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US 20050202088A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0202088 A1 Hanshermann et al. (43) Pub. Date: Sep. 15, 2005

(54) PHARMACEUTICAL COMPOSITION (86) PCT No.: PCT/EP03/05115 HAVING A DELAYED ACTIVE SUBSTANCE RELEASE, AND METHOD FOR THE (30) Foreign Application Priority Data PREPARATION THEREOF May 31, 2002 (DE)...... 102 24 170.8 (76) Inventors: Franke Hanshermann, Tangstedt (DE); Peter Lennartz, Hamburg (DE); Jorn Publication Classification Raimer, Hamburg (DE) (51) Int. Cl." ...... A61K 9/24 Correspondence Address: (52) U.S. Cl...... 424/471; 264/109 MARSHALL, GERSTEIN & BORUN LLP (57) ABSTRACT 233 S. WACKER DRIVE, SUITE 6300 SEARS TOWER A pharmaceutical composition with Sustained drug release is CHICAGO, IL 60606 (US) described which is obtainable by a Specific compaction process wherein organic Solvents and water are not required (21) Appl. No.: 10/516,268 and which is preferably in form of Single drug compartments or which disintegrates into Such compartments upon contact (22) PCT Filed: May 15, 2003 with aqueous media. US 2005/0202088 A1 Sep. 15, 2005

PHARMACEUTICAL COMPOSITION HAVING A 0007 Briquetting represents a further possibility for the DELAYED ACTIVE SUBSTANCE RELEASE, AND dry preparation of granulated materials. During this process, METHOD FOR THE PREPARATION THEREOF the active ingredient is tabletted alone or together with 0001. The invention relates to a pharmaceutical compo excipients into large briquettes which are then further Sition with Sustained drug release, which is present in crushed to the desired size. particular in the form of a multiple unit dosage form, and a 0008. The aim of all these dry granulation processes is to proceSS for its preparation. compact the Substances used in order to improve their flow 0002. In the development of pharmaceutical composi properties or also improve their compressibility, e.g. during tions with Sustained release of the active ingredient, So a Subsequent tabletting. called multiple unit dosage forms (MUDs) are to be pre 0009. In WO 00/08092, the preparation of polyacrylic ferred over single unit dosage forms (SUDs) because of acid granulates by compression between two rollerS is various advantages. The multiple unit dosage forms repre described. The granulated material prepared is then mixed Sent orally administered compositions which are either with theophylline as drug and further tabletting excipients already present in the form of a plurality of functional drug and pressed into tablets with Sustained release of the active compartments or decompose after intake into Such func ingredient. tional drug compartments. They thus make possible an optimum therapy from biopharmaceutical aspects. For 0010 Furthermore, microtablets with a high theophylline example, the release of the active ingredient from them is content in a polymer matrix were prepared by H. Rey et al. largely independent of the Stomach fill level of the patient in Drug Development and Industrial Pharmacy 26, 21-26 and a very uniform release of the active ingredient is (2000). The microtablets displayed a sustained release of the achieved even with different patients. Finally the phenom active ingredient and were prepared from granulate in a enon of so-called "dose dumping” is avoided (cf. J. Butler et tablet preSS. It was also established that the compression al., Pharm. Technol. 1998, pages 122 to 138). By “dose preSSure used during the tabletting had no influence what dumping” is meant the uncontrolled, rapid release of all or Soever on the release behaviour of the active ingredient. a large part of the drug dose from a dosage form which is 0011 Paul J. Scheskey et al. describe in Pharm. Technol. actually intended to release the drug in a Sustained and Eur, 11/11, 18-35 (1999) the compaction of mixtures of controlled manner. theophylline with hydroxypropylmethyl cellulose using roll 0003. The drug compartments of a multiple unit dosage ers. During the compaction the roller temperature was kept form ideally measure 2 mm at most in every direction in at 22 C. with the help of a circulating coolant. The authors Space. Only compartments of this order of magnitude tested the influence of various parameters of the compaction achieve the desired optimum in-vivo release pattern with process and found that the compaction preSSure used had a only a very Small influence being exerted by the type and negligible influence on the release behaviour of drug from quantity of food eaten. corresponding tablets. 0004 Multiple unit dosage forms can be e.g. granulates 0012. A similar result was achieved by Paul J. Scheskey and minitablets with particle sizes of in particular 2 mm at et al. in Pharmaceutical Technology 18, 132-150 (1994) most in every direction in Space or also tablets which when examining Sustained-release tablets with niacinamide decompose after intake to particles containing drug and as drug and methylcellulose or hydroxypropylmethyl cellu measuring in particular 2 mm at most in every direction in lose. The granulate used to prepare the tablets was prepared Space. by compaction using rollers at different preSSures. Although 0005 Multiple unit dosage forms releasing the drug in a a better flow behaviour was able to be achieved, no rela Sustained manner are usually prepared by pelletizing, mini tionship between roller preSSure used and rate of release of or microtabletting or wet granulation. The drug is present in the active ingredient was found. a Sustained-release matrix or the drug compartments are 0013 Furthermore, the process parameters during the dry provided with a Sustained-release film. However, Solvents, granulation of theophylline formulations with Sustained Such as organic Solvents and water, are necessary for all release of active ingredient were examined by P. Scheskey these proceSS Steps. However, organic Solvents are ecologi et. al. in Pharmaceutical Technology 24, 30-52 (2000) with cally and toxicologically unacceptable. The use of water can the aim of transferring these from laboratory Scale to indus also mean that the finished dosage form does not have the trial Scale. Compaction forces per linear length unit of the desired Stability, for which reason costly and uneconomical roller width of 2.8, 3.1 and 3.4 t/inch were used, which in SI drying Steps are necessary as a rule. Also, the use of water units corresponds to 10.8 kN/cm, 12.0 kN/cm and 13.2 can already lead to Stability problems during preparation. kN/cm, respectively. 0006 A known process for the preparation of granulates without Solvents is forced compression, also called compac 0014 All in all the above publications show that the force tion, and Subsequent crushing of the compressed Solids. The exerted by the rollers during the compaction process has a aim of this variant, also called dry granulation, is as a rule negligible influence, or none whatsoever, on the release to improve the flowability or increase the relative density of profile of Sustained-release dosage forms. In every case, the the powdery materials used. The drug can be compressed, compaction was used to influence physical Solids param between two rollers, alone or together with excipients, to eters, but not to achieve a controlled release. produce a Strand, also called a ribbon. This Strand is then 0015. At most, it was found in the case of roller com further crushed into a granulated material which has a paction of a mixture of low-Substituted hydroxypropylm clearly improved flowability compared with the powder ethyl cellulose and acetaminophen that, when the compac mixture used. tion pressure was increased, the rate of release of US 2005/0202088 A1 Sep. 15, 2005 acetaminophen actually increased (cf. Y. Kawashima et al. in 0040 nootropics, Chem. Pharm. Bull. 41, 1827-1831 (1993)). 0041 non-steroid antirheumatics, 0016. There is thus a need for a pharmaceutical compo Sition with Sustained drug release and a process for its 0.042 Sedatives and hypnotics. preparation in which a granulation takes place without the 0043 Preferred representatives of the above groups of help of organic Solvents or water and which allows the active ingredients are: preparation of compositions, in particular in the form of multiple unit dosage forms with excellent Sustained-release 0044) For anticonvulsants in particular effect despite just Small quantities of Sustained-release poly 0045 10-hydroxycarbamazepine C. 0046 3-methyl-5-phenylhydantoin 0.017. This object is achieved by the process according to one of claims 1 to 15 and the pharmaceutical compositions 0047 4-amino-3-hydroxybutyric acid according to claims 16 to 19. 0048 5-methyl-5-(3-phenanthryl)hydantoin 0.018 Surprisingly, it was shown that by selecting a 0049 acetazolamide Specific compaction force and adjusting a specific tempera ture in the rollers used for compacting, pharmaceutical 0050 acetyl pheneturide compositions in the very form of multiple unit dosage forms 0051 albutoin can be obtained which have a Sustained drug release. 0.052 aloxidone 0019. The process according to the invention for the preparation of a pharmaceutical composition with Sustained 0053 aminoglutethimide drug release is characterized in that 0054 aminopentamide 0020 (a) a mixture is provided which contains drug 0055 atrolactamide and a polymer effecting Sustained drug release, 0056 beclemide 0021 (b) the mixture is compressed by passing it between two rollers which have a temperature of 0057 benzodiazepine more than 40 C. and which exert a force in the range 0.058 bromine and bromides from more than 15 and up to 40 kN/cm of roller width on the mixture, 0059) buramate 0022 (c) the compressed mixture is reduced to the 0060 carbamazepine desired particle size and 0061 clobazam 0023 (d) optionally the compressed and reduced 0062) clomethiazole mixture is further processed. 0063 clonazepam 0024. In step (a) a mixture of drug and polymer is provided with the polymer effecting a Sustained drug release. 0064 decimenide AS drugs there can be considered a whole range of Sub 0065 Dilantin stances, and in particular the drug is Selected from one of the following groups: 0.066 dimethadione 0025 alpha- or beta-adrenergics, 0067 diphenylan 0026 alpha- or beta-adrenolytics, 0068 diphenylhydantoin 0027 analgesics, 0069 doxenitoin 0028 antirheumatics, 0070) eterobarb 0029) antiarthritics, 0071 ethadione 0030 , 0072) ethoin 0073 ethosuximide 0031 anticonvulsants, 0032 , 0074 0075) felbamate 0033 antiparkinson agents, 0.076 fluoresone 0034) antipsychotics, 0.077 fosphenytoin 0035) anxiolytics, 0078 gabapentin, 0036 receptor agonists, 0079 hakoseride 0037 antimigraine agents 0080 L-5-hydroxytryptophan and salts derived there 0038 neuroleptics, from and complex compounds and mixtures of these, 0039) neuroprotectives, 0081 lamotrigine US 2005/0202088 A1 Sep. 15, 2005 3

0082) levetiracetam 0125 bietanautine 0083 magnesium Sulphate 0126 0084 mephenytoin 0127 0085 mephobarbital 0128 0.086 metharbital 0129 0.087 methetoin 0130 deprenyl 0088 methsuximide 0131 0089) narcobarbital 0132) diethazine 0090 divalproex sodium 0133) droxidopa 0091 mimetazepam 0.134 0092) nitrazepam 0.135 ethopropazine 0093 oxcarbazepine 0136 ethylbenzhydramine 0094) paramethadione 0137 0.095 phenacemide 0138 levodopa 0096) phenetharbital 0139 0097 pheneturide 0140 0.098 phenobarbital 0141 piroheptine 0099) phensuximide 0.142 0100 phenylmethylbarbituric acid 0143 0101 phenytoin 0144) prodipine 0102 phenytoin Sodium 0145 0103) phethenylate sodium 0146 0104 pregabalin 0147 0105 primidone 0148 terguride 0106 progabide 0149 tiapride 0107 reboxetine 0150 0108) remacemide 0151 0109 rufinamide 0152 hydrochloride 0110. Suclofenide 0153. For antipsychotics, neuroleptics and antidepres 0111 Sulthiame Sants in particular: 0112 talampanel 0154) 0113 tetrantoin 0155) alizapride 0114 tiagabine 0156 0115 topiramate 0157 amisulpride 0116 trimethadione 0158 0117 valproate sodium 0159) befloxatone 0118 valproic acid 0160 benperidol 0119) valpromide 0161 0120 vigabatrin 0162 benzcuinamide 0121 Zonisamide 0163 bietanautine 0122) For antiparkinson agents in particular: 0164 biperiden 0123 amantadine 0165 0.124 benserazide 0166 bromperidol US 2005/0202088 A1 Sep. 15, 2005

0167) budipine 0210) molindone 0168) buramate 0211) moperone 0169 0212 0170) butyrophenone 0213) nemonapride 0171 cabergoline 0214) 0172 carbidopa 0215) opipramol 0173 carbipromin 0216) Oxaflumazine 0174) carphenazine 0217) 0175) 0218) 0176) chlorproethazine 0219) 0177) O220) pericyazine 0178) 0221) perimethazine 0179 clocapramine 0222 0180) clomacran 0223) 0181) clopenthixole 0224 pimozide 0182 clospirazine 0225) pipamperone 0183) clothiapine 0226 piperacetazine 0184 0227) piroheptine 0185 0228 pramipexole 0186 deXetimide 0229) pridinol 0187) diethazine 0230) 0188) diXyrazine 0231) prodipine 0189) 0232) 0190. entacapone 0233 prothipendyl 0191) ethopropazine 0234 0192) ethylbenzhydramine 0235) remoxipride 0193) fluianisone 0236 retigabine 0194) flupentiXole 0237) 0195 0238) ropinirole 0196) 0239) rotigentin 0197) haloperidol 0240 Selegiline 0198) iloperidones 0241) Sertindole 0199. imiclopazine 0242 Spiperone 0200) lazabemide 0243) 0201) levodopa 0244) Sulpride 0202) 0245) Sultopride 0203) 0246 talipexole 0204) memantine 0247) terguride 0205) mepazine 0248 tetrabenazine 0206 0249) 0207 methoxypromazine 0250) thioproperazine 0208) metofenazate 0251) 0209) mofegiline 0252) thiothixene US 2005/0202088 A1 Sep. 15, 2005

0253) thioxanthene 0277 Conventional mixers or mills are used to prepare the mixture. 0254 timiperone 0278 It is preferred that the mixture contains 5 to 90 and 0255 tolcapone in particular 70 to 85 wt.-% of drug. The quantity of polymer in the mixture is preferably 2 to 50 and in particular 5 to 30 0256 trifluoperazine wt.-% of polymer. 0257 trifluperidol 0279 The mixture is then compressed in step (b). The process is in particular that the mixture is transported by 0258 Suitable conveying means, Such as e.g. a conveyor worm, to 0259 trihexyphenidyl hydrochloride the two rollers turning in opposite directions and passed between these two rollers. The rollers have a temperature 0260 greater than 40 C. and for this purpose they are usually provided with a thermostatting apparatus. It is preferred that 0261 the temperature of the rollers does not exceed 100° C. The 0262 For agonists in particular: temperature of the rollerS is particularly preferably in the range from 70 to 90° C. 0263) bromocripitine 0280. It is also important that the rollers exert a force on 0264 fenoldopam the mixture which is in the range from 15 and up to 40 kN/cm of roller width. This force is set as a rule by 0265 lisuride measuring the deformation at the engine frame using wire resistance Strain gauges or by measuring pressures in the 0266 naxagolide hydraulics area and also calibrating the measuring apparatus using force-measurement heads which are mounted between 0267 pergolide the rollers. The force is then controlled via SPC. In this 0268 For neuroprotectives in particular: connection, roller width means the length of the direct connection line between the roller edges. With this definition 0269 B-alanine derivatives used according to the invention, there are no problems in determining the roller width, as can occur e.g. in the case of 0270 dizocilpine rollers with uneven Surfaces. 0271 xaliproden 0281. It was shown that the rollers particularly preferably exert a force on the mixture in the range from 18 to 23 0272 Combinations of drugs can also be used. It is kN/cm of roller width. particularly preferred that the drug is an anticonvulsant, an , an antiparkinson agent, an antipsychotic, an 0282 Customary roller compacters which make it pos anxiolytic or a dopamine receptor agonist. sible to adjust the force exerted on the mixture to be compacted in the range according to the invention and to 0273 Oxcarbazepine, valproic acid or its salts, Sulthiame, heat the rollers to the required temperatures are Suitable for carbamazepine, lamotrigine or levetiracetam are particularly the process according to the invention. Suitable are for preferred. example 3-W-Polygran machines from Gerteis Maschinen Processengineering AG, Jona, Switzerland. 0274 Polymers conventionally used for the sustained release of an active ingredient in pharmaceutical composi 0283 As a result of the compression of the mixture by the tions come into consideration as polymers. Primarily there two rollers, the mixture usually assumes the form of a Strand can be named here polymers or copolymers of acrylic acid which is also called a ribbon. or acrylic acid derivatives or of methacrylic acid and meth 0284. In step (c), the compressed mixture is reduced to acrylic acid derivatives, cellulose polymers, waxes or fats. the desired particle size with particle sizes of 50 to 1000 um Further suitable substances are polyvinylpyrrolidone (PVP), in every direction in Space being preferred. The reducing to PVP derivatives, polyethylene glycol (PEG), PEG deriva the desired particle Size is carried out with customary means, tives, Starch, Starch derivatives, polyvinylchloride, polyeth Such as Screening, milling or breaking. ylene, polyvinyl acetate, polyvinyl , celluloses Such as ethylcellulose, methylcellulose, hydroxypropylmethyl 0285) The compressed and reduced mixture present after cellulose (HPMC), HPMC derivatives, hydroxypropyl cel this step already represents a multiple unit dosage form, i.e. lulose, cellulose acetate, ethylene-Vinyl acetate-copolymer a granulated material which consists of functional drug or polyvinyl acetate-crotonic acid-copolymer. compartments. 0275 An acrylic acid or methacrylic acid polymer, an 0286. In step (d), the compressed and reduced mixture is acrylic acid or methacrylic acid copolymer or a Salt thereof then optionally further processed. The mixture is usually is particularly preferably used as polymers. Mixtures of firstly classified for this purpose, which can be carried out different Substances can also be used as polymers. e.g. with the help of a vibrating Screen. 0276 Furthermore, excipients from the groups colorants, 0287. The classified compacted material can then be flow regulators, lubricants, dry binders, disintegrants and packaged e.g. in capsules or minipacks, i.e. Small pouches Stabilizers can also be added to the drug and the polymer. (Sachets). US 2005/0202088 A1 Sep. 15, 2005

0288. It is likewise possible that the classified compacted 0299 The composition according to the invention is material is pressed directly into tablets together with cus preferably present in the form of capsules, pouches, Styli, tomary excipients. tablets or minitablets. 0289. It is likewise also possible that the classified com 0300 Particularly preferred is a pharmaceutical compo pacted material is Subjected to a wet granulation and the sition which contains (i) more than 25 wt.-% particles granulated material obtained is then pressed into tablets. containing drug and measuring <2 mm in every direction in 0290 The tablets obtained have the advantageous prop Space or (ii) which upon contact with aqueous media disin erties that upon contact with aqueous media they disinte tegrates into more than 25.-% particles containing drug and grate into particles measuring <2 mm in every direction in measuring <2 mm in every direction in Space. Space and thus represent a multiple unit dosage form, just 0301 A mixture of different compacted materials of the like, the classified compacted material. Same drug can also be used in order to arrive in this way at 0291. According to the invention, multiple unit dosage a composition according to the invention which has a forms are preferred which (a) contain more than 25 wt.-% of Specific release profile for the drug. particles containing drug and measuring <2 mm in every 0302) The invention will be explained below in more direction in space or (b) disintegrate in the presence of detail using examples. aqueous media to an extent of more than 25 wt.-% to form particles containing drug and measuring <2 mm in every direction in Space. EXAMPLES 0292. The advantage of such small particles is that they Example 1 can pass through the pylorus unhindered, unlike monolithic dosage forms Such as conventional tablets. Sustained-release Compacted Material 0293 When preparing tablets according to the invention, customary additives Such as lubricants, flow regulators, 0303 Formulation: disintegrants, colorants, plasticizers, anti-adherent agents or 0304 Oxacarbazepine 30 kg binders can also be added to the compacted material. Par ticularly preferred here are microcrystalline cellulose, mag 0305 Ammonium methacrylate copolymer (Eudragit nesium Stearate, Aerosil R 972, Sodiumcarboxymethyl RSPO) 9 kg Starch and triethyl citrate. 0306 The oXcarbazepine is mixed with the ammonium 0294. During the granulation of the compressed and methacrylate copolymer in a high-Shear mixer (Diosna P reduced mixture, aqueous granulation can also take place as 100) for 5 mins. The mixture was then compressed using a the active ingredient is protected by the pretreatment with compactor, namely 3-W-Polygran, Gerteis Maschinen+Pro the polymer. Finally, the finished pharmaceutical composi cessengineering AG, Jona, Switzerland (roller width 10 cm tion can also still be provided with a rapidly disintegrating and roller speed 7 rpm) with a force of more than 15 and up film. to 40 kN/cm of roller width after the rollers were heated to 80 C., thermostat-controlled. The resultant ribbon was 0295) An examination of the compressed and reduced crushed by means of forced Screening (1-mm Screen tray), mixture reveals particles in which the polymer develops a and the compacted material obtained was classified using a coherent matrix which leads to the Sustained release of the vibrating Screen (Engelmann Screen channel with 0.25 drug. SEM photoS accordingly show particles with a homo Screen tray). The classified compacted material was then geneous structure, and particles of the Starting material are packed into hard gelatin capsules of sizes 3, 2, 1 and 0 on a no longer recognizable. It is assumed that, as a result of the capsule-packing machine. Dosage units of 150 to 300 mg of high compression of the mixture which took place in Step (b) drug per Single dose resulted. and the brief increase in temperature introduced via the rollers, a flowing of the polymer around the drug particles 0307 The classified compacted material was also packed results without the polymer entering into a liquid aggregate into Small pouches, also called minipacks or Sachets, on a State. bagging machine. Dosage units of 50 to 2400 mg per Single 0296 At any rate it can be established that even without dose thereby resulted. the use of organic Solvents and water, pharmaceutical com positions are obtained with the process according to the Example 2 invention from which the drug is released in a Sustained manner, although according to the State of the art the Sustained-release Granulated Material compaction used merely Served to improve the flow or increase of density of the compacted material. 0308 Formulation: 0297. It was shown that the compositions obtained according to the invention released the drug over a period of Oxcarbazepine 30 kg up to 8 hours. However, a composition with rapid release Ammonium methacrylate copolymer (Eudragit RSPO) 9 kg obtained in conventional manner examined under the same (1st part) conditions already released the drug within an hour. 30- % ammonium methacrylate copolymer dispersion 2.5 kg in water (Eudragit RS 30 D) 0298 Finally therefore the invention also relates to a Ammonium methacrylate copolymer (Eudragit RSPO) 2.5 kg pharmaceutical composition which is obtainable by the (2nd part) process according to the invention. US 2005/0202088 A1 Sep. 15, 2005

-continued -continued Talcum 0.9 kg Sodiumcarboxymethyl starch 0.2 kg Triethyl citrate 0.2 kg Magnesium stearate 0.5 kg Microcrystalline cellulose 5.8 kg 0309 The oXcarbazepin was firstly mixed with the first part of the ammonium methacrylate copolymer in a high 0315. The oXcarbazepine was mixed with the first part of Shear mixer for 5 mins. The mixture was then compacted on the ammonium methacrylate copolymer in a high-Shear a compactor at 20 kN/cm of roller width after the rollers mixer for 5 mins. The mixture was then compacted on a were heated to 80° C. The resulting ribbon was then crushed roller compactor at 20 kN/cm of roller width after the rollers using forced Screening and the resultant compacted material were heated to 80 C. The resultant ribbon was crushed was classified using a vibrating Screen. The classified com using forced Screening and the resultant compacted material pacted material was then mixed in a fluidized-bed granulator was classified using a vibrating Screen. The classified com (Glatt WSG 60) with the second part of the ammonium pacted material was then mixed in a fluidized-bed granulator methacrylate copolymer and granulated with the help of the with the Second part of the ammonium methacrylate copoly aqueous ammonium methacrylate copolymer dispersion mer and granulated with the aqueous polymer dispersion accompanied by the addition of triethyl citrate and talcum. with the addition of triethylcitrate and talcum. 0310. The granulated material obtained was packed into 0316 The granulated material was then mixed with hard-gelatin capsules of sizes 3, 2, 1 and 0 on a capsule Sodium carboxymethyl Starch, magnesium Stearate and packing machine. Dosage units of 150 to 300 mg active microcrystalline cellulose and pressed into tablets resulting ingredient per Single dose thereby resulted. in dosage units between 150 and 600 mg. 0311. The classified compacted material was furthermore 1. Process for the preparation of a pharmaceutical com packaged in pouches on a bagging machine and dosages of position with Sustained drug release wherein 500 to 2400 mg per individual dose thereby resulted. (a) a mixture is provided which contains a drug and a Example 3 polymer effecting Sustained drug release, (b) the mixture is compressed by passing it between two Sustained-release Tablet from Compacted Material rollers which have a temperature of more than 40 C. and which exert a force in the range from more than 15 0312 Formulation: and up to 40 kN/cm of roller width on the mixture, and (c) the compressed mixture is reduced to the desired particle size. Oxcarbazepine 30 kg Ammonium methacrylate copolymer 9 kg 2. Process according to claim 1, wherein the rollers have Sodiumcarboxymethyl starch 0.2 kg a temperature of up to 100° C. Magnesium stearate 0.5 kg 3. Process according to claim 2, wherein the rollers have Microcrystalline cellulose 10.3 kg a temperature in the range from 70 to 90° C. 4. Process according to claim 1, wherein the rollers exert a force on the mixture in the range from 18 to 23 kN/cm of 0313 The oXcarbazepine was mixed with the ammonium roller width on the mixture. methacrylate copolymer in a high-Shear mixer for 5 mins. 5. Process according to claim 1, wherein the mixture The mixture obtained was then compacted on a roller contains 5 to 90 wt.% drug. compacter at 20 kN/cm after the rollers were heated to 80 6. Process according to claim 5, wherein the mixture C. The resultant ribbon was crushed using forced Screening contains 2 to 50 wt.% polymer. and the compacted material obtained was classified using a 7. Process according to claim 1, wherein the drug is Vibrating Screen. The compacted material was then mixed Selected from the group consisting of with the Sodiumcarboxymethyl Starch, the magnesium Stear ate and the microcrystalline cellulose and pressed into alpha- or beta-adrenergics, tablets resulting in dosage units between 150 and 600 mg. alpha- or beta-adrenolytics, Example 4 analgesics;

Sustained-release Tablets from Granulated Material antirheumatics, antiarthritics, 0314 Formulation: anticholinergics, anticonvulsants, Oxcarbazepine 30 kg Ammonium methacrylate copolymer (1 part) 9 kg antidepressants, 30- % ammonium methacrylate copolymer dispersion 2.5 kg Ammonium methacrylate copolymer (2" part) 2.5 kg antiparkinson agents, Talcum 0.9 kg antipsychotics, Triethyl citrate 0.2 kg anxiolytics, US 2005/0202088 A1 Sep. 15, 2005

dopamine receptor agonists, 13. Process according to claim 19, wherein in step (d) the mixture is classified. antimigraine agents, 14. Process according to claim 19, wherein in step (d) the neuroleptics, mixture is packaged in capsules or pouches. 15. Process according to claim 19, wherein in step (d) the neuroprotectives, mixture is processed to tablets. non-Steroid antirheumatics, 16. Pharmaceutical composition which is obtainable by the process of claim 1. nootropics, 17. Pharmaceutical composition according to claim 16, Sedatives, which is in the form of capsules, pouches, Styli, tablets or hypnotics, and combinations thereof. minitablets. 8. ProceSS according to claim 7, wherein the drug is an 18. Pharmaceutical composition according to claim 16, anticonvulsant, an antidepressant, an antiparkinson agent, an which contains (i) more than 25 wt.% particles containing antipsychotic, an anxiolytic or a dopamine receptor agonist. drug and measuring <2 mm in every direction in space or (ii) 9. Process according to claim 8, wherein the drug is which upon contact with aqueous media disintegrates into oXcarbazepine, Valproic acid or a Salt thereof, Sulthiame, more than 25 wt.% particles containing drug and measuring carbamazepine, lamotrigine or levetiracetam. <2 mm in every direction in Space. 10. ProceSS according to claim 1, wherein the polymer is 19. Process according to claim 1, further including Step an acrylic acid polymer or acrylic acid copolymer or a Salt (d) further processing the compressed and reduced mix thereof. ture. 11. Process according to claim 1, wherein the mixture in 20. Process according to claim 19, wherein in step (d) the Step (a) also contains at least one Substance Selected from the mixture is granulated. group consisting of a colorant, a flow regulator, a lubricant, 21. ProceSS according to claim 20, wherein the granulated a dry binder, a disintegrant and a Stabilizer. mixture is processed to tablets. 12. ProceSS according to claim 1, wherein the mixture in step (c) is reduced to a particle size of 50 to 1000 um. k k k k k