as claimed in any of the preceding claims, wherein a circulating bar is present on the base of the annular groove, and the teeth have a corresponding recess.
5. A process as claimed in any of the preceding claims, wherein the resulting dosage forms are deflashed.

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