(19) TZZ¥_ ZZ_T (11) EP 3 124 008 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 01.02.2017 Bulletin 2017/05 A61J 3/06 (2006.01) (21) Application number: 16189646.9 (22) Date of filing: 04.11.2011 (84) Designated Contracting States: • LEFEBVRE, Didier AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Mundelein, IL 60060 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • WIESNER, Bryan PL PT RO RS SE SI SK SM TR Lake Forest, IL 60045 (US) Designated Extension States: • BREITENBACH, Joerg BA ME 68199 Mannheim (DE) • KESSLER, Thomas (30) Priority: 04.11.2010 US 410344 P 67105 Schifferstadt (DE) (62) Document number(s) of the earlier application(s) in (74) Representative: Modiano, Micaela Nadia et al accordance with Art. 76 EPC: Modiano & Partners 11785864.7 / 2 635 247 Thierschstrasse 11 80538 München (DE) (71) Applicants: • AbbVie Inc. Remarks: North Chicago, IL 60064 (US) This application was filed on 20.09.2016 as a • AbbVie Deutschland GmbH & Co. KG divisional application to the application mentioned 65189 Wiesbaden (DE) under INID code 62. (72) Inventors: • GHOSH, Soumojeet Gurnee, IL 60031 (US) (54) METHOD FOR PRODUCING MONOLITHIC TABLETS (57) The present invention relates to a process for producing monolithic tablets. The method employs a melt-processed composition containing at least on active agent and at least one thermoplastic binder. The inven- tion further relates to a method for cutting and deflashing a belt of pre-shaped bodies of a melt-processed compo- sition, wherein the pre-shaped bodies are interconnected by flash. EP 3 124 008 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 3 124 008 A1 2 Description organism, flash or ridges might even be hazardous by injuring mouth cavities or esophagus or otherwise inter- Related Application Information fering with swallowing the tablet,. [0005] Consequently, the flash (e.g., burrs) have to be [0001] This application claims priority to U.S. Applica- 5 removed. Present methods comprise cutting off the flash, tion number 61/ 410,344 filed on November 4, 2010, the or reducing their volume by polishing the surface of the contents of which are herein incorporated by reference tablets by methods such as tumbling. However, cutting in their entirety. or tumbling may not be effective to completely remove disturbing flash or ridges, but rather leaves remnants Field of the Invention 10 thereof, soften visible as rough spots, on the surface. Moreover, in the case of tablets made from impact re- [0002] The present invention relates to methods for sistant materials, tumbling is ineffective. It is possible to producing monolithic tablets using melt-extrusion tech- cool down the tablets to temperatures, where the tablet nology. material becomes brittle enough to allow flash removal 15 by tumbling. However, performing the tumbling proce- Background dure at low temperature increases the danger of moisture condensation on the surface of the tablets, which may [0003] Various methods for producing tablets are affect the shape of the tablet, cause decomposition of known in the art. Widely used methods comprise starting the ingredients or affect the shelf life of the tablet. As materials in powder form, such as the active agent and 20 such effects are not acceptable, tumbling at low tempara- one or more additive. The starting materials are blended, tures requires a strict control of ambient moisture, thus and the obtained blend is compressed in a die between rendering the production of the tablets more difficult and the moving punches of a tablet press, yielding a tablet. more expensive. Therefore, there is a need for a method Other methods are based on a sequence of melting and for obtaining tablets having acceptably even tablet sur- solidification rather than compression. In these methods 25 faces. thermoplastic polymers serve as binders in the final tab- let. For the preparation of the tablets, the starting mate- Summary rials, including the thermoplastic binders, the active agents and optionally further additives are blended, heat- [0006] Surprisingly, in the present invention it was ed in an extruder to melt into a homogenous extrudate. 30 found that the problems mentioned above in the Back- The extrudate can be further processed to obtain the de- ground section can be avoided and tablets with superior sired shape and size of the tablet, for example by directly surface characteristics can be produced if an extrudate introducing the extrudate in a cavity of appropriate shape is compressed between punches of a tabletting press. (injection molding). Alternatively, the extrudate can be Specifically, the methods of the present invention allow expelled from the extruder and be shaped using calen- 35 for the control of the content uniformity of each unit dose dars, die cutter, and the like. of a solid dosage form. Content uniformity is the ability [0004] A disadvantage of methods requiring the shap- to deliver a dose in a repeatable manner according to ing of an extrudate lies in the fact, that the shaping step the US Pharmacopeia. The methods of the present in- leaves marks on the finished tablets. After calendering, vention provide flexibility in terms of providing dosage for example, the tablets may be connected by so-called 40 forms with having more conventional shapes that were flash (also referred as burrs) after separation. Even after not previously achievable using melt-extrusion tech- separating the tablets by additional processes such as niques. cutting the flash, it is difficult to completely remove them. [0007] In one embodiment, the present inventon re- Likewise, tablets formed by injection molding usually also lates to a method of producing a monolithic tablet. The have flash due to the fact that for release of the tablets 45 method comprises the steps of: the injection molding cavity must be opened. For that reason, the wall of the molding cavity is usually formed a) providing a melt-processed composition contain- by two or more partial walls, which form a closed cavity ing at least one active agent and at least one ther- during the shaping step, and are removed to release the moplastic binder; shaped tablet. Since it is difficult to create a perfectly50 b) charging a predetermined amount by weight of smooth surface in the regions, where the partial wall con- the melt-processed mixture into a die cavity; tact each other during the injection molding, extrudate c) compressing the melt-processed composition to can also enter those regions, leading to flash or at least simultaneously shape and (1C11iiS11 the composi- visible ridges ("burrs") on the surface of the finished tab- tion to form a monolithic tablet, using compression let. Flash or ridges, however, are aestheticafly inaccept- 55 equipment; and able, and might modify the release profile of the active d) ejecting the monolithic tablet from the die. agents, e.g. by altering the surface area or shape of the tablet. In case the tablet is to be swallowed by a higher [0008] Suitably, the (lie cavity is located between 2 3 EP 3 124 008 A1 4 punches within a tabletting press. [0024] In yet another aspect, the melt-processed com- [0009] In one aspect, the melt-processed composition position is reheated to a temperature at or above the is renderedplastically reformable byheating priorto com- softening temperature of the composition. pression. In another aspect, the melt-processed compo- [0025] In still yet another aspect, the die cavity or a sition does not need to be re-heated prior to compression. 5 feed system is provided with temperature control means. [0010] The melt-processed composition may comprise [0026] In yet another aspect, at least one punch has plastifying a composition containing at least one active an embossed or debossed die face. In a second embod- agent and at least one thermoplastic binder by heating iment, there is provided a method for producing mono- and/or shearing to obtain a melt, and forcing the melt lithic tablets. The method comprises the steps of: through at least one orifice. 10 [0011] Suitably, the melt-processed composition is a) providing a belt of pre-shaped bodies of a melt- manufactured by melt-extrusion or injection molding. processed composition, the pre-shaped bodies in [0012] In one aspect, particles of the melt-processed said belt being interconnected by flash, each pre- composition are fed gravimetrically or by pressure into shaped body having an predetermined weight, the die cavity. 15 b) cutting the interconnecting flash to obtain singu- [0013] Providing particles of the melt-processed com- lated or singular pre-shaped bodies, and position may comprise calendered pre-shaped lentils, c) compressing the singulated pre-shaped bodies to hot spheronization, cold pelletization, or clyo-milling. simultaneously shape and deflash to obtain mono- [0014] In another aspect, pre-shaped bodies of the lithic tablets. melt-processed composition are provided, each having 20 a predetermined weight, and a pre-determined number [0027] In the above method, lite cutting and deflashing of the pre-shaped bodies is charged into the die cavity. are performed sequentially. For example, the deflashing [0015] Inyet anotheraspect, the number of pre-shaped can be performed by placing the singular pre-shaped bodies to be charged into the die cavity is one. body into a compress to simultaneously shape and de- [0016] In still another aspect, providing pre-shaped 25 flaslt the body. Alternatively, in the above method, the bodies of the melt-processed mixture comprises a cal- cutting and deflashing are performed simultaneously. endering process. [0028] In the above method, the cutting and deflashing [0017] Providing pro-shaped bodies of the melt-proc- are performed using a means selected among mechan- essed mixture may comprise a calendering process to ical means, a laser beam or a water jet.