(12) Patent Application Publication (10) Pub. No.: US 2005/0202088 A1 Hanshermann Et Al
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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.