US007438929B2 (12) United States Patent (10) Patent No.: US 7438,929 B2 Beckert et al. (45) Date of Patent: *Oct. 21, 2008 (54) MULTI-PARTICULATE FORM OF (56) References Cited MEDICAMENT, COMPRISING AT LEAST U.S. PATENT DOCUMENTS TWO DIFFERENTLY COATED FORMS OF PELLET 4,600,577 A 7/1986 Didriksen 4,720,387 A 1/1988 Sakamoto et al. (75) Inventors: Thomas Beckert, Warthausen (DE): 6,897.205 B2 * 5/2005 Beckert et al. .............. 514f159 Hans-Ulrich Petereit, Darmstadt (DE): Jennifer Dressman, Frankfurt (DE); Markus Rudolph, Neu-Isenburg (DE) OTHER PUBLICATIONS (73) Assignee: Roehm GmbH & Co. KG, Darmstadt Schmidt, C., "A Multiparticulate Drug-delivery System Based on (DE) Pellets Incorporated into Congealable Polyethylene Glycol Carrier (*) Notice: Subject to any disclaimer, the term of this Materials'. International Journal of Pharmaceutics 216 (2001) 9-16, patent is extended or adjusted under 35 Elsevier. U.S.C. 154(b) by 614 days. * cited by examiner This patent is Subject to a terminal dis claimer. Primary Examiner Johann Richter Assistant Examiner Danielle Sullivan (21) Appl. No.: 10/949,323 (74) Attorney, Agent, or Firm Oblon, Spivak, McClelland, (22) Filed: Sep. 27, 2004 Maier & Neustadt, P.C. (65) Prior Publication Data (57) ABSTRACT US 2005/OO53660 A1 Mar. 10, 2005 The invention relates to a multiparticulate drug form suitable Related U.S. Application Data for uniform release of an active pharmaceutical ingredient in the Small intestine and in the large intestine, comprising at (63) Continuation of application No. 10/239.209, filed as least two forms of pellets A and B which comprise an active application No. PCT/EP01/02679 on Mar. 9, 2001, pharmaceutical ingredient in the core and have different poly now Pat. No. 6,897,205. mer coatings which determine the release of the active ingre dient at different pH values, characterized in that pellet form (30) Foreign Application Priority Data A is provided with an inner polymer coating which enables continuous release of active ingredient, and has an outer Jan. 31, 2001 (DE) ................................ 101 O4504 enteric coating which rapidly dissolves above about pH 5.5, Feb. 1, 2001 (DE) ................................ 101 04 880 and pellet form B is provided with a polymer coating which, in the USP release test, releases less than 20% of the active (51) Int. Cl. ingredient at pH 6.8 in 6 hours and releases more than 50% of A 6LX 9/52 (2006.01) the active ingredient at pH 7.2 in 6 hours. The invention A6 IK 9/14 (2006.01) additionally relates to a process for producing the multipar (52) U.S. Cl. ....................................... 424/490; 424/489 ticulate drug form and to the use of pellet forms A and B for (58) Field of Classification Search ................. 514/159; producing the drug form. 424/489, 490 See application file for complete search history. 13 Claims, No Drawings US 7,438,929 B2 1. 2 MULTI-PARTICULATE FORM OF Problem and Solution MEDICAMENT, COMPRISING AT LEAST There is a need for drug forms which release active ingre TWO DIFFERENTLY COATED FORMS OF dients in the intestinal tract and moreover comply with spe PELLET cific active ingredient release profiles. The intention was to provide a drug form which releases This is a continuation application of U.S. application Ser. virtually no active ingredient in the stomach and enables No. 10/239,209 filed on Feb. 12, 2003, which is the national release of active ingredient which is as uniform and long stage of PCT/EP01/02679, filed Mar. 9, 2001. lasting as possible both in the Small intestine and in the large The invention relates to a multiparticulate drug form which intestinal region. The drug form is intended to be suitable for comprises at least two differently coated pellet forms and 10 example for the therapy of inflammatory bowel disorders enables release of active ingredient to be substantially uni Such as ulcerative colitis and, in particular, Crohn's disease. form over the entire intestinal region. The invention further The object is achieved by a relates to a process for producing the multiparticulate drug multiparticulate drug form suitable for uniform release of form and to the use of the pellet forms A and B for producing an active pharmaceutical ingredient in the Small intestine and the drug form. 15 in the large intestine, comprising at least two forms of pellets A and B which comprise an active pharmaceutical ingredient PRIOR ART in the core and have different polymer coatings which deter mine the release of the active ingredient at different pH val Multiparticulate drug forms obtained by compression of a lues, binder with active ingredient-containing pellets coated with characterized in that (meth)acrylate copolymers resistant to gastric juice are dis pellet form A is provided with an inner polymer coating closed in Beckert et al. (1996), “Compression of enteric which enables continuous release of active ingredient, and coated pellets to disintegrating tablets' International Journal has an outer enteric coating which rapidly dissolves above of Pharmaceuticals 143, pp. 13–23. about pH 5.5, and (Meth)acrylate copolymers which comprise monomers 25 with quaternary ammonium groups, e.g. trimethylammoniu pellet form B is provided with an inner polymer coating methly sic methacrylate chloride, and their use for release which, in the USP release test, releases less than 20% of the slowing medicament coatings have been known for a long active ingredient at pH 6.8 in 6 hours and releases more than time (for example from EP-A 181515 or from DE-C 1617 50% of the active ingredient at pH 7.2 in 6 hours. 751). Processing takes place in organic Solution or as aqueous 30 The invention further relates to a process for producing a dispersion, for example by spraying onto medicament cores multiparticulate drug form by the different pellet forms A and or else without solvent in the presence of flow aids by appli B being produced by coating active ingredient-containing cation in the melt (see EP-A 0 727 205). cores with the stated polymer coatings, being mixed together EP-A 629 398 describes pharmaceutical formulations and being converted into a multiparticulate drug form by which have a core with an active ingredient and an organic 35 introduction into a capsule or compression to a tablet unit in acid, where the core has a two-layer covering. The inner the presence of excipients. covering in this case is formed by a release-slowing (meth) The invention likewise relates to the use of the, described acrylate copolymer with quaternary ammonium groups pellet forms A and B in the claimed process for producing a (EUDRAGITR) RS), while the outer covering has an enteric multiparticulate drug form with uniform release of active coating, for example a copolymer of the type EUDRAGITR) 40 ingredient in the pH range of 6.8 and sic 7.2, corresponding L30D-55 (ethyl acrylate/methacrylic acid, 50:50). The to the conditions in the Small and large intestine, in particular release characteristics achieved can be described by a rapid for the treatment of Crohn's disease or ulcerative colitis. release of active ingredient after a time lag at elevated pH. EP 0 704 207 A2 describes thermoplastic materials for MODE OF OPERATION OF THE INVENTION drug coverings soluble in intestinal juice. These comprise 45 copolymers of 16 to 40% by weight acrylic or methacrylic The multiparticulate drug form may be in the form of a acid, 30 to 80% by weight methyl acrylate and 0 to 40% by capsule filled with pellets, e.g. a gelatin capsule, or it may be weight of other alkyl esters of acrylic acid and/or methacrylic a tablet in which the pellets have been compressed together acid. with conventional excipients to give the tablet unit. EP 0704208A2 describes coating agents and binders for 50 The multiparticulate drug form is suitable for substantially drug coverings soluble in intestinal juice. These comprise uniform release of an active pharmaceutical ingredient in the copolymers of 10 to 25% by weight methacrylic acid, 40 to Small intestine and in the large intestine and comprises at least 70% by weight methyl acrylate and 20 to 40% by weight two forms of pellets, A and B, which comprise an active methyl methacrylate. The description mentions not only pharmaceutical ingredient in the core, but have different poly monolayer coatings but also multilayer coating systems. 55 mer coatings which determine the release of the active ingre These may consist of a core which comprises, for example, a dient at different pH values. In vitro, the USP release test basic or a water-sensitive active ingredient, have a sealing (USP 23, method 2) results at pH 6.8 and at pH 7.2 in com layer of another coating material Such as cellulose ether, bined profiles which are between the individual release cellulose ester or a cationic polymethacrylate, for example of curves for the two pellet forms A and B. In vivo, the release the EUDRAGITR type, inter alia including EUDRAGITR) 60 profile of pellet form A predominates in the small intestine, RS and RL, and are then additionally provided with the and release of active ingredient from pellet form B starts abovementioned covering soluble in intestinal juice. while in the large intestinal region. Multiparticulate drug forms in the form of capsules or The pellet cores consist entirely or partly of an active compressed tablets have been known for some time. It is also pharmaceutical ingredient. The cores are usually spherical or known to introduce pellets with different polymer coatings 65 round and have diameters in the range from about 0.3 to 2 into multiparticulate drug forms in order in this way to mm.