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(19) United States (12) Patent Application Publication (10) Pub US 20130122061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0122061 A1 Vergnault et al. (43) Pub. Date: May 16, 2013 (54) DELAYED RELEASE TABLET WITH (30) Foreign Application Priority Data DEFINED CORE GEOMETRY Apr. 24, 2003 (GB) ................................. .. 03093424 (71) Applicant: J agotec AG, MuttenZ (CH) (72) Inventors: Guy Vergnault, Kembs (FR); Pascal Publication Classi?cation Grenier, Kappelen (FR); Christophe Dragan, GeispitZen (FR) (51) Int. Cl. A61K 9/00 (2006.01) (73) Assignee: JAGOTEC AG, MuttenZ (CH) (52) us. c1. CPC .................................. .. A61K 9/0002 (2013.01) (21) App1.No.: 13/713,528 USPC ......................................... .. 424/400; 514/178 (22) Filed: Dec. 13, 2012 (57) ABSTRACT Related US. Application Data A tablet comprising a core containing an active agent, and a (63) Continuation of application No. 13/428,548, ?led on coating, the core being disposed Within the coating such that Mar. 23, 2012, noW Pat. No. 8,394,407, Which is a the coating has a thickness about a longitudinal axis (X-Y) of continuation of application No. 10/554,538, ?led on about 4.85 to 4.95 mm. The position of the core Within the Jan. 16, 2007, noW Pat. No. 8,168,218, ?led as appli coating dictating that the active agent is released rapidly after cation No. PCT/lB2004/001693 on Apr. 23, 2004. a lag time during Which time no active agent is released. Patent Application Publication May 16, 2013 Sheet 1 of2 US 2013/0122061 A1 8 a e 4 1 a a i. - - “Wham...” ij zz i , Patent Application Publication May 16, 2013 Sheet 2 0f 2 US 2013/0122061 A1 % Reiease - Prednisnna Wigwam WTTR482 680Q09 rmww . amiw an .r! ‘W61... ECm. e wnv8% SM gm mum., mme ‘m.. P34;3% d+m US 2013/0122061Al May 16,2013 DELAYED RELEASE TABLET WITH This dosage form is characteriZed by a coating containing a DEFINED CORE GEOMETRY natural or synthetic gum that gels in the presence of aqueous media. The coating acts as a barrier to the ingress of aqueous [0001] This invention is concerned With a tablet comprising media into an active-agent-containing core and thereby cre a core containing a drug substance and a coating that is ating a lag time during Which no drug substance is released. applied to said core by means of compression-coating tech The gellable coating acts as a medium through Which drug is niques. The tablet can contain all manner of drug substances, released in a delayed or modi?ed manner. It is stated that the but is particularly suitable for administering those that are advantageously released only after a predetermined lag time lag time can be modulated by varying the coating Weight. after administration. The tablets are particularly suitable for [0009] There are several problems With such an approach: administering lucocorticosteroids selected from prednisone, First, release of the drug occurs by means of diffusion through prednisolone or methylprednisolone. the gelled coating, in the case of drugs that have a narroW [0002] Research into the chronopharmacological ?eld has absorption WindoW, or in the case of drugs adapted to treat a demonstrated the importance of biological rhythms in drug relatively small affected area of the GI tract or colon, once the therapy. Very often, optimal clinical outcomes cannot be lag time has expired it is desirable to release the drug as achieved if a drug is released constantly after ingestion. This rapidly as possible to ensure that all or substantially all of the is particularly the case if symptoms of a disease display drug released at the desired site. A sloW diffusion of the drug circadian variations. In such cases, drug release should vary is not appropriate in such cases. Further, by attempting to in a manner that is sympathetic to these variations in order control lag time by controlling the coating Weight, the formu that drug plasma concentrations are at an optimal therapeutic lator’s latitude is limited in this regard, because increasing level only When required to treat symptoms of a disease state. coating Weight adds additional cost to the dosage form, and it [0003] In particular, if symptoms of a disease become also adds to the siZe of the dosage form, Which may make it apparent at night, or in the early hours upon Waking, the time dif?cult to sWalloW for certain patient populations such as When a patient must take its medication in order to affect the minors and for the elderly or in?rm. Still further, merely best clinical outcome requires detailed consideration. For adjusting coat Weight does not ensure that a coating is of a example, most asthma attacks occur in the early hours of the desired thickness at a particular site. It remains that if the core morning, eg 4 am to 6 am. This is a result of complex is not correctly positioned Within a die of a press coating circadian rhythms such as the secretion of hydrocortisone and machine, despite having selected a particular coat Weight, adrenaline. Ischaemic heart diseases occur most often during part of the coating may be unintentionally thinner than the night or in the early Waking hours around breakfast time. desired, resulting in unforeseen premature release of the drug. Stiffness and pain associated With rheumatoid arthritis and [0010] The applicant has noW surprisingly found that by osteoarthritis occur in the early Waking hours, Which is carefully selecting the geometry of a core Within its coating, believed to be as a result of the secretion of IL-6 in the early it is possible to manipulate the coating thickness at speci?c hours of the morning, e.g. around 2 am to 4 am. points on the tablet to ensure an appropriate coating thickness [0004] With conventional immediate release dosage forms, to produce tablets having a speci?cally tuned lag time. Fur synchronization of drug administration With a nocturnal cir thermore, because one is able to increase thickness Where it is cadian rhythm responsible for the symptoms experienced by needed in the coating, one can reduce coating material to a patient Would require a patient having to be disturbed from alloW use of the minimum amount necessary to achieve the sleep to take a medicament during the early hours of the desired release characteristics, thus saving on cost of materi morning in order to achieve the most ef?cacious clinical als and also reducing the overall tablet siZe. outcome. Of course, this Would be highly inconvenient for a [0011] Still further, the applicant has found that by select patient. ing appropriate core and coating materials, one is able not [0005] Accordingly, there remains a need to provide do sage only to accurately control the lag time, one is also to ensure forms that can be taken at a convenient hour before bedtime that all, or substantially all, of the drug substance upon expiry that Will release an effective dose of a drug substance only of the lag time is released rapidly and at the absorption site, or after a pre-determined lag time in order to synchronise peak the locally affected site. plasma concentrations of drug With a particular circadian [0012] Accordingly, in a ?rst aspect of the present invention rhythm. there is provided a tablet comprising a core containing an [0006] Furthermore, particularly in relation to drug sub drug substance, and a coating around said core, the core being stances that have a narroW absorption WindoW, or in the case disposed Within said coating such that the coating thickness of drug substances that are adapted to treat a local condition in about an axis Qi-Y) (see FIG. 1) is thicker than the coating the colon such as Crohn’s disease, ulcerative colitis, IBS and about an axis (AB) (see FIG. 1) orthogonal to Qi-Y), and IBD there is also a need to provide a dosage forms that rapidly Wherein the thickness of the coating about the axis Qi-Y) is releases the drug substances after reaching the end of the lag selected such that the coating is adapted to rupture upon time. immersion in an aqueous medium after a period of betWeen [0007] Still further, having regard to the varied life styles of about 2 to 6 hours. patients, in order to reduce the inter- and intra-subject vari [0013] According to the present invention, the coating ance inbioavailability there is a need to provide a dosage form thickness about the axis Qi-Y) is thicker than the coating that releases a drug With a reliable lag time, and to provide about the axis (A-B). The ratio of the thickness of the coating peak plasma drug concentrations at a pro-determined time, about the axis Qi-Y) to the thickness of the coating about the irrespective of Whether a patient is in a fed or fasted state. axis (A-B) may be from 2.2 to 2.6:l.0 to 1.6. [0008] Time controlled release formulations are knoWn in [0014] In another aspect of the invention there is provided a the art that are able to deliver drug substances With a de?ned tablet comprising a core containing an drug substance and a release rate after a lag time during Which no drug substance is coating around said core, the core being disposed Within said released. Such a dosage form is disclosed in WO 02/072033. coating such that the coating thickness about an axis Qi-Y) is US 2013/0122061A1 May 16,2013 thicker than the coating about an axis (A-B) orthogonal to [0019] During the compression of the coating around the (X-Y), and the thickness of the coating about the axis Qi-Y) core, the coating material above and beloW the core (the is at least about 2.2 mm, particularly about 2.2 to 2.6 mm, material along and about the (A-B) axis) is relatively highly more particularly about 235 to 2.35 to 2.45 nm.
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