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Home , Apronal, Benproperine, Dimetotiazine, Distigmine, Droxypropine, Etanautine

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(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. Alternatively, in obtain a belt of pre-shaped bodies, the pre-shaped bod- 30 the above method, the cutting and deflashing are per- ies being interconnected by flash; followed by cutting of formed using a rotary cutting tool. the belt into individual pre-shaped bodies or strips of pre- [0029] Inthe above method,the cutting and de-flashing shaped bodies prior to feeding the pre-shaped bodies are performed using an automated system directly on a into the die cavity. cooling belt post calendering and while a production line [0018] In an embodiment, a belt of pre-shaped bodies 35 is running. of the melt-processed mixture is provided, each of the [0030] In the above method, the cutting and de-Hash- pre-shaped bodies having a predetermined weight, the ing are performed using tumbling below the hardening pre-shaded bodies being interconnected by flash, a pre- point of the melt-processed composition. shaped body is cut out from the belt and is charged into [0031] Inthe above method,the cutting and de-flashing the die cavity. 40 are performed by blast cleaning. More specifically, the [0019] The cutting and charging action may be syn- blast cleaning is carried out using a stream of pharma- chronized with the advancing action of the compression ceutically acceptable particles. equipment or with the advancing of the extruded belt. [0032] In the above method, the separation and de- [0020] In another aspect, the cutting and calendaring flaslting are performed by tumbling at a temperature be- is synchronized with the advancing action of the com- 45 low the hardening point of the melt-processed composi- pression equipment or by the advancing of the extruded tion. belt. [0033] In the above method, the separation and de- [0021] Providing the belt of pre-shaped bodies of the flashing are performed by tumbling under ultrasound. melt-processed composition may comprise a calender- [0034] In the above method, the separation and de- ing process. 50 flashing are performed by a brief exposure to steam, wa- [0022] In still yet another aspect, the belt of pre-shaped ter or a suitable solvent. bodies of the melt-processed composition is unwound [0035] The pre-shaped bodies used in the methods of from a spool. the present invention can be in the form of a cylinder with [0023] The belt may comprise a single row of pre- hemispherical extremcities. shaped bodies of the melt-processed composition, or the 55 belt may comprise more than one row of pre-shaped bod- Brief Description of the Figures ies of the melt-processed composition. The belt may be cut into a plurality of single-row belts. [0036]

3 5 EP 3 124 008 A1 6

Figure 1 shows a two step cutting process that can agent used in the method of the present invention can be used pursuant to the methods of the present in- be amorphous or crystalline. The crystalline nature of the vention. More specifically, as shown in the figure, active agent can be detected using powder X-ray diffrac- slitting cutters can be used to cut pre-shaped bodies tion analysis, by differential scanning calorimetry or any from the belt and gear cutters can be used to deflash 5 other techniques known in the art. Examples of active the pre-shaped bodies. The slitting cutters and gear agents that can be used in the present invention are: cutters can be used in series and can be used in a [0041] Examples of active agents that can be used in manual method or as part of a continuous production the present invention include: line. Figure 2 is a general schematic outlining the method 10 , such as, , Natural alka- of the present invention. Starting with the first box of loids, semi-synthetic opium , , the figure, a blend of ingredients which includes one Opium, , Nicomorphine, Oxyco- or more active ingredients and at least one thermo- done, , Diamorphine, Papaveretum, plastic binder (PEO) is provided and then charged , Phenylpiperidine derivatives, Ketobemi- in to a melt-extruder to provide an extrudate The15 done, , Pentanyl, Diphenylpropylamine de- melt-processed compsition is then cut to a predeter- rivatives, Dextromoramide, Piritramide, Dextropro- mined weight. The cut melt-processed composition poxyphene, Bezitramide, , Benzomor- can then optionally heated. If not heated, the extru- phan derivatives, , Phenazocine, Oripa- date is then compressed in compression equipment. vine derivatives, Buprenorphine, Morphinan deriva- As a result of the compression, the melt-processed 20 tives, , Nalbuphine, Tilidine, , composition is shaped and deflashed into a mono- , Salicylic acid and derivatives, Acetylsali- lithic composition. The monolithic composition can cylic acid, Aloxiprin, salicylate, Sodium sal- be optionally coated. icylate, Salicylamide, Salsalate, Ethenzamide, Mor- Figure 3 shows the simultaneous shaping and de- pholine salicylate, Dipyrocetyl, Benorilate, Diflunisal, burring that occur during the compression of the25 Potassium salicylate, Guacetisal, Carbasalate calci- melt-processed composition to form the monolithic um, salicylate, Pyrazolones, Phenazone, tablet according to the methods of the present inven- Metamizole sodium, Anlinophenlzone, Propyphen- tion. azone. Nifenazone, Anilines, , Phen- acetin, Bucetin, Propacetamol, Other analgesics Detailed Description of the Invention 30 and antipyretics, Rimazolium, Glafenine, Hoctafe- nine, Viminol, , , Ziconotide, Allyl- I. Definitions prodine, Prodine, Alphaprodine, Betaprodine, Anile- ridine, , Bezitramide, Buprenor- [0037] Section headings as used in this section and phine, Clonitazene, Diampronicte, Dihydromor- theentire disclosure herein are not intended to be limiting. 35 phine, Dimenoxadol, Dimepheptanol, Dimethylthia- [0038] As used herein, the singular forms "a," "an" and mbutene, Dioxaphetyl butyrate, dipipanone, eptazo- "the" include plural referents unless the context clearly cine, ethoheptazine, ethylmethylthiambutene, ethyt- dictates otherwise. For the recitation of numeric ranges morphine, elonitazene, , , hydroco- herein, each intervening number there between with the done, hydromorphone, hydroxypethidine, same degree of precision is explicitly contemplated. For 40 , kelohemidone, levallorphan, lev- example, for the range 6-9, the numbers 7 and 8 are ophenacylmorphan, levorphanol, lofentanil, meperi- contemplated in addition to 6 and 9, and for the range dine, meptazinol, metazocine, methadone, me- 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, topon, morphine, myrophine, nalbulphine, narceine, 6.8, 6.9 and 7.0 are explicitly contemplated. nicomorphine, norpipanone, opium, oxycoclone, ox- [0039] As used herein, the term "about" is used syn- 45 ymorphone, papvretum, paladone, pentazocine, onymously with the term "approximately." Illustratively, phenadoxone, phenazocine, phenomorphan, phe- the use of the term "about" indicates that values slightly noperidine, piminodine, propiram, propoxyphene, outside the cited values, namely, plus or minus 10%. , tapenadol, tilidine, and tramadol; Such dosages are thus encompassed by the scope of , suchas, forexample; Esthers, Dimethyl the claimsreciting the terms "about"and "approximately." 50 ether, Vinyl ether, Halogenated hydrocarbons, Ha- [0040] The term "active agent" as used herein refers lothane, , , , to one or more chemical entities (or pharmaceutically ac- , , , Sevoflu- ceptable salts thereof) that display certain pharmacolog- rane, , , Hexobarbilal, Thi- ical effects in a subject and are administered for such opental, , anesthetics, Fenta- purpose. The term "active agent", "active ingredient" and 55 nyl, , Sufentanil, , Anilerid- "" are used interchangeably herein. The form of the ine, , Other general anesthetics, active agent used in preparing the dosage forms of the , , , , Eto- present disclosure is not critical. For example, active midate, , Hydroxybutyric acid, ,

4 7 EP 3 124 008 A1 8

Esketamine, Xenon, Esters of aminobenzoic acid, phenazone, , Benzodiazepineemepro- Metabutethamine, Procaine, Tetracaine, Chloropro- nium derivatives, Flurazepain, , Fluni- caine, Benzocaine, Amides, Bupivacaine, Lido- trazepam, , , , caine, Mepivacaine, Prilocaine, Butanilicaine, Cine- , , , , hocaine, Etidocaine, Articaine, Ropivacaine, Lev- 5 , , , Piperid- obupivacaine, Esters of benzoic acid, , Oth- inedione derivatives, , , Py- er local anesthetics, Ethyl , Dyclonine, Phe- rithyidione, related , Zopi- nol, Capsaicin; clone, , , , Other hyp- Antiepileptic drug substances such as, for example; notics and , , Clomethia- Barbiturates and derivatives, , 10 zole, , , , Propi- , , Barhexaclone, Metharbi- omazine, , , , Hexa- tal, Hydantoin derivatives, Ethotoin, , Ami- propymate, , , , no(diphenylhydantoin) valeric acid, Mephenytoin, ,, ,Dexmedeto- Fosphenytoin, Oxazolidine derivatives, Parameth- midine, Dipiperonylaminoethanol; adione, Trimethadione, Ethadione, Succinimide de- 15 Anxiolytic drug substances, such as, for example; rivatives, Ethosuximide, Phensuximide, Mesux- Benzodiazepine derivatives, , Chlo- imide, Benzodiazepine derivatives, , rdiazepoxide, , , Potassium Carboxamide derivatives, , Oxcar- , , , Bro- bazepine, Rufinamide, Fatty acid derivatives, Valp- mazepam, ,, , Alpra- roic acid, Valpromide, Aminobutyric acid, Vigabatrin, 20 zolam, , , , Nor- Progabide, Tiagabine, Other antiepileptics, dazepam, , , , Sultiame, Phenacemide, , , , , Tofisopam, Diphenyl- , , Pheneturide, Levetira- methane derivatives, , , cetam, Zonisamide, , , Lacosa- , Meprohamate, , Mebuta- mide, Beclamide; 25 mate, Dibenzo-bicyclo-octadiene derivatives, Ben- drug substances, such as, for exam- zoctamine, Azaspirodecanedione derivatives, Bus- ple; with an aliphatic side-chain, pirone, Other anxiolytics, , Gedo- , , , camil, . drug substances, Acepromazine, , , such as, for example tricyclic , non- Chlorproethazine, Phenothiazines with piperitzine 30 selective monoamine reuptake inhibitors, structure, Dixyrazine, , , , , Imipramine oxide, Clomi- , , , pramine, , , , , Thioproperazine, , , , , Protripty- , Phenothiazines with structure, ime, , , , , Do- , , , Pipo-35 sulepin, , , , tiazine, Butyrophenone derivatives, , , , Selective re- Trinuperidol, , Moperone, , uptakeinhibitors, Zimeldine, ,Citatopram, Bromperidol, Benperidol, Droperidol, , In- , , Alaproclate, , dole derivatives, Oxypertine, , , , , Monoamine oxidase in- , derivatives, , 40 hibitors, non-selective, Isocarboxazid, Nialamide, , , , Zuclopen- Phenelzine, , Iproniazide, Iprocloz- thixol, Diphenylbutylpiperidine derivatives, Fluspir- ide, Monoamine oxidase A inhibitors, Moclobemide, ilene, , , Diazepines, ox- Toloxatone, Other antidepressants, Oxitriptan, Tryp- azepines and thiazepines, , , tophan, , , , Ne- , , Neuroleptics, in tardive45 fazodone, Minaprille, Bifemelane, Viloxazine, Oxa- dyskinesia, Tetrabenazine, Benzamides, Sulpiride, flozane, , , Tianeptine, Sultopride, Tiapride, , , Ve- Pivagabine, , Milnacipran, Reboxetine, ralipride, Levosulpiride, Lithium, Other antipsychot- , Duloxetine, , Desvenlafax- ics, Prothipendyl, , , Mos- ine, Centrally acting sympathomimetics, Ampheta- apramine, , , ; 50 mine, Dexamphetamine, Metamphetamine, Methyl- and drug substances, such as, for phenidate, , , , example; Barbiturates, , , , , Fenetylline, de- , , , , rivatives, , , Other psychos- , , , , Hep- timulants and nootropics, Medofenoxate, Pyritinol, tabarbital, , Methohexital, Hexoharbital, Thi- 55 Piracetam, Deanol, Fipexide, , Oxira- opental, Etallobarbital, , Proxibarbal, Al- cetam, , Linopirdine, Nizofenone, Anira- dehydes and derivatives, hydrate, Chloral- cetam, , Idebenone, , odol, Acetylglycinamide , Dichloral- , Pramiracetam, , Vinpocetine;

5 9 EP 3 124 008 A1 10

Drug substances used in addictive disorders, such drug substances, such as, for exam- as, for example; , , , ple; Tertiary amines, , , Disulfiram, carbimide, Acamprosate, Nal- , , , , trexone, Buprenorphine, Methadone, Levacctyl- , , Bomaprine, methadol, . Antivertigo drug substances, 5 , Ethers chemically close to antihista- such as, for example; , , Flu- mines, , (chloride), Ethers narizine, Acetylleucine, other nervous system drugs, of tropine or tropine derivatives, , Ety- Gangliosides and ganglioside derivatives, Tirilazad, benzatropine; Riluzole, , Hydroxybutyric acid, Amifam- active substances, such as, for exam- pridine; further drugs such as , Co- 10 ple; Dopa and dopa derivatives, Levodopa, Melevo- deine, Opium alkaloids with morphine, Normetha- dopa, , derivatives, Aman- done, , , , tadine, agonists, , Per- , , , golide, mesylate, , , , , , , , , , , , , , 15 , Monoamine, oxidase B inhibitors, Sele- , Bibenzonium , , Fe- giline, , other dopaminergic agents, Tol- drilate, , , , Prenoxdi- capone, , ; azine, , , , Pip- Anti-dementia drug substances, such as, for exam- eridione, , , , Lev- ple; Anticholinesterases, , , Ri- odropropizine, ; opioicl agonists/an- 20 vastigmine, , Other anti-dementia tagonists such as Cyclazonine; opiate analogues drugs, , Ginkgo biloba; and other nervous such as Desomorphine; system drug substances, such as, for example; Par- Antiinflammatory and antirheumatic drug substanc- asympathomimetics, Anticholinesterases, Neostig- es, such as, for example,; Butylpyrazolidines, Phe- mine, , Distigmine, Ambenonium, nylbutazone, Mofebutazone, Oxyphenbutazone,25 Choline esters, , , Other par- Clofezone, Kebuzone, Acetic acid derivatives and asympathomimetics, , Choline alfoscer- related substances, Indometacin, Sulindac, Tolme- ate. tin,Zonlepirac, Diclofenac, Alclofenac, Bumadizone, Etodolac, Lonazolac, Fentiazac, Acemetacin, Difen- [0042] Examples of other active agents include antibi- piramide, Oxametacin, Proglumetacin, Ketorolac, 30 otics, analgesics, vaccines, antidiabetic agents, antifun- Accclofenac, Bufexamac, Oxicams, Piroxicam, Ten- gal agents, antineoplastic agents, anti-parkinsonian oxicam, Droxicam, Lornoxicam, Meloxicam, Propi- agents, antiviral agents (such as, for example, amprena- onic acid derivatives, Ibuprofen, Naproxen, Ketopro- vir (Agenerase), atazanavir (Reyataz), fosamprenavir fen, Fenoproten, Fenbuten, Benoxaprofen, Supro- (Lexiva), indinavir (Crixivan), lopinavir, ritonavir (norvir), fen, Pirprofen, Flurbiprofen, Indoprofen, Tiaprofenic 35 nelfinavir (Viracept), saquinavir (Invirase), tipranavir (Ap- acid, Oxaprozin, Ibuproxam, Dexibuprofen, Flunox- tivus), brecanavir, darunavir (Prezista)), appetite sup- aprofen, Alnlinol7rofen, Dexketoprofen, Fenamates, pressants, biological response modifiers, cardiovascular , , , agents, central nervous system , chemother- Meclotenamic acid, Coxibs, Celecoxib, Rofecoxib, apeutic agents(such as, for example, everolimus,trabec- Valdecoxib, Parecoxib, Etoricoxib, Lumiracoxib,40 tedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, Nabumetone, , Azapropazone, Glu- GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY- cosamine, , Glucosaminoglycan 142886), AMN-107, TKI-258, GSK461364, AZD 1152, polysulphate, Proquazone, Orgotein, Nimosulide, enzastaurin, vandetanib, ARQ-197, MK-0457, Feprazone, Diacerein, Morniflumate, Tenidap, Oxa- MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhib- ceprol, Chondroitin sulphate, Feprazone, Dipy-45 itor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora rocetyl, Acetylsalicylic acid, Quinolines, Oxycin- kinase inhibitor, a PIK-1 modulator, a BcI-2 inhibitor, a chophen, Gold preparations, Sodium aurotiti- Bcl-xl inhibitor, an HDAC inhibitor, a c-MET inhibitor, a omatate, Sodium aurotiosulphate, Auranofin, Au- PARP inhibitor (such as, for example, PJ34. AG14699, rothioglucose, Aurotioprol, Penicillamine, Buci- AG14361, CEP-6800, CEP-8983, INO-1001, KU59436, llamine; 50 BSI-201, GPI 21016, CPI15427 or AZD2281), a Cdk in- Anlimigraine drug substances, such as, for example; hibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an Ergot alkaloids, , , anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhib- , , Corticosteroid derivatives, itor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, Flumedroxone, Selective serotonin (5HT1 ) ago- a local adhesion kinase inhibitor, a Map kinase kinase nists, , , , Riza- 55 (mek) inhibitor, a VEGF trap antibody, , er- , , , , Other lotinib, dasatanib, nilotinib, decatanib, panitumumab, antimigraine preparations, , , Ipra- amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, zochrome, Dimetotiazine, ; batabulin, ofatumumab, zanolimumab, edotecarin,

6 11 EP 3 124 008 A1 12 tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimu- 779,450, PEG-filgrastim, darbepoetin, erythropoietin, mab, ipilimumab, gossypol, Bio 111, 131-1-TM-60I, ALT- granulocyte colony-stimulating factor, zolendronate, 110, BIO 140, CC 8490, cilengitide, gimatecan, IL13- prednisone, cetuximab, granulocyte macrophage colo- PE38QQR, INO 1001, IPdR, KRX-0402, lucanthone, LY ny-stimulating factor, histrelin, pegylated interferon alfa- 317615, neuradiab, vitespan, Rta 744, Sdx 102, talam- 5 2a, interferon alfa-2a, pegylated interferon alfa-2b, inter- panel, atrasentan, Xr 311, romidepsin, ADS-100380, feron alfa-2b, azacitidine, PEG-L-asparaginase, lenalid- chlamydocin, JNJ-16241199, etoposide, gemcitabine, omide, gemtuzumab, hydrocortisone, interleukin-11, doxorubicin, liposomal doxorubicin, 5’-deoxy-5-fluorou- dexrazoxane, alemtuzumab, all-transretinoic acid, keto- ridine, vincristine, temozolomide, ZK-304709, seliciclib; conazole, interleukin-2, megestrol, immune globulin, ni- PD0325901, AZD-6244, capecitabine, L-Glulamic acid, 10 trogen mustard, methylprednisolone, ibritgumomab tiux- N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d] etan, androgens, decitabine, hexamethylmelamine, bex- pyrimidin-5-yl)ethyl]- benzoyl]-, disodium salt, heptahy- arotene, tositumomab, arsenic trioxide, cortisone, editr- drate, camptothecin, irinotecan; PEG-labeled irinotecan, onate, mitotane, cyclosporine, liposomal daunorubicin, tamoxifen, toremifene citrate, anastrazole, exemestane, Edwina-asparaginase, strontium 89, casopitant, netupi- letrozole, DES (diethylstilbestrol), , estrogen, 15 tant, an NK-1 antagonists, , apre- conjugated estrogen, bevacizumab, IMC-1CI1, CHIR- pitant, , hydroxyzine, , 258, vatalanib, AG-013736, AVE-0005, goserelin ace- lorazepam, alprarolam, haloperidol, droperidol, dronab- tate,leuprolide acetate, triptorelin pamoate,medroxypro- inol, dexamethasone, methylprednisolone, prochlorper- gesteroneacetate, hydroxyprogesteronecaproate, meg- azine, , , , , estrol acetate, raloxifene, bicalutamide, flutamide, niluta- 20 pegfilgrastim, erythropoietin, epoetin alfa and darbepo- mide, megestrol acetate, CP-724714; TAK-165, HKI- etin alfa), contraceptive agents, dietary supplements, vi- 272, erlotinib, lapalanib, canertinib, ABX-EGF antibody, tamins, minerals, lipids, saccharides, metals, amino ac- erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, ids (and precursors), nucleic acids and precursors, con- amifostine, NVP-LAQ824, suberoyl analide hydroxamic trast agents, diagnostic agents, ag- acid, valproic acid, trichostatin A, FK-228, SU11248, sor- 25 onists, erectile dysfunction agents, fertility agents, gas- afenib, KRN951, aminoglutethimide, amsacrine, anagre- trointestinal agents, hormones, immunomodulators, an- lide, L-asparaginase, Bacillus Calmette-Guerin (BCG) tihypercalcemia agents, mast cell stabilizers, muscle re- vaccine, bleomycin,buserelin, busulfan,carboplatin, car- laxants, nutritional agents, ophthalmic agents, oste- mustine, chlorambucil, cisplatin, cladribine, clodronate, oporosis agents, respiratory agents, skin and mucous cyclophosphamide, cyproterone, cytarabine, dacar-30 membrane agents, smoking cessation agents, steroids, bazine, dactinomycin, daunorubicin, diethylstilbestrol, urinary tract agents, uterine relaxants, vaginal agents, epirubicin, fludarabine, fludrocortisone, fluoxymester- vasodilator, anti-hypertensive, hyperthyroids, anti- one, flutamide, hydroxyurea, idarubicin, ifosfamide, im- hyperthyroids, anti-asthmatics and vertigo agents. atinib, leuprolide, levamisole, lomustine, mechlo- [0043] As used herein, the term "cutting" refers to any rethamine, melphalan, 6-mercaptopurine, , meth- 35 process which is suitable of separating one entity into otrexate, mitomycin, mitotane, mitoxantrone, nilutamide, two entities. For example, cutting can involve separating octreotide, oxaliplatin, pamidronate, pentostatin, pli- two pre-shaped bodies interconnected by a flash into two camycin, porfimer, procarbazine, raltitrexed, rituximab, singulated or singular pre-shaped bodies (thus forming streptozocin, teniposide, , thalidomide, thi- two individual pre-shaped bodies) by dividing or remov- oguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic 40 ing the interconnecting flash. Cutting can include the use acid, mustard, mustard, estramus- of a blade or blade-like device. tine, altretamine, floxuridine, 5-deooxyuridine, [0044] As used herein, the term "glass transition tem- arabinoside, 6-mercaptopurine, deoxycoformycin, calci- perature" or "T g" refers to temperature at which an amor- triol, valrubicin, mithramycin, vinblastine, vinorelbine, to- phous solid becomes soft upon heating or brittle upon potecan, razoxin, marimastat, COL-3, neovastat, BMS- 45 cooling. More specifically, as the temperature of a poly- 275291, squalamine, endostatin, SU5416, SU6668, mer drops below Tg, it behaves in an increasingly brittle EMD121974, interleukin-12, IM862, angiostatin, vitaxin, manner. As the temperature rises above the T g, the pol- droloxifene, idoxyfene, spironolactone, finasteride, cim- ymer becomes more rubber-like. In general, values of T g itidine, trastuzumab, denileukin diftitox, gefitinib, bortez- well below room temperature define the domain of elas- imib, paclitaxel, cremophor-free paclitaxel, docetaxel, 50 tomers and values above room temperature define rigid, epithilone B, BMS-247550, BMS-310705, droloxifene, 4- structural polymers. hydroxylamoxifen, pipendoxifene, ERA-923, arzoxilene, [0045] As used herein, the term, "monolithic" when fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, used in connection with the term "tablet" refers to a tablet HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, comprised of one continuous block of solid having at least VX-745, PD 184352, rapamycin, 40-O-(2-hydroxye-55 one dimension that is more than 5 millimeters. In contrast thyl)-rapamycin, temsirolimus, AP-23573, RAD001, to"monolithic tablets", "multiparticulate"tablets, are com- ABT-578, BC-210, LY294002, LY292223, LY292696, prised of a plurality of discrete subunits. These subunits LY293684, LY293646, wortmannin, ZM336372, L- are separated, e. g., by grain boundaries. Such tablets,

7 13 EP 3 124 008 A1 14 although seemingly constituting one block of solid, usu- ide). ally disintegrate in the stomach or in the intestines, there- by simultaneously or successively releasing the individ- II. Methods for Producing Monolithic Tablets ual subunits. Alternatively for an eroding matrix, materials are released at pre determined rates. 5 A. Use of Compression with Individually Separate [0046] By "pharmaceutically acceptable," refers in a Calendered Intermediates broad sense to compounds, materials, compositions and/or dosage forms, which are, within the scope of [0050] In one embodiment, the present invention re- sound medical judgment, suitable for use in contact with lates to a method for producing a monolithic tablet. The tissues of a subject without excessive toxicity, irritation, 10 method comprises the steps of: allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio. a) providing a melt-processed composition compris- [0047] As used herein, the term "softening tempera- ing a mixture of at least one active agent and at least ture" refers to a temperature (or a temperature range) one thermoplastic binder; above the glass transition temperature or the melting 15 b) charging or introducing a predetermined amount point of semicrystalline domain, where a material be- by weight of the melt-processed composition into a comes thermoplastic. die cavity; [0048] The term "subject" refers to an animal. In one c) compressing the melt-processed composition to aspect, the animal is a mammal, including a human or shape and deflash the compostion into a monolithic non-human. The terms patient and subject may be used 20 tablet, using compression equipment; and interchangeably herein. d) ejecting the monolithic tablet having the final tablet [0049] As used herein, the term, "thermoplastic" when shape from the die. describing a binder or polymer refers to one or more ma- terials that melt and/or soften when heat is applied to [0051] In step a) of the method of the present invention, allow molding while maintaining good chemical stability. 25 a melt-processed composition containing a mixture of at Exemplary pharmceutically acceptable thermoplastic least one active agent and at least one thermoplastic polymers that may be used in the present invention in- binder is provided. Methods and techniques for making clude (1) homopolymers and copolymers of N-vinyl such a melt-processed composition, such as by melt- lactams, especially homopolymers and copolymers of N- extruion or injection molding, are well-known to those vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP), copol- 30 skilled in the art. For example, such a melt-processed ymers of N-vinyl pyrrolidone and vinyl acetate or vinyl composition comprising the mixture of the at least one propionate; (2) cellulose esters and cellulose ethers, in active agent and the at least one thermoplastic agent can particular methylcellulose and ethylcellulose, hydroxy- be prepared by mixing the at least one active agent(s) alkylcelluloses, in particular hydroxypropylcellulose, hy- and the at least one thermoplastic binder(s) to form a droxyalkylalkylcelluloses, in particular hydroxypropyl-35 mixture. The mixture is heated until melted and then ho- methylcellulose, cellulose phthalates or succinates, in mogenized to provide a uniform melt. This uniform melt particular cellulose acetate phthalate and hydroxypropyl- is then cooled. The process of providing a melt-proc- methylcellulose phthalate, hydroxypropylmethylcellu- essed composition can comprise plastifying a composi- lose succinate or hydroxypropylmethylcellulose acetate tion containing the at least one active agent, and the at succinate; (3) high molecular polyalkylene oxides such 40 least one thermoplastic binder by heating and/or shear- as polyethylene oxide and polypropylene oxide and co- ing to obtain a melt, and then forcing the melt through at polymers of oxide and propylene oxide, (4) pol- least one orifice. yvinyl -polyethylene glycol-graft copolymers [0052] As mentioned previously herein, techniques for (available as Kollicoat® IR from BASF AG, Ludwigshaf- melt-extrusion and injection molding techniques arc well en, Germany); (5) polyacrylates and polymethacrylates 45 known to those skilled in the art. Specifically, melt-extru- such as methacrylic acid/ethyl acrylate copolymers, sion involves mixing or kneading the heated mixture in methacrylic acid/methyl methacrylate copolymers, butyl an extruder. Suitable extruders for heating and kneading methacrylate/2-dimethylaminoethyl methacrylate copol- the heated blend include single screw extruders, in- ymers, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl termeshing screw extruders or multiscrew extruders methacrylates); (6) polyacrylamides; (7) vinyl acetate 50 (such as twin screw extruders), which can be corotating polymers such as copolymers of vinyl acetate and crot- or counterrotating. The extruders can be optionally onic acid, partially hydrolyzed polyvinyl acetate (also re- equipped with kneading disks or other screw elements ferred to as partially saponified "polyvinyl alcohol"); (8) for mixing or dispersing the melt. polyvinyl alcohol; (9) oligo- and polysaccharides such as [0053] It will be appreciated by those skilled in the art carrageenans, galactomannans and , or 55 that the working temperatures of melt-extrusion or injec- mixtures of one or more thereof. In one aspect of the tion molding will be determined, in part, by the properties present invention, the thermoplastic binder is a pharma- of the active agent (including, for example, the melting ceutically acceptable polymer, such as poly(ethylene ox- point of the active agent) and the thermoplastic binder(s)

8 15 EP 3 124 008 A1 16 as well as by any pharmaceutically acceptable excipients present invention, the number of pre-shaped bodies to (such as, for example, one or more fillers, binders, lubri- be filled into the die cavity is one. In this case, the pre- cants/glidants, solubility enhancing agents, suspending determined weight matches, within limits that are accept- agents, sweetness and/or flavoring agents, preserva- able in the art of tablet manufacturing, the intended final tives, buffers, wetting agents, disintegrating agents, ef- 5 weight of the tablet. fervescent agents, surfactants, humectants, solution re- [0057] The shape of the bodies is not critical and may tarders,absorbents, solvents, other pharmaceutically ac- be selected from a variety of shapes. If one pre-shaped ceptable additives and combinations thereof) which body is charged into the die cavity, it may have a shape, might be optionally present, as well as by the kind of which is already close to the shape of the final tablet. extruder or the kind of configuration within the extruder 10 However, any other shape is acceptable, as long as its that is being used. A portion of the energy needed to melt dimensions do not impede charging, introducing, insert- the mixture in the extruder can be provided by heating ing or placing the pre-shaped body into the die cavity. elements. However, the friction and shearing of the ma- Examples of such shapes include spheres, elongated terial in the extruder can also provide a substantial spheres, such as e.g. ellipsoids or asymmetrical ellip- amount of energy to the mixture and aid in the formation 15 soids having an egg-like shape, spheres with hemispher- of a homogeneous melt of the components. After leaving ical extremeties, cylinders with hemispherical extreme- the extruder through an orifice, the melt-processed com- ties, cylinders with round or polygonal cross section, such position is considered to be an "extrudate", which can be as pentagonal, hexagonal, heptagonal or octagonal subjectto furtherprocessing. For example, themelt-proc- cross section, cubes, elongated cubes, pyramids, and ess composition or extrudate can be cut into various size 20 the like. pieces (which can be referred to herein as individual tab- [0058] In one aspect of the invention, the pre-shaped let intermediates) of any size and/or weight. In fact, the bodies (individual tablet intermediates) are obtained by extrudate can be cut to a specific size in order to provide a calendering process. Calendering is a process well- a piece of extrudate having a desired predetermined known in the art for shaping thermoplastic materials. In weight. 25 a calender, gaps are formed by one or more sets of coun- [0054] In step b) of the method, a predetermined terrotating rolls, or by rolls arranged over a transport belt. amount by weight of the melt-processed composition or Thethermoplastic material canbe a hot extrudate(a melt- extrudate (said predetermined amount by weight of the processed composition) that has just left the extruder and melt-processed composition or extrudate being referred has a temperature that still ensures thermoplasticity. If to herein as an individual tablet intermediate) is charged, 30 appropriate, the extruder temperature can be lowered to introduced, inserted or placed into a die cavity. The con- temperatures suitable for calendering using suitable tours of the die cavity match the the desired form of the cooling means. Examples for suitable cooling means in- tablet. clude cooling chambers through which the extrudate or [0055] The predetermined amount by weight of the the thermoplastic material passes before entering the melt-processed compositionor extrudate (e.g.,individual 35 calender, or refrigerated transport bands. As the thermo- tablet intermediate) equals or is within limits acceptable plastic material is forced through one or more gaps be- in the art of tablet manufacturing and can be readily de- tween such sets of rolls or between rolls and the transport termined by one skilled in the art. Specifically, the pre- band, the structures on the surface of the gap(s) and/or determined amount by weight of the melt-process com- the moving transport belt are imprinted on the thermo- position or extrudate (e.g., individual tablet intermediate) 40 plastic material, thus determining or imparting the shape is close or equal to the intended final weight of the mon- on the thermoplastic material. By appropriate arrange- olithic tablet having its final tablet shape. ments of elevations and depression on the surface of the [0056] In one aspect of the method of the present in- counterrotating rolls, or on the surface of a roll and, where vention, pre-shaped bodies of the melt-processed com- applicable, on the transport belt forming a gap together position or extrudate (namely, the individual tablet inter- 45 with the roll, calendering can transform the thermoplastic mediates) are provided. Each pre-shaped body has a material into pre-shaped bodies. The pre-shaped bodies predetermined weight. A pre-determined number of the may be a precursor to the final tablet shape so as to pre-shaped bodies are then charged, introduced, insert- minimize the extent of plastic deformation and/or facilite ed or placed into the die cavity. The number of pre- transport through the feeding system of the press. The shaped bodies to be inserted or filled into the die cavity 50 pre-shaped bodies may take a variety of forms, such as, can be any number from one up to 1000, such as, for spheres, elongated spheres, such as e.g. ellipsoids or example, I to 100, 1 to 50, 1 to 25, 1 to 10, 1 to 7, 1 to 5, asymmetrical ellipsoids having an egg-like shape, cylin- such as 1, 2, 3, 4 or 5 pre-shaped bodies. Ultimately, ders with round or polygonal cross section, such as pen- however, there is no limit to the number of pre-shaped tagonal, hexagonal, heptagonal or octagonal cross sec- bodies that can be fed continuously into the die cavity. 55 tion, cubes, elongated cubes, pyramids, and the like. In Each particle may constitute a considerably fraction of particular, the pre-shaped bodies may take a form rem- the predetermined weight, e.g. 100 percent, 50 percent iniscent of a tablet, e.g. a coin-like form (flat cylinder) or or 25 percent of said weight. In another aspect of the a lentil-like form. If the elevations and depressions on the

9 17 EP 3 124 008 A1 18 surfaces of the rolls or the transport belt are arranged [0063] If the melt-processed composition or extrudate such that between two combinations thereof, each of does not have sufficient plastic deformabilty at ambient which forming a pre-shaped body, a thin strand of ther- temperature, the melt-processed composition or extru- moplastic material can pass through the gap, a belt of date may be rendered plastically deformable by heating pre-shaped bodies will be formed, wherein the pre-5 prior to compression, for example by heating or re-heat- shaped bodies will be connected by so-called flash, i.e. ing prior to charging into the die cavity. This heating may thin bridges of thermoplastic material between the pre- occur outside of the compression equipment. For exam- shaped bodies. If the elevations on the rolls and/or the ple, the melt-processed composition or extrudate may transport belt repeatedly touch during the revolution of be placed into an oven or may pass through a heating the rolls, the calender squeezes off the strand of extru- 10 zone before being transferred into the compression de- date or thermoplastic material at those spots, thus dis- vice. Alternatively, the die cavity or a feed system, which charging unconnected pre-shaped bodies. is used to introduce the melt-processed composition or [0059] In step c) of the method of the present invention, extrudate into the compression equipment, can be the melt-processed composition is compressed and equipped with temperature control means. Said temper- shaped into a monolithic tablet. Compression equipment 15 ature control means allow actively changing the temper- (such as tablet presses (such as single-punch machines, ature of the melt-processed composition, in particular rotary tablet machines, high-speed rotary tablet ma- heating it from a lower temperature to the desired tem- chines, multilayer rotary tablet machines, etc.), a roller perature (by heating elements). Optionally, the heating compactor, etc.) is used for compressing and shaping. means may also comprise measuring probe for deter- Such compression equipment and its use thereof is well 20 mining the temperature of the melt-processed composi- known to those skilled in the art. In compression, a force tion. is used which presses the melt-processed composition [0064] Typically, the calendaring process yields a belt against the die thereby having the effect that the compo- of pro-shaped bodies, wherein the pre-shaped bodies sition adopts the shape stipulated by the die surface at are interconnected by flash. Belts of pre-shaped bodies the moment of compression. The melt-processed com- 25 to be used in a method according to the invention in gen- position is, at least to some degree, plastically deforma- eral may comprise a single row of pre-shaped bodies, ble at the temperature prevailing during the compression. which are interconnected by flash, or may comprise more In step c), in one aspect, the shaping and deflashing oc- than one row of pre-shaped bodies. A belt comprising cur simultaneously. more than one row represents a matrix of pre-shaped [0060] If the predetermined amount by weight of the 30 bodies, wherein pre-shaped bodies of one row are inter- melt-processed composition or extrudate (individual tab- connected by flash, and wherein pre-shaped bodies of let intermediate) is constituted by a multitude of the par- neigboring rows also are interconnected by flash. The ticles of the melt-processed composition, each of which thickness of the flash between pre-shaped bodies of one only represent a small fraction of the predetermined row may be identical to or different from the thickness of amount by weight, the compression unites the particles 35 the flash between pre-shaped bodies of neighbouring into on monolithic tablet, which matches the shape of the rows. A belt representing a single row may comprise 2 die cavity. In the event that the shape of the melt-proc- to 10, or more than 10, such as tens, or hundreds, or essed composition already matches or is identical the thousands, or tens of thousands, or hundreds of thou- intended final shape of the tablet, except for surface de- sands of pre-shaped bodies. For example, a belt may fects such as flash (burrs), rims, rought spots, blebs or 40 comprise a number of pre-shaped bodies in the range the like, pressing against the surface of the die removes from 10 to 100,000, 100 to 10,000, or 1,000 to 5,000. In said defects. belts comprising more than one row, the number of rows [0061] In step d), the monolithic tablet is ejected from may, e.g., range from 2 to 1,000, 2 to 100, 2 to 50, 2 to the die, using means well-known in the art, such as de- 25, or 2 to 10. Preferred belts comprising more than one flectors. 45 row comprise 5 to 15, 6 to 14, 7 to 13, 8 to 12, or 9 to 11 [0062] The die cavity is suitably located between rows. In particular, a belt may comprise 7, 8, 9, 10, 11 or punches of a tabletting press. The punches may, e.g. be 12 rows. The length of each individual row may be as opposed movable punches. For example, a lower punch described for belts comprising one row. seals off the bottom of the die cavity, which then is [0065] In one aspect, the belt of the pre-shaped bodies charged with the predetermined amount of the melt-proc- 50 is cut or separated into either individual pre-shaped bod- essed composition or extrudate. An upper punch is low- ies or into strips of pre-shaped bodies, wherein cutting ered and seals off the top of the die cavity. By pressing may be performed by technologies known in the art, such the upper punch against the lower punch, the predeter- as by the action of knives, cutting blades etc. Strips of mined amount of melt-processed composition or extru- pro-shaped bodies may either be shorter portions of a date, are compressed into a monolithic tablet. The upper 55 single row, or smaller portions of a matrix (thus compris- punch is then retracted from the die cavity, the lower ing shorter portions of two or more neighboring rows). punch is pushed upwards and thereby ejects the mono- For example, a belt comprising one row of 2000 pre- lithic tablet from the die cavity. shaped bodies may be separated into 2000 individual

10 19 EP 3 124 008 A1 20 pre-shaped bodies, or into 20 rows, each of which com- tablets for subsequent cutting into individual pre-shaped prising 100 pre-shaped bodies interconnected by bodies, or strips (having a single row of pre-shaped bod- flashed, or into 40 rows, each of which comprising 50 ies) or matrices (having more than one row) of pre- pre-shaped bodies. A belt comprising 10 rows, each of shaped bodies, and/or for subsequent feeding of the belt, which comprising 1,000 pre-shaped bodies, may for ex- 5 the strips, the matrices or the individual pre-shaped bod- ample be cut into 10,000 individual pre-shaped bodies, ies into a die cavitiy for producing a monolithic tablet. or into 10 rows, each of which comprising 1,000 pre- Alternative methods for storing belts comprise curling up shaped bodies, or into two matrices, each of which com- the belts of pre-shaped bodies in the absence of a spool, prising 5 rows with 1,000 pre-shaped bodies and a total or folding up the belts. Inadvertent uncurling or unfolding number of 5,000 pre-shaped bodies per matrix, or into 10 of the belts may be prevented by fastening means, such 1000 small matrices, each of which comprising 2 rows as ribbons, wrappings or boxes, which contain the curled of 5 pre-shaped bodies. Finally, the individual bodies, the up or folded belts. From such storage forms, the belts rows of pre-shaped bodies, or the smaller matrices of may be uncurled or unfolded. In particular, boxes con- pre-shaped bodies as obtained by cutting, are fed into taining curled or folded belts may serve as dispenser the die cavity. In a continuous process, the number of 15 devices from which one end of the belt can be inserted pre-shaped bodies per row could be unlimited. The pre- into a device for uncurling or unfolding the belt, cutting shaped bodies that are obtained by cutting are collected and/or charging the belt into die cavities. via a suitable feeding and then sent to compression [0069] In all aspects of the methods for producing a equipment for shaping and deflashing. monolithic tablet as described in this section, the melt- [0066] The cutting and charging action may be syn- 20 processed composition may be transferred from melt chronized with the advancing action of the compression processing via optional steps, such as providing particles equipment Consequently, the overall production process or providing pre-shaped bodies or cutting belts of pre- can be synchronized in an advantageous manner, obvi- shaped bodies, into the die cavity without additional heat- ating the necessity to coordinate two separate subproc- ing steps. For example, a melt-processed composition esses (i.e. cutting the belt of pre-shaped bodies and25 can be extruded in a thermoplastic state, immediately or charging the cut belt into the die cavity), but efficiently after moderate cooling be shaped into pre-shaped bodies combines both subprocesses into one integrated proc- or belts of pre-shaped bodies by calenderering in a still ess. For example, a pre-shaped body can be stamped thermoplastic state, and, optionally after cutting into out from the belt by the upper edge of the die wall and shorter belts or individual pre-shaped bodies, be charged the upper punch by the advancing action of the upper 30 into a die cavity for compression and shaping into a mon- punch, and the pre-shaped body is simultaneously olithic tablet. charged into the die cavity. [0070] Alternatively, all embodiments of methods for [0067] Additionally, the cutting and calendaring action producing a monolithic tablet as described in this section may be synchronized with the advancing action of the may also comprise reheating the melt-processed com- compression equipment. 35 position to a temperature at or above the softening tem- [0068] A belt of pre-shaped bodies to be used in a peratureof the composition. Duringthe compressionstep method according to the invention may be unwound from c) of the method according to the invention, the temper- a spool. This option is applicable for all melt-processed ature of the melt-processed composition or extrudate can compositions which, at the temperature of the belt during be at or above the softening point of the respective melt- unwinding are not brittle, but has enough flexibility to be 40 processed composition or extrudate to allow a shaping unwound. The present invention therefore also compris- into the desired shape. Alternatively, in the case of melt- es a method for storing belts of pre-shaped bodies by processed compositions or extrudate already having the winding up said belts on spools. The process of winding desired shape, but displaying defects, such as minor de- up may be performed after producing the belt, e.g. by viations from the intended form, or remnants of intercon- calendering, optionally after cooling down the belts to 45 necting flash on individual pre-shaped bodies after cut- temperatures where the tensile strength in particular of ting bells of interconnected pro-shaped bodies, a tem- the interconnecting flashed is high enough to prevent perature at or above the softening point allows correcting tearing of the belt during winding up. In the present in- such defects or incorporating the flash remnants into the vention, the belts of pre-shaped bodies on the spools pre-shaped body, yielding an acceptable surface. In one constitute a useful strorage form, which allows storing 50 aspect, the interconnecting flash in the belts of pre- the belts in a form which is compact; which easily can be shaped bodies can be thin. Wherein the weight of a pre- protected from environmental conditions such as radia- shaped body in a belt of pre-shaped bodies matches the tion, dust, chemical or microbial contamination by sealing intended final weight, the weight of interconnecting flash- in suitable containers, such as plastic bags, metal or glas es or cut flashes will not significantly alter the final weight containers; and which easily can be reactivated for use 55 of the tablet. Alternatively, the weight of the flashes can in a method for producing a monolithic tablet according be taken into consideration when setting the weight of to the invention. Said reactivation may comprise inserting the pre-shaped bodies, thus exactly reaching the intend- the spool in a device for unwinding the belt of pre-shaped ed final weight after incorporation the flash remnants into

11 21 EP 3 124 008 A1 22 the tablet during compression. Examples for thin flash of amounts of active agent are from 0.01 mg to 5000 mg, are flash, the thickness of which corresponds to a range from 0.1 mg to 500 mg, or from 1 mg to 50 mg. of 0.1% to 25% of the thickness of the pre-shaped body, [0074] The monolithic tablets made pursuant to the such as 25%, 20%, 10%, 5%, 3%, 1%, or 0.1% of the processes described herein can be further treated as thickness of the pre-shaped body, or is selected from a 5 customary in the art of tablet manufacturing, e.g. they range of 50 micrometers to 1000 micrometers, such as can be provided with a film coat. A film coat can optionally 1000 mm, 500 mm, 250 mm, 200 mm, 150 mm, 125 mm, contain part of an active agent or ingredients. Alterna- 100 mm, 75 mm, or 50 mm. tively a film coat can also improve taste and provides an [0071] Reheating of the melt-processed composition elegant appearance. If desired, the film coat may be an or extrudate may he required when the subprocesses of 10 enteric coat. The film coat usually includes a polymeric providing the melt-processed composition in step a) and film-forming material such as hydroxypropyl methylcel- compressing the melt-processed composition in step c) lulose, hydroxypropyl cellulose, acrylate or methacrylate are temporally separated enough to allow a decrease of copolymers or polyvinyl alcohol-polyetllylene glycol graft the temperature of the melt-processed composition be- copolymer. Besides a film-forming polymer, the film coat low thesoftening point. Reheating isoptionally when stor- 15 may further comprise a plasticizer, e.g. polyethylene gly- age forms as described above are used. Optionally, no col, a surfactant, e.g. a Tween® type, and optionally a reheating is necessary. Reheating can be achieved by pigment, e.g. titanium dioxide or iron oxides or commonly various ways, such as continous passing of the melt- used dyes. The film-coating may also comprise talc as processed composition though a heated zone (in contin- anti-adhesive. uous production processes) or transfer of the melt-proc- 20 essed composition into a heated zone,such as an incu- B. Use of Compression with Individually Separate bator, and removing it from that zone before further Calendered Intermediates processing (discontinous production process). In partic- ular, reheating can occur immediately prior to charging [0075] In a second embodiment, the present invention or introducing the predetermined amount of the melt- 25 generally relates to a method for producing monolithic processed composition or extrudate into the die cavity, tablets. The method comprises the steps of: in the compression device itself, such as a tablet press or in a separate device prior to transferring the reheated a) providing a belt of pre-shaped bodies of a melt- melt-processed composition into the compression de- processed composition, the pre-shaped bodies in vice. In case the method comprises cutting a belt of pre- 30 said belt being interconnected by flash, each pre- shaped bodies prior to charging strips of pro-shaped bod- shaped body having an predetermined weight ies or individual pro-shaped bodies into the die cavity, (which can be weight to volume - the weight is con- heating may occur before cutting, but occurs after cutting trolled by the volume of the molding cavity); and before charging into the die cavity. b) cutting the interconnecting flash to obtain singu- [0072] In all aspects of methods according to the in- 35 lated pre-shaped bodies, and vention, at least one punch optionally has an embossed c) deflashing the singulated pre-shaped bodies to or debossed die face, or combinations thereof. Said die obtain monolithic tablets. faces allow modelling the surface of the tablet by creating scores or ridges. Said scores or ridges enlarge the sur- [0076] In one aspect of the present invention, after the face of the tablet, thus allowing a modification of the re- 40 cutting and deflashing of the pre-shaped bodies, no fur- lease of the active agents. Alternatively, they can be used ther shaping of the obtained monolithic tablets is re- to display logos or other information. Scores on tablets quired. may in particular be used to define breaking lines for safe [0077] The belts and the pro-shaped bodies contained and accurate dividing tablets into subunits. The tablets within said belt that are interconnected by flash can be can also be printed. 45 the belts and pre-shaped bodies as described above in [0073] The monolithie tablets of the invention can be Section A in the context of the method for producing a provided in unit dosage form, for example, in the form of monolithic tablet. In addition, the belts and the pre- tablets, pills or suppositories, suitable for adminstration shaped bodies contained within the belt that are inter- to humans, non-human mammals or other animal. The connected by flash can also be pre-shaped bodies which administration may be oral, by implantation into tissues, 50 are not used for producing tablets or for pharmaceutical e.g. subcutaneous, vaginal or anal. The amounts of ac- purposes. tive agents(s) will depend on the respective ingredients, [0078] With respect to the cutting and deflashing a belt the patient group to be treated in dependence of factors of pre-shaped bodies of a melt-processed composition, such as age, gender, severity of the treated condition, said belt is formed by pre-shaped bodies, which have an the intended frequency of administration. Such factors 55 predetermined weight and are interconnected by flash. are known to those skilled in the art and can be deter- The method of the present invention comprises cutting mined appropriately. While therefore exact amounts are of the interconnected flash in the belt to obtain individual determined in each case, examples for generic ranges pre-shaped bodies, and, simultaneously with cutting or

12 23 EP 3 124 008 A1 24 sequentially after cutting, comprises the deflashing of the by a robot. For example, cutting and deflashing may be pre-shaped bodies. performed by a precise cutting functionality integrated in [0079] In one aspect, the method can comprise cutting the robot, leaving no remnants of flash, or cutting may only one interconnecting flash, thereby separating one be performed by a cutting functionality and subsequent terminal pro-shaped body from the remainder of the belt. 5 deflashing may be performed by a tumbling functionality Alternatively, the method can comprise cutting the belt integrated in the robotic arm. Cutting and deflashing can into two strips of interconnected pre-shaped bodies. In be performed while the production line, which comprises another aspect, several interconnecting flash are cut, calendaring and cooling after calendering, is running. thus releasing a mixture of individual pre-shaped bodies The production line may, for example, be a production and/or strips of interconnected pre-shaped bodies there- 10 line for producing cut and deflashed pre-shaped bodies, by separating all the interconnecting flash of a belt. In or a production line for producing monolithic tablets, e.g. still yet another aspect, all interconnecting flash are cut, final tablets as referred to above, The production line may thus turning a belt of pre-shaped bodies into individual for example be running in a stepwise mode, and in par- pre-shaped bodies. ticular may be running in a continuous mode. [0080] In the method of the present invention, the cut- 15 [0085] Instill another aspect, thecutting and deflashing ting of step b) and the deflashing of step c) can be per- may be performed sequentially or simultaneously using formed simultaneously. Alternatively, both steps can be tumblingbelow the hardening pointof themelt-processed performed sequentially, e.g., namely, step c) of deflash- composition. ing being performed subsequently after cutting in step b). [0086] In yet still another aspect, a two step cutting [0081] In the event that the cutting and deflashing are 20 process can be used (See Figure 1). Slitting cutters can performed simultaneously, the act of cutting automatical- be used to cut the pre-shaped bodies from the belt and ly also causes deflashing of the released pre-shaped gear cutters can be used to deflash the pre-shaped bod- body or the strip of pro-shaped bodies, In case cutting ies. The use of said slitting cutters and gear cutters can and deflashing occur sequentially, cutting will release a be used in series and can be used in a manual method pre-shaped body (or a strip of pre-shaped bodies) having 25 or as part of a continuous production line. at least a remnant of the cut interconnecting flash. Said [0087] In still yet another aspect, the separation and remnant is deflashed after cutting, wherein deflashing denashing are performed by so-called "blast cleaning" may occur using the same means as used for cutting, or using projectiles. In particular, the projectiles may be par- may occur using a separate means. ticlesof a pharmaceutically acceptableexcipient or a mix- [0082] Suitable means that can be used for cutting30 ture of such excipients. In one aspect, a pharmaceutically and/or deflashing may, e.g., be selected from mechanical acceptable excipient or a mixture of pharmaceutically ac- means (including, robotic mechanical means), such as ceptable excipients may be used which is already present linear, rotary or scissor-like cutting tools, or tumbling, in the melt-processed composition underlying the pre- from a laser beam, and from a fluid jet, such as a water shaped bodies. jet. Robotics may, for example, be characterized by one 35 [0088] In still yet another aspect, separation and de- or morefeatures, selectedamong the abilityof movement flashing are performed by tumbling at a temperature be- with one or, in particular, several degrees of freedom, low the hardening point of the melt-processed composi- the ability to be programmed and/or controlled by soft- tion. ware or a computer, the ability of sending feedbacks to [0089] In yet still another aspect, the separation and a control software or computer, the ability of having more 40 deflashing are performed by tumbling under ultrasound. than one functionality, or the ability of sensing the envi- While not wishing to be bound by any theory, the ther- romment and performing actions in response to the de- moplastic binder (polymer) represented by the melt-proc- tected environmental situation. However, instead of the essed composition behaves in a glassy manner by re- previously mentioned characteristics, other characteris- ducing its loss modulus under dynamic deformations of tics commonly used for defining robotics may apply. 45 sufficient frequency. Appropriate frequencies for given [0083] In one aspect, simultaneous or sequential cut- melt-processed compositions can routinely be deter- ting and deflashing are performed using a rotary tool. In mined by those skilled in the art. the case of simultaneous cutting and deflashing, the ro- [0090] In still yet another aspect, separation and de- tary tool may, e.g., cut out the interconnecting flash, re- flashing are performed by or comprise a brief exposure leasing pre-shaped bodies without remnants of flash. In 50 to steam, water or a suitable solvent. Said exposure sof- the case of sequential cutting and deflashing, the rotary tens the flash before softening the pro-shaped bodies. tool may, e.g divide the interconnecting flash, releasing While variations may occur depending on the melt-proc- pre-shaped bodies having remnants of flash, which in a essed composition used, it is assumed that in general subsequent step are removed, e.g. by tumbling, by the the diffusion time of said agents to the center line of the action of a robotic arm, and the like. 55 flash is at least one order of magnitude smaller than the [0084] In another aspect, while the belt is on a cooling diffusion time necessary to induce superficial swelling of belt to lower the temperature after calendering, cutting the pro-shaped bodies. Suitable solvents for use on a and deflashing are performed directly on the cooling belt given melt-processed composition can readibly be de-

13 25 EP 3 124 008 A1 26 termined by those skilled in the art. ies into the die cavity. [0091] The melt-processed composition to be used in 9. The method of item 1, comprising providing a belt this process for cutting and deflashing a belt of pro- of pre-shaped bodies of the melt-processed mixture shaped bodies may be any formulation, but in particular each having an predetermined weight, the pre- may be be a melt-extrudate, such as an extrudate as 5 shaped bodies being interconnected by flash, cutting described in context with the method for producing a out a pre-shaped body from the belt and charging monolithic tablet as described above in Section A. the pre-shaped body into the die cavity. [0092] The pro-shaped bodies to be subjected to the 10. The method of item 9, wherein the cutting and method for producing a monolithic tablet may - after per- charging action is synchronized with the advancing forming the method on them - be used for their intended 10 action of the compression equipment. purpose, for example a use as tablets (and may for ex- 11. The method of item 9, wherein providing the belt ample constitute the final tablets as referred to in the of pre-shaped bodies of the melt-processed compo- context of the method for producing a monolithic tablet sition comprises a calendering process. according to the first aspect of the invention), or may be 12. The method of item 9, wherein the belt of pre- subjected to further processing steps, such as for exam- 15 shaped bodies of the melt- processed composition ple coating and/or packaging. is unwound from a spool. [0093] The invention regards the following items: 13. The method of item 9, wherein the belt comprises a single row of pre-shaped bodies of the melt-proc- 1. A method for producing a monolithic tablet, the essed composition. method comprising the steps of: a) providing a melt- 20 14. The method of item 9, wherein the belt comprises processed composition containing at least one ac- more than one row of pre- shaped bodies of the melt- tive agent and at least one thermoplastic binder; b) processed composition. charging a predetermined amount by weight of the 15. The method of item 9, wherein the belt is cut into melt-processedcomposition into a die cavity; c)com- a plurality of single-row belts. pressing the melt-processed composition to simul- 25 16. The method of item 9, wherein deflashing of the taneously shape and deflash the composition to form pre-shaped bodyoccurs through plasticdeformation a monolithic tablet, using compression equipment; during shaping. and d) ejecting the monolithic tablet from the die. 17. A method for producing monolithic tablets, the 2.The method of item 1, wherein the melt-processed method comprising the steps of: a) providing a belt composition is rendered plastically deformable by 30 of pre-shaped bodies of a melt-processed composi- heating prior to compression. tion, the pre-shaped bodies in said belt being inter- 3.The method of item 1, wherein providing the melt- connected by flash, each pre- shaped body having processed composition comprises plastifying a com- an predetermined weight; b) cutting the intercon- position containing at least one active agent and at necting flash in the belt to obtain singulated pre- least one thermoplastic binder by heating, shearing 35 shaped bodies; and c) compressing the singulated and heating and shearing to obtain a melt, and forc- pre-shaped bodies to shape and deflash to obtain ing the melt through at least one orifice. monolithic tablets. 4.The method of item 1, wherein the melt-processed 18. The method of item 17, wherein cutting and de- composition is manufactured by melt-extrusion or in- flashing are performed sequentially. jection molding. 40 19. The method of item 17, wherein cutting and de- 5.The method of item 1, comprising providing pre- flashing are performed simultaneously. shaped bodies of the melt- processed composition, 20. The method of item 9, wherein the cutting and wherein each pre-shaped body has a predetermined calendaring is synchronized with the advancing ac- weight, and charging a predetermined number of the tion of the compression equipment. pre-shaped bodies into the die cavity. 45 21. The method of items 5 or 17 wherein the pre- 6. The method of item 5, wherein the number of pre- shaped bodies are a cylinder with hemispherical ex- shaped bodies to be charged into the die cavity is tremities. one. 7. The method of item 5, wherein providing pre- shaped bodies of the melt- processed mixture com- 50 Claims prises a calendering process. 8. The method of item 5, wherein providing pre- 1. A method for producing a monolithic tablet, the meth- shaped bodies of the melt- processed mixture com- od comprising the steps of: prises a calendering process to obtain a belt of pre- shaped bodies, the pre-shaped bodies being inter- 55 a) providing a melt-processed composition con- connected by flash; followed by cutting of the belt taining at least one active agent and at least one into individual pre-shaped bodies or strips of pre- thermoplastic binder; shaped bodies prior to charging the pre-shaped bod- b) charging a predetermined amount by weight

14 27 EP 3 124 008 A1 28

of the melt-processed composition into a die shaped bodies of the melt-processed composition is cavity; unwound from a spool. c) compressing the melt-processed composition to simultaneously shape and deflash the com- 11. The method of claim 7, wherein the belt comprises position to form a monolithic tablet, using com- 5 either a single or more than one row of pre-shaped pression equipment; and bodies of the melt-processed composition. d) ejecting the monolithic tablet from the die. 12. The method of claim 7, wherein the belt is cut into a 2. The method of claim 1, wherein providing the melt- plurality of single-row belts. processed composition comprises plastifying a com- 10 position containing at least one active agent and at 13. The method of claim 7, wherein deflashing of the least one thermoplastic binder by heating, shearing pre-shaped body occurs through plastic deformation and heating and shearing to obtain a melt, and forc- during shaping. ing the melt through at least one orifice; wherein the melt-processed composition is manufactured by15 14. The method of claim 7, wherein the pre-shaped bod- melt-extrusion or injection molding. ies are a cylinder with hemispherical extremities.

3. The method of claim 1 , comprising providing pre- shaped bodies of the melt-processed composition, wherein each pre-shaped body has a predetermined 20 weight, and charging a pre-determined number of the pre-shaped bodies into the die cavity.

4. The method of claim 3, wherein the number of pre- shaped bodies to be charged into the die cavity is 25 one.

5. The method of claim 3, wherein providing pre- shaped bodies of the melt-processed composition comprises a calendering process. 30

6. The method of claim 3 wherein providing pre-shaped bodies of the melt-processed composition compris- es a calendering process to obtain a belt of pre- shaped bodies, the pre-shaped bodies being inter- 35 connected by flash; followed by cutting of the belt into individual pre-shaped bodies or strips of pre- shaped bodies prior to charging the pre-shaped bod- ies into the die cavity. 40 7. The method of claim 1, comprising providing a belt of pre-shaped bodies of the melt-processed compo- sition each having an predetermined weight, the pre- shaped bodies being interconnected by flash, cutting out a pre-shaped body from the belt and charging 45 the pre-shaped body into the die cavity.

8. The method of claim 7, wherein the cutting and charging action is synchronized with the advancing action of the compression equipment. 50

9. The method of claim 7, wherein providing the belt of pre-shaped bodies of the melt-processed composi- tion comprises a calendering process; wherein the cutting and calendaring is synchronized with the ad- 55 vancing action of the compression equipment.

10. The method of claim 7, wherein the belt of pre-

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 61410344 A [0001]

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