(19) TZZ ¥_T (11) EP 2 285 355 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/20 (2006.01) A61J 3/10 (2006.01) 24.01.2018 Bulletin 2018/04 B01J 2/22 (2006.01) B07B 7/00 (2006.01) (21) Application number: 09742166.3 (86) International application number: PCT/EP2009/055628 (22) Date of filing: 08.05.2009 (87) International publication number: WO 2009/135948 (12.11.2009 Gazette 2009/46) (54) PROCESS FOR PREPARING A HIGH DRUG LOAD TABLET VERFAHREN ZUR HERSTELLUNG EINER TABLETTE MIT HOHEM WIRKSTOFFGEHALT PROCÉDÉ POUR PRÉPARER UN COMPRIMÉ À FORTE CHARGE EN SUBSTANCE MÉDICAMENTEUSE (84) Designated Contracting States: • HEILAKKA, Erkki AT BE BG CH CY CZ DE DK EE ES FI FR GB GR FI-00950 Helsikni (FI) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR (74) Representative: Teuten, Andrew John et al Sagittarius IP (30) Priority: 09.05.2008 FI 20080352 Three Globeside Fieldhouse Lane (43) Date of publication of application: Marlow, Buckinghamshire SL7 1HZ (GB) 23.02.2011 Bulletin 2011/08 (56) References cited: (73) Proprietor: Atacama Labs Oy WO-A1-98/35672 WO-A1-99/11261 00100 Helsinki (FI) WO-A1-99/25343 WO-A1-2006/066930 WO-A1-2009/101258 WO-A2-2008/056021 (72) Inventors: WO-A2-2009/135950 WO-A2-2009/135951 • POLITI, Giovanni US-A1- 2004 126 429 FI-00310 Helsinki (FI) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 285 355 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 285 355 B1 2 Description applications"written by Peter Kleinebudde and published in European Journal of Pharmaceutics and Biopharma- TECHNICAL FIELD OF INVENTION ceutics 58 (2004) at pages 317-326. [0007] Direct compression is generally considered to [0001] The invention relates to a method for preparing 5 be the simplest and the most economical process for a tablet involving dry granulation as claimed. producing tablets. However, it may only be applied to materials that do not need to be granulated before tab- BACKGROUND OF THE INVENTION leting. Direct compression requires only two principal steps; i.e., the mixing of all the ingredients and the com- [0002] Tablets are one of the most frequently em-10 pression of this mixture. However, direct compression is ployed delivery forms for most medicinal preparations. applicable to only a relatively small number of substances This situation can be explained by the fact that this dos- as the ingredients of the tablets often need to be proc- age form allows for accurate dosage of the active com- essed by some granulation technique to make them com- ponent of the medicinal formulation. Furthermore, han- pressible and/or for improving their homogeneity and dling and packaging are easier and shelf life and stability 15 flow-ability. of these preparations are generally better than those of [0008] A component of a tablet is usually described as other formulations. being either an excipient or an active ingredient. Active [0003] These same arguments also explain the reason ingredients are normally those that trigger a pharmaceu- whytablets are often used asmedia for other applications tical, chemical or nutritive effect and they are present in such as food, including confectionery products, aromas 20 the tablet only in the amount necessary to provide the or sweeteners, detergents, dyes or phytosanitary prod- desired effect. Excipients are inert ingredients that are ucts. included to facilitate the preparation of the dosage forms [0004] A solid bulk of granulate mass, which is neces- or to adapt the release characteristics of the active in- sary for manufacturing tablets, can be manufactured us- gredients, or for other purposes ancillary to those of the ing two main processes, wet granulation or dry granula- 25 active ingredients. tion. Tablets may also be manufactured using direct com- [0009] Excipients can be characterized according to pression. Direct compression relates to the tableting their function in the formulation as, for instance, lubri- process itself rather than preparation of the starting ma- cants, glidants, fillers (or diluents), disintegrants, binders, terial. flavors, sweeteners and dyes. [0005] In wet granulation, components are typically 30 [0010] Lubricants are intended to improve the ejection mixed and granulated using a wet binder. The wet gran- of the compressed tablet from the die of the tablet-making ulates are then sieved, dried and optionally ground prior equipment and to prevent sticking in the punches. to compressing into tablets. Wet granulation is used ex- [0011] Glidants are added to improve the powder flow. tensively in the pharmaceutical industry although it has They are typically used to help the component mixture provento be a difficult method, mainlybecause the liquids 35 to fill the die evenly and uniformly prior to compression. needed in the granule and tablet manufacturing process [0012] Fillers are inert ingredients sometimes used as often have an adverse effect on the characteristics of the bulking agents in order to decrease the concentration of active pharmaceutical ingredients (APIs) and/or on the the active ingredient in the final formulation. Binders in end product such as a tablet. many cases also function as fillers. [0006] Dry granulation is usually described as a meth- 40 [0013] Disintegrants may be added to formulations in od of controlled crushing of precompacted powders den- order to help the tablets disintegrate when they are sified by either slugging or passing the material between placed in a liquid environment and so release the active two counter-rotating rolls. More specifically, powdered ingredient. The disintegration properties usually are components that may contain very fine particles are typ- based upon the ability of the disintegrant to swell in the ically mixed prior to being compacted to yield hard slugs 45 presence of a liquid, such as water or gastric juice. This which are then ground and sieved before the addition of swelling disrupts the continuity of the tablet structure and other ingredients and final compression to form tablets. thus allowsthe differentcomponents toenter into solution Because substantially no liquids are used in the dry gran- or into suspension ulation process, the issues related to wet granulation are Binders are used to hold together the structure of the avoided. Although dry granulation would in many cases 50 tablets. They have the ability to bind together the other appear to be the best way to produce products such as ingredients after sufficient compression forces have tablets containing APIs, it has been relatively little used been applied and they contribute to the integrity of the because of the challenges in producing the desired kind tablets. of granules as well as managing the granulated material [0014] Finding the proper excipients for particular APIs in the manufacturing process. Known dry granulation 55 and determining the proper manufacturing process for methods, as well as the known issues related to them the combination of excipients and APIs can be a time- are well described in scientific articles, such as the review consuming job that may lengthen the design process of article "Roll compaction / dry granulation: pharmaceutical a pharmaceutical product, such as a tablet significantly, 2 3 EP 2 285 355 B1 4 even by years. maceutical industry, to use dry granulation techniques [0015] Both the dry and wet granulation methods of whenever possible. However, the dry granulation meth- the prior art may produce solid bridges between particles ods known in the prior art produce granules that are sel- within granules that may be undesirable for example in dom usablein atablet manufacturingprocess. Conflicting that they lead to unsatisfactory subsequent tablet char- 5 process design parameters often lead to compromises acteristics. The solid bridges may be caused by partial where some qualities of the resulting granule product melting, hardening binders or crystallization of dissolved may be good, but other desirable qualities are lacking or substances. Partial melting may for example occur when absent. For example, the flow characteristics of the gran- high compaction force is used in dry granulation meth- ules may be insufficient, the non-homogeneity of the ods. When the pressure in the compaction process is 10 granules may cause segregation in the manufacturing released, crystallization of particles may take place and process or capping in tablets, or some of the granules bind the particles together. Introduction of hardening may exhibit excessive hardness, all of which can make binders is common in pharmaceutical wet granulations the tableting process very difficult, slow and sometimes when a binder is included in the granulating solvent. The impossible. Furthermore, the bulk granules may be diffi- solvent forms liquid bridges, and the binder will harden 15 cult to compress into tablets. Alternatively or additionally, or crystallize on drying to form solid bridges between the the disintegration characteristics of the resulting tablets particles. Examples of binders which can function in this may be sub-optimal. Such problems commonly relate to way are polyvinylpyrrolidone, cellulose derivatives (e.g. the non-homogeneity and granule structure of the gran- carboxymethylcellulose) and pregelatinized starch. Sub- ulate mass produced by the compactor. For instance, the stances, e.g. lactose, which can dissolve during a wet 20 mass may have too high a percentage of fine particles granulation process may subsequently crystallize on dry- or some granules produced by the compactor may be ing acting as a hardening binder.