USOO8865213B2 (12) United States Patent (10) Patent No.: US 8,865,213 B2 Sheth et al. (45) Date of Patent: Oct. 21, 2014 (54) MODIFIED RELEASE PHARMACEUTICAL (52) U.S. Cl. COMPOSITIONS CPC ........... A6 IK3I/4422 (2013.01); A61 K9/5078 (2013.01); A61 K9/5042 (2013.01); A61 K (75) Inventors: Nitin Vadilal Sheth, Raleigh, NC (US); 9/5084 (2013.01); A61K 9/5026 (2013.01); Sunil Suresh Jog, Maharashtra (IN); 461s 9/2 ost (2013.01) Santosh Sadashiv Chothe, Maharashtra (58) folassification s 424/489: 514/264.1 e O SSCO Sea (IN); Sampada Hemant Tupe, USPC ................................ 424/489, 469: 514/264.1 Maharashtra (IN) See application file for complete search history. (73) Assignees: USV Limited (IN); Indicus Pharma (56) References Cited LLC, Raleigh, NC (US) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 4,892,741 A * 1/1990 Ohm et al. .................... 424/479 6,897.205 B2 * 5/2005 Beckert et al. ................ 514f159 U.S.C. 154(b) by 435 days. 2004/O126358 A1* 7/2004 Warne et al. ................. 424/85.2 2005/0020613 A1 1/2005 Boehmet al. ................. 514,282 (21) Appl. No.: 12/981,077 * cited by examiner (22) Filed: Dec. 29, 2010 Primary Examiner — Ali Soroush (65) Prior Publication Data (74) Attorney, Agent, or Firm — Schwegman Lundberg & Woessner, P.A. US 2011 FO159093 A1 Jun. 30, 2011 (57) ABSTRACT (30) Foreign Application Priority Data Disclosed herein are multiparticulate modified release phar maceutical compositions comprising: (a) a first portion com Dec. 30, 2009 (IN) ......................... 3018/MUMA2009 prising an active ingredient, at least one surfactant and at least one release modifying agent and (b) a second portion com (51) Int. Cl. prising an active ingredient and optionally a release modify A6 IK 9/26 (2006.01) ing agent. Particularly, the active ingredient in the first portion A6 IK 9/14 (2006.01) is a calcium channel blocker and the modified release com A 6LX 9/50 (2006.01) position is in the form of a multiparticulate tablet. A6 IK3I/4422 (2006.01) A6 IK9/20 (2006.01) 25 Claims, 2 Drawing Sheets U.S. Patent Oct. 21, 2014 Sheet 1 of 2 US 8,865,213 B2 Contparative dissolution of Nisoleipiae ER tablets 34ng in pH6.8 phosphate buffer with 1/e SLS 8 : 60 s as S Time (hrs.) rer Inovator's product(Sular 34mg) -- Example 1 Fig. 1 U.S. Patent Oct. 21, 2014 Sheet 2 of 2 US 8,865,213 B2 Comparative dissolution of Nisodipine ER tablets 34ang in pH6.8 phosphate buffer with 10 SES t s s s s : Time (hrs.) re. In oyator's product (Sulair 34 rig -- Example 2 Fig. 2 US 8,865,213 B2 1. 2 MODIFIED RELEASE PHARMACEUTICAL There exists a need for an improved multiparticulate for COMPOSITIONS mulation that would improve the bioavailability and release rate and would ameliorate the drawbacks of prior art compo RELATED APPLICATION sitions. This application claims the benefit of Indian Provisional OBJECT OF INVENTION Application No. 3018/MUM/2009, filed on Dec. 30, 2009, Entitled: MODIFIED RELEASE PHARMACEUTICAL One object of the invention is to provide a multiparticulate COMPOSITIONS, which application is incorporated in its modified release pharmaceutical composition comprising: entirety. 10 (a) a first portion and (b) a second portion, wherein the active ingredient in the first and second portion is same or belong to TECHNICAL FIELD OF THE INVENTION a different therapeutic class. Another object of the invention is to provide multiparticu The present invention relates to multiparticulate modified late modified release compositions in which a first portion of release compositions. More particularly, the invention relates 15 the active ingredient is released in a delayed manner upon to Solid oral dosage forms comprising multiparticulate modi administration and a second portion of the active ingredient is fied release compositions. released in an extended manner. BACKGROUND OF THE INVENTION Another object of the invention is to provide multiparticu late modified release composition comprising: (a) a first por Multiparticulate drug delivery systems are dosage form, tion providing the release of the active ingredient in a delayed which consists of multiple small discrete units, where each manner and (b) a second portion providing the release of the unit exhibits some intended characteristics. Multiparticulates active ingredient in an extended manner; wherein the active are well-known dosage forms that comprise a plurality of ingredient present in the first portion and that of the second particles for different therapeutic use of the drug. 25 portion is a Dihydropyridine calcium channel blocker, Such as Modified release formulation aims at minimizing the peak Nisoldipine. to-trough variation in drug plasma levels that are associated Yet another object of the invention is to provide multipar with conventional frequent dosage regimes. ticulate modified release compositions in which the active Several attempts have been made to develop formulations ingredient in the first portion is a calcium channel blocker and that provide a Zero-order release of the drug compound. Most 30 the active ingredient present in the second portion is selected of the modified release formulations today offer the release from the group comprising angiotensin-converting enzyme profile as a zero order, first order or have a delayed release inhibitor, beta-blocker, anti-angina agents, anti-arrhythmic profile. Combination of different types of release i.e. either agents, anti-ischaemic agents, vasodilators, bronchodilators, extended-release or delayed-release and combinations hypolipidaemic agents and antidiabetics. thereof can be achieved by multiparticulates in the dosage 35 Another object of the invention is to provide multiparticu form. However these also offer difficulty in achieving the late modified release compositions in which a first portion of right combination of pellets/particles or where a very high Nisoldipine is released in a delayed manner and a second dose needs to be given. portion of Nisoldipine is released in an extended manner. U.S. Pat. No. 4,892,741 discloses solid medicament prepa Another object of the invention is to provide multiparticu ration having a long-lasting action in the form of a press 40 late modified release compositions in which a first portion of coated tablet which containing dihydropyridine. The press Nisoldipine is provided in the form of delayed release pellets coated tablet comprises (a) a core which contains a dihydro and a second portion of Nisoldipine is provided in the form of pyridine in rapid-release form, and (b) a coat around the core, matrix granules. Particularly, said composition is in the form the coat containing a dihydropyridine in slow-release form. of a tablet. US20062 10631 discloses a multi-particulate, modified-re 45 Another object of the invention is to provide multiparticu lease pharmaceutical composition for the oral administration late modified release compositions in which the first portion of an active ingredient to the colon, said particles comprising of the active ingredient is release in a delayed or extended a core comprising an active ingredient or a pharmaceutically manner and the second portion of the active ingredient is acceptable salt or ester thereof, and optionally one or more released immediately upon administration. excipients; a first coating applied to the Surface of the core, 50 Another object of the invention is to provide multiparticu wherein said first coating is insoluble in gastric juice and in late modified release compositions in which both portions of intestinal juice below pH 7, but soluble in colonic intestinal active ingredients are released in an extended manner. juice; and a second coating applied to the Surface of the first coating. SUMMARY OF INVENTION Studies have shown that there are adverse effects with the 55 coat-core systems compared to other drug delivery systems. The present invention provides multiparticulate modified Further, the core-coat technology requires the use of special release pharmaceutical composition comprising: (a) a first ized equipment thereby rendering an expensive process of portion and (b) a second portion, wherein the active ingredi manufacture. ent in the first and second portion is same or belong to a Therefore, there still exists a need to formulate modified 60 different therapeutic class. release formulations containing two different portions of Particularly, said multiparticulate compositions releases active ingredient which will provide for modified release of one or more active ingredient(s) in a modified manner. the active ingredient and which will have reduced or no According to one aspect, the present invention provides a adverse effects compared to prior art compositions. There multiparticulate modified release pharmaceutical composi also exists a need to develop process which could be simple 65 tion comprising: and cost effective and would not involve any tedious tech (a) a first portion comprising an active ingredient, at least one niques. Surfactant and at least one release modifying agent; US 8,865,213 B2 3 4 (b) a second portion comprising an active ingredient and from about 40% to about 100% of Nisoldipine is released; optionally a release modifying agent. after about 12 hours, more than about 80% of Nisoldipine is Preferably, the active ingredient in the first portion is a released. calcium channel blocker. Preferably, the active ingredient in According to one aspect, the invention provides multipar the first portion and the second portion is a calcium channel 5 ticulate modified release pharmaceutical composition com blocker selected from the group comprising Nisoldipine, prising: Nifedipine, Nitrendipine, Nicardipine, Nimodipine, Felo (a) a first portion comprising Nisoldipine, at least one dipine, Amlodipine, Aranidipine, AZelnidipine, Barnidipine, Surfactant and at least one release modifying agent; Benidipine, Cilnidipine, Clevidipine, Efonidipine, Lacid (b) a second portion comprising Nisoldipine and optionally ipine, Lercanidipine, Manidipine, Nilvadipine, Nitrendipine 10 a release modifying agent. or Pranidipine.