(12) United States Patent (10) Patent No.: US 8,865,213 B2 Sheth Et Al

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 :

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. According to another aspect, the invention provides mul According to another aspect, the present invention pro tiparticulate modified release pharmaceutical composition vides multiparticulate modified release pharmaceutical com comprising: positions wherein the active ingredient present in the first 15 (a) a first portion comprising: the active ingredient loaded portion and the second portion are same or belong to a dif on an inert inner core, a delayed release coat and option ferent therapeutic class. ally a separating coat between the inner core and delayed According to another aspect, the present invention pro release coat; vides multiparticulate modified release pharmaceutical com (b) a second portion comprising: the active ingredient and positions wherein the first portion provides the release of the one or more release modifying polymer. active ingredient in a modified manner and the second portion According to preferred aspect, the invention provides mul provides the release of the active ingredient in an extended tiparticulate modified release pharmaceutical composition manner. Particularly, said first and second portion of the com comprising: position may be in the form of pellets, tablets, mini-tablets, (a) a first portion comprising: the active ingredient granules, microparticles or nanoparticles. 25 adsorbed on an inert inner core, a delayed release coat According to a preferred aspect, the invention provides and optionally a separating coat between the inner core multiparticulate modified release pharmaceutical composi and delayed release coat; tions wherein the first portion provides the release of the (b) a second portion comprising: the active ingredient and active ingredient in a delayed manner and the second portion one or more release modifying polymer; provides the release of the active ingredient in an extended wherein said first portion of the active ingredient is released at pH above 5.5. a. According to a preferred aspect, the invention provides According to another aspect, the present invention pro multiparticulate modified release pharmaceutical composi vides multiparticulate modified release pharmaceutical com tion comprising: positions wherein the first portion of the active ingredient is 35 (a) a first portion comprising Nisoldipine loaded on an inert release in a delayed or extended manner and the second inner core, a delayed release coat and optionally a sepa portion of the active ingredient is released immediately upon rating coat between the inner core and delayed release administration. COat, According to another aspect, the invention provides mul (b) a second portion comprising Nisoldipine and optionally tiparticulate modified release compositions in which both 40 a release modifying agent; portions of active ingredients are released in an extended wherein said first portion of the active ingredient is released at a. pH above 5.5. According to another aspect, the present invention pro According to another aspect, the present invention pro vides multiparticulate modified release pharmaceutical com vides process for preparation of said multiparticulate modi positions wherein the active ingredient present in the first 45 fied release compositions. portion is a calcium channel blocker and the active ingredient According to one aspect, the invention provides a process present in the second portion is selected from the group com for preparation of multiparticulate modified release pharma prising angiotensin-converting enzyme inhibitor, beta ceutical composition comprising: blocker, anti-angina agents, anti-arrhythmic agents, anti-is (a) preparing a first portion comprising: the active ingredi chaemic agents, vasodilators, bronchodilators, 50 ent loaded on an inert inner core, a delayed release coat hypolipidaemic agents and antidiabetics. and optionally a separating coat between the inner core According to a preferred aspect, the invention provides and delayed release coat; multiparticulate modified release pharmaceutical composi (b) preparing a second portion comprising: the active tions wherein the first portion of the composition is provided ingredient and one or more release modifying polymer; in the form of delayed release pellets and the second portion 55 (c) formulating the first portion and the second portion into of the composition is provided in the form of matrix granules. multiparticulate dosage form. Preferably, the multiparticulate modified release pharma Additional aspects and/or advantages of the present inven ceutical composition is in the form of multiparticulate tablet tion will be evident from the description that follows. or multiparticulate capsule, more preferably as multiparticu late tablet. 60 BRIEF DESCRIPTION OF THE DRAWINGS Preferably, the active ingredient present in the first portion and the second portion is Nisoldipine. More preferably, the FIG. 1 shows in vitro-dissolution profile of Nisoldipine composition is in the form of a multiparticulate tablet. Said extended release tablet prepared according to Example 1 of compositions of Nisoldipine exhibits a dissolution profile the present invention versus Sular(R) such that after about 2 hours, from about 5% to about 50% of 65 FIG. 2 shows in vitro-dissolution profile of Nisoldipine Nisoldipine is released; after about 4 hours, from about 20% extended release tablet prepared according to Example 2 of to about 90% of Nisoldipine is released; after about 8 hours, the present invention versus Sular(R) US 8,865,213 B2 5 6 DESCRIPTION OF THE INVENTION According to another embodiment, the present invention provides multiparticulate modified release compositions pro The present invention provides multiparticulate modified viding a first order release. release pharmaceutical composition comprising: (a) a first According to one embodiment, the present invention pro portion and (b) a second portion, wherein the active ingredi vides multiparticulate modified release compositions ent in the first and second portion is same or belong to a wherein the active ingredient in the first portion and the sec different therapeutic class. ond portion is a calcium channel blocker. Particularly, said multiparticulate compositions releases According to a preferred embodiment, the present inven one or more active ingredient(s) in a modified manner. tion provides multiparticulate modified release compositions 10 wherein the active ingredient in the first portion is a dihydro According to one embodiment, the invention provides pyridine calcium channel blocker. multiparticulate modified release compositions in which a The calcium channel blocker may be selected from the first portion of the active ingredient is released in a delayed group comprising Nisoldipine, Nifedipine, Nitrendipine, manner upon administration and a second portion of the Nicardipine, Nimodipine, Felodipine, Amlodipine, Aranid active ingredient is released in an extended manner, thereby 15 ipine, AZelnidipine, Barnidipine, Benidipine, Cilnidipine, delaying the release of the active ingredient to a region within Clevidipine, Efonidipine, Lacidipine, Lercanidipine, Manid the gastrointestinal tract and providing greater uptake of the ipine, Nilvadipine, Nitrendipine or Pranidipine. active ingredient as compared to a formulation comprising an According to another embodiment, the present invention enteric polymer coating on the core or a formulation contain provides multiparticulate modified release compositions ing polymer which gives the Sustained release effect. wherein the active ingredient present in the first portion and The inventors of the present invention have developed the second portion are same or belong to a different therapeu compositions which not only give the appropriate drug tic class. release from the drug product produced but also improves the Particularly, said first and second portion of the composi bioavailability. tion may be in the form of pellets, tablets, mini-tablets, gran According to one embodiment, the present invention pro 25 ules, microparticles or nanoparticles. vides multiparticulate modified release pharmaceutical com According to one embodiment, the present invention pro position comprising: vides a multiparticulate modified release composition com (a) a first portion comprising an active ingredient, at least one prising: (a) a first portion providing the release of the active Surfactant and at least one release modifying agent; ingredient in a delayed manner and (b) a second portion (b) a second portion comprising an active ingredient and 30 providing the release of the active ingredient in an extended optionally a release modifying agent. manner, wherein the active ingredient present in the first portion and that of the second portion are the same. According to one embodiment, the invention provides According to another embodiment, the present invention multiparticulate modified release compositions which pro provides a multiparticulate modified release composition vide a combination of two or more different release profiles in 35 comprising: (a) a first portion providing the release of the a single dosage form. active ingredientina delayed manner and (b) a second portion In the practice of the present invention, the amount of providing the release of the active ingredient in an extended active ingredient present in the first portion and the second manner, wherein the active ingredient present in the first portion depend on the dosing regime that is desired. portion and that of the second portion belong to the same or According to one embodiment, the invention provides 40 different therapeutic class. multiparticulate modified release compositions wherein the According to one embodiment, the present invention pro first portion provides the release of the active ingredient in a vides a multiparticulate modified release composition com modified manner and the second portion provides the release prising: (a) a first portion providing the release of the active of the active ingredient in an extended manner. ingredient in an extended manner and (b) a second portion According to another embodiment, the invention provides 45 providing the release of the active ingredient immediately multiparticulate modified release compositions wherein the upon administration; wherein the active ingredient present in first portion provides the release of the active ingredient in a the first portion and that of the second portion are the same. delayed manner and the second portion provides the release In accordance with the features of the present invention, the of the active ingredient in an extended manner. inventors have developed formulations of Nisoldipine, a According to yet another embodiment, the invention pro 50 dihydropyridine calcium channel blocker. Formulations of vides multiparticulate modified release compositions other therapeutic drugs may similarly be prepared using the wherein the first portion of the active ingredient is release in features of the invention. a delayed or extended manner and the second portion of the A wide variety of active agents can be used in conjunction active ingredient is released immediately upon administra with the present invention. The active agents which may be tion. 55 used according to the present invention include water soluble According to one embodiment, the present invention pro and water insoluble drugs. Examples of Such active agents vides a multiparticulate modified release composition com include antihypertensives, such as inhibitor of angiotensin prising: (a) a first portion providing the release of the active converting enzyme, beta-blockers, calcium channel blockers, ingredient in a modified manner and (b) a second portion anti-angina agents, anti-arrhythmic agents, anti-ischaemic providing the release of the active ingredient immediately 60 agents, angiotensin receptor blockers, vasodilators, bron upon administration and/or in a delayed manner and/or in an chodilators, hypolipidaemic agents, antithrombotics, anti-in extended manner, wherein the active ingredient present in the flammatory agents, diuretics, anti-allergics, skeletal muscle first portion and that of the second portion are either the same relaxants, antispasmodics, antidiabetics such as insulin sen or belong to the same or different therapeutic class. sitizer, insulin secretagogue and the like. According to one embodiment, the present invention pro 65 Calcium channels blockers are a group of drugs that slow vides multiparticulate modified release compositions provid the entry of calcium into cells by regulating cellular calcium ing a first order release followed by Zero order release. channels. Calcium channel blockers disrupt the calcium US 8,865,213 B2 7 8 (Ca2+) conduction of calcium channels. Clinically calcium Prior art discloses various formulations of Nisoldipine. channel blockers are used to decrease the blood pressure. Various attempts have been made to improve the characteris Calcium channel blockers work by blocking Voltage-gated tics of controlled release formulations of Nisoldipine. Prior calcium channels (VGCCs) in cardiac muscle and blood ves art discloses formulations of Nisoldipine involving the core sels. This decreases intracellular calcium leading to a reduc coat technology. The disadvantages associated with the core tion in muscle contraction. In the heart, a decrease in calcium coat technology is that it is a multiple step process and tedious available for each beat results in a decrease in cardiac con technique. The manufacturing involves use of specialized tractility. In blood vessels, a decrease in calcium results in less equipments and the cost of manufacturing is high. contraction of the vascular Smooth muscle and therefore an In view of the aforementioned drawbacks associated with 10 prior art compositions it is apparent that there still exists a increase in arterial diameter (CCB's do not work on venous need for developing a drug delivery system which would Smooth muscle), a phenomenon called vasodilation. Vasodi ameliorate the aforementioned drawbacks. lation decreases total peripheral resistance, while a decrease According to another embodiment, the present invention in cardiac contractility decreases cardiac output. Since blood provides multiparticulate modified release compositions pressure is determined by cardiac output and peripheral resis 15 wherein the active ingredient present in the first portion is a tance, blood pressure drops. calcium channel blocker and the active ingredient present in There are different types of calcium channel blockers such the second portion is selected from the group comprising as Dihydropyridine calcium channel blockers, Phenylalky angiotensin-converting enzyme inhibitor, beta-blocker, anti lamine calcium channel blockers, Benzothiazepine calcium angina agents, anti-arrhythmic agents, anti-ischaemic agents, channel blockers. Dihydropyridine calcium channel blockers vasodilators, bronchodilators, hypolipidaemic agents and include Nisoldipine, Nifedipine, Nitrendipine, Nicardipine, antidiabetics. Nimodipine, Felodipine, Amlodipine, Aranidipine, AZelnid According to one preferred embodiment, the present ipine, Barnidipine, Benidipine, Cilnidipine, Clevidipine, invention provides a multiparticulate modified release com Efonidipine, Lacidipine, Lercanidipine, Manidipine, Nilvad position comprising: (a) a first portion providing the release ipine, Nitrendipine or Pranidipine. Phenylalkylamine cal 25 of the active ingredient in a modified manner and (b) a second portion providing the release of the active ingredient imme cium channel blockers include drugs such as Verapamil and diately upon administration and/or in a delayed manner and/ Benzothiazepine calcium channel blockers include drugs or in an extended manner, wherein the active ingredient Such as Diltiazem. present in the first portion and that of the second portion is a Nisoldipine is one of the representative drug belonging to 30 calcium channel blocker. the dihydropyridine calcium channel blocker. Nisoldipine is According to a more preferred embodiment, the multipar used in the treatment of hypertension. Nisoldipine is also used ticulate modified release composition comprises: (a) a first in combination with other antihypertensive agents for the portion providing the release of the active ingredient in a treatment of hypertension. modified manner and (b) a second portion providing the Nisoldipine is a yellow crystalline Substance, practically 35 release of the active ingredient immediately upon adminis tration and/or in a delayed manner and/or in an extended insoluble in water but soluble in ethanol. Nisoldipine has a manner, wherein the active ingredient present in the first molecular weight of 388.4. Nisoldipine is 3.5-pyridinedicar portion and that of the second portion is a Dihydropyridine boxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)- calcium channel blocker. methyl 2-methyl-propyl ester, CoH NO and has a struc 40 According to one embodiment, the present invention pro ture which is represented as below in Formula I, vides a multiparticulate modified release composition com prising: (a) a first portion providing the release of the active ingredient in a delayed manner and (b) a second portion Formula I providing the release of the active ingredient in an extended 45 manner, wherein the active ingredient present in the first portion and the second portion is a calcium channel blocker NO selected from the group comprising Nisoldipine, Nifedipine, Nitrendipine, Nicardipine, Nimodipine, Felodipine, Amlo dipine, Aranidipine, AZelnidipine, Barnidipine, Benidipine, H3COOC COOCH2CH(CH3)2 50 Cilnidipine, Clevidipine, Efonidipine, Lacidipine, Lercanid ipine, Manidipine, Nilvadipine, Nitrendipine or Pranidipine. According to one preferred embodiment, the present H3C N CH3 invention provides a multiparticulate modified release com position comprising: (a) a first portion providing the release 55 of the active ingredient in a delayed manner and (b) a second portion providing the release of the active ingredient in an Nisoldipine is marketed as SULAR(R) by Sciele Pharma, extended manner, wherein the active ingredient present in the Inc. SULAR(R) tablets are available as 10 mg, 20 mg. 30 mg or first portion and that of the second portion is Nisoldipine. 40 mg of Nisoldipine for once-a-day oral administration. According to one embodiment, the present invention pro SULAR(R) tablets were initially developed using core-coat 60 vides a multiparticulate modified release composition com technology. SULAR(R) tablets consist of an external coat and prising: (a) a first portion providing the release of the active an internal core. Nisoldipine is present in both core and coat. ingredient in an extended manner and (b) a second portion The core is present as a fast release formulation and coat as providing the release of the active ingredient immediately slow release formulation. SULAR(R) tablets developed using upon administration; wherein the active ingredient present in Geomatrix R technology are also available as 8.5 mg, 17 mg, 65 the first portion and the second portion is a Dihydropyridine 25.5 mg and 34 mg dose of Nisoldipine for once-a-day oral calcium channel blocker selected from the group comprising administration. Nisoldipine, Nifedipine, Nitrendipine, Nicardipine, Nimo US 8,865,213 B2 10 dipine, Felodipine, Amlodipine, Aranidipine, AZelnidipine, According to another preferred embodiment, the invention Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonid provides a multiparticulate modified release composition ipine, Lacidipine, Lercanidipine, Manidipine, Nilvadipine, comprising: (a) a first portion comprising Nisoldipine or Nitrendipine or Pranidipine. Nifedipine and (b) a second portion comprising an Angio According to one preferred embodiment, the invention 5 tensin receptor blocker selected from Valsartan, Telmisartan, provides a multiparticulate modified release composition Irbesartan, Losartan, Candesartan and Olmesartan. comprising: (a) a first portion providing the release of the Suitable Angiotensin-Converting Enzyme inhibitors for active ingredient in an extended manner and (b) a second use in accordance with the present invention include portion providing the release of the active ingredient imme benazepril, captopril, cilaZapril, enalapril, fosinopril, lisino diately upon administration; wherein the active ingredient 10 pril, moexipril, perindopril, quinapril, ramipril, and trandola present in the first portion and that of the second portion is pril or pharmaceutically acceptable salts. Nisoldipine. According to another preferred embodiment, the Suitable beta-blockers include compounds selected from present invention provides a multiparticulate modified Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, release composition comprising: (a) a first portion providing 15 Esmolol, Labetalol, Metoprolol, Timolol, Nadolol, Oxpre the release of the active ingredient in a delayed manner and nolol, Penbutolol, Pindolol, Propranolol and Sotalol. (b) a second portion providing the release of the active ingre Suitable Angiotensin receptor blockers include Valsartan, dient immediately upon administration; wherein the active Telmisartan, Irbesartan, Losartan, Candesartan and Olm ingredient present in the first portion and that of the second eSartan. portion is Nisoldipine. Suitable insulin sensitizer consists of a thiazolidinedione According to one embodiment, the present invention pro which includes compounds selected from the group consist vides a multiparticulate modified release composition com ing of TroglitaZone, CiglitaZone, PioglitaZone or Rosiglita prising: (a) a first portion providing the release of the active ZO. ingredient in a delayed manner and (b) a second portion Suitable insulin secretagogue include Sulphonylureas providing the release of the active ingredient in an extended 25 selected from the group consisting of Glipizide, Glimepiride, manner, wherein the active ingredient present in the first Glibenclamide, Gliclazide and the like. portion is a calcium channel blocker and the active ingredient In one embodiment, the multiparticulate modified release present in the second portion is an inhibitor of angiotensin composition comprises: (a) a first portion provided in the converting enzyme, beta-blocker, anti-angina agents, anti form of delayed release tablet and (b) a second portion pro arrhythmic agents, anti-ischaemic agents, vasodilators, bron 30 vided in the form of matrix granules; wherein the active chodilators, hypolipidaemic agents, antidiabetics such as ingredient present in the first portion and that of the second insulin sensitizer, biguanide, insulin secretagogue. portion is Nisoldipine. According to one embodiment, the present invention pro In certain embodiment, the first or second portion of the vides a multiparticulate modified release composition com multiparticulate modified release composition providing the prising: (a) a first portion providing the release of the active 35 release of the active ingredient in a delayed manner may be in ingredient in an extended manner and (b) a second portion the form of delayed release tablets or delayed release pellets providing the release of the active ingredient immediately or delayed release granules. upon administration; wherein the active ingredient present in In certain embodiment, the first or second portion of the the first portion is a calcium channel blocker selected from the multiparticulate modified release composition providing the group comprising Nisoldipine, Nifedipine, Nitrendipine, 40 release of the active ingredient in an extended manner may be Nicardipine, Nimodipine, Felodipine, Amlodipine, Aranid in the form of an extended release tablet or extended release ipine, AZelnidipine, Barnidipine, Benidipine, Cilnidipine, granules or extended release pellets. Clevidipine, Efonidipine, Lacidipine, Lercanidipine, Manid In certain embodiment, the portion of the multiparticulate ipine, Nilvadipine, Nitrendipine or Pranidipine and the active modified release composition that provides the release of the ingredient present in the second portion is an inhibitor of 45 active ingredient immediately upon administration may be in angiotensin-converting enzyme. the form of tablets, capsules, pellets, granules or powders. According to a preferred embodiment, the invention pro According to one embodiment, the invention provides vides a multiparticulate modified release composition com multiparticulate modified release composition of Nisoldipine prising: (a) a first portion comprising a calcium channel comprising: (a) a first portion providing the release of Nisol blocker selected from the group comprising Nisoldipine, 50 dipine in a delayed manner and (b) a second portion providing Nifedipine, Nitrendipine, Nicardipine, Nimodipine, Felo the release of Nisoldipine in an extended manner. dipine, Amlodipine, Aranidipine, AZelnidipine, Barnidipine, According to one embodiment, the invention provides Benidipine, Cilnidipine, Clevidipine, Efonidipine, Lacid multiparticulate modified release composition comprising: ipine, Lercanidipine, Manidipine, Nilvadipine, Nitrendipine (a) a first portion comprising the active ingredient, at least or Pranidipine and (b) a second portion comprising a beta 55 one surfactant and at least one release modifying agent; blocker selected from Acebutolol, Atenolol, Betaxolol, Biso (b) a second portion comprising the active ingredient and prolol, Carteolol, Esmolol, Labetalol, Metoprolol, Timolol. optionally a release modifying agent. Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol and According to one embodiment, the invention provides Sotalol. multiparticulate modified release composition comprising: According to a preferred embodiment, the invention pro 60 (a) a first portion comprising the active ingredient, at least vides a multiparticulate modified release composition com one surfactant and at least one release modifying agent; prising: (a) a first portion comprising Nisoldipine and (b) a (b) a second portion comprising the active ingredient and second portion comprising Atenolol. optionally a release modifying agent; According to another preferred embodiment, the invention wherein said first portion of the active ingredient is released at provides a multiparticulate modified release composition 65 pH above 5.5 comprising: (a) a first portion comprising Nisoldipine and (b) According to one embodiment, the invention provides a second portion comprising Propranolol. multiparticulate modified release composition comprising: US 8,865,213 B2 11 12 (c) a first portion comprising Nisoldipine, at least one about 8 hours, from about 40% to about 100% of Nisoldipine Surfactant and at least one release modifying agent; is released; after about 12 hours, more that about 80% of (d) a second portion comprising Nisoldipine and optionally Nisoldipine is released. a release modifying agent. According to preferred embodiment, the modified release According to one embodiment, the invention provides composition comprises about 2.0% to about 20% by weight multiparticulate modified release composition comprising: of Nisoldipine, about 10% to about 50% by weight of release (a) a first portion comprising: the active ingredient loaded modifying agents, 2% to about 90% by weight of diluents, on an inert inner core, a delayed release coat and option about 2% to about 20% by weight of binders, about 0.2% to ally a separating coat between the inner core and delayed about 3.0% by weight of lubricants, about 0.2% to about 5% release coat. 10 by weight of glidants, about 2.0 to about 20% by weight of (b) a second portion comprising: the active ingredient and coating agents. one or more release modifying polymer. According to one embodiment, the delayed release pellets According to one embodiment, the invention provides comprises: (a) an inert core; (b) a drug layer applied to the multiparticulate modified release composition comprising: 15 inert core comprising: Nisoldipine and a Surfactant (c) (a) a first portion comprising: the active ingredient loaded optionally, a separating coat on the drug loaded core and (d) on an inert inner core, a delayed release coat and option a delayed release coating Surrounding the drug layer. ally a separating coat between the inner core and delayed According to one embodiment, the delayed release pellets release coat; comprises: (a) an inert core; (b) a drug layer applied to the (b) a second portion comprising: the active ingredient and inert core comprising: Nisoldipine and a Surfactant (c) one or more release modifying polymer; optionally, a separating coat on the drug loaded core and (d) wherein said first portion of the active ingredient is released at a delayed release coating Surrounding the drug layer, wherein pH above 5.5 the delayed release coating comprises a delayed release poly According to one embodiment, the invention provides mer such as methacrylate derivative or their mixtures. multiparticulate modified release composition comprising: 25 According to one embodiment, the delayed release pellets (a) a first portion comprising Nisoldipine adsorbed on an comprises: (a) an inert core; (b) a drug layer applied to the inert inner core, a delayed release coat and optionally a inert core comprising: Nisoldipine and a Surfactant (c) separating coat between the inner core and delayed optionally, a separating coat on the drug loaded core and (d) release coat. a delayed release coating Surrounding the drug layer, wherein (b) a second portion comprising Nisoldipine and one or 30 the delayed release coating comprises a delayed release poly more release modifying polymer. mer selected from the group consisting of methacrylic acid According to one embodiment, the first portion of Nisol copolymers. dipine is provided in the form of delayed release pellets and According to another embodiment, the present invention the second portion of the composition is provided in the form provides a process for preparation of modified release com of matrix granules. 35 positions; said process facilitating the incorporation of high The inert inner core according to the invention is either amount of active ingredient/(s) in a single dosage form. non-pareil seeds or Sugar spheres. Spheres of Sugars like In one embodiment, the present invention provides a pro dextrose, lactose, anhydrous lactose, spray-dried lactose, lac cess for preparation of multiparticulate modified release com tose monohydrate, mannitol, starches, Sorbitol, or Sucrose position of Nisoldipine, said process comprising: may be used. The drug is loaded onto the inert inner core and 40 (a) preparing delayed release pellets comprising: drug the core may optionally be seal coated and further coated with adsorbed on an inert inner core, a delayed release coat delayed release polymer. and optionally a separating coat between the inner core Preferably, the multiparticulate modified release composi and delayed release coat; tion of Nisoldipine is in the form of a multiparticulate tablet. (b) preparing extended release granules comprising Nisol Said Nisoldipine compositions may be provided in a dose of 45 dipine and optionally a release modifying agent; 8.5 mg, 17 mg, 25.5 mg and 34 mg. (c) blending the delayed release pellets of step (a) and the According to one embodiment, said multiparticulate tablet extended release granules of step (b) with suitable phar composition of Nisoldipine exhibits a dissolution profile such maceutical excipients and compressing into multipar that after about 2 hours, from about 5% to about 50% of ticulate tablets. Nisoldipine is released; after about 4 hours, from about 20% 50 According to one embodiment, the invention provides a to about 90% of Nisoldipine is released; after about 8 hours, process for preparation of multiparticulate modified release from about 40% to about 100% of Nisoldipine is released; pharmaceutical composition comprising: after about 12 hours, more than about 80% of Nisoldipine is (a) preparing a first portion comprising: the active ingredi released. ent adsorbed on an inert inner core, a delayed release According to another embodiment, the multiparticulate 55 coat and optionally a separating coat between the inner modified release composition of Nisoldipine comprises: core and delayed release coat; (1) a first delayed release portion comprising: active ingre (b) preparing a second portion comprising: the active dient loaded on an inert inner core; optionally a separat ingredient and one or more release modifying polymer; ing coat on the inner core and a delayed release coat (c) formulating the first portion and the second portion into thereon; 60 multiparticulate dosage form. (2) a second extended release portion comprising: drug in According to a preferred embodiment, the invention pro combination with at least one extended release polymer vides a process for preparation of multiparticulate modified and suitable pharmaceutical excipients; release pharmaceutical composition comprising: wherein said modified release composition exhibits a disso (a) preparing a first portion of delayed release pellets com lution profile such that after about 2 hours, from about 5% to 65 prising the active ingredient adsorbed on an inert inner about 50% of Nisoldipine is released; after about 4 hours, core, a delayed release coat and optionally a separating from about 20% to about 90% of Nisoldipine is released; after coat between the inner core and delayed release coat; US 8,865,213 B2 13 14 (b) preparing a second portion of matrix granules compris (c) adding the active ingredient into the dispersion of step ing the active ingredient and one or more release modi (b): fying polymer; (d) optionally adding an anti-foaming agent; (c) mixing the delayed release pellets and matrix granules (e) loading the active ingredient dispersion of step (c) or and further lubricating the mixture; step (d) on to the inert core to form active ingredient (d) compressing the lubricated mixture into multiparticu loaded inert core; late tablet. (f) optionally seal coating the active ingredient loaded inert According to a preferred embodiment, the invention pro core; vides a process for preparation of multiparticulate modified (g) coating the active ingredient loaded inert core with release pharmaceutical composition comprising: 10 enteric coating polymer. (a) preparing a first portion of delayed release pellets com According to a preferred embodiment, the process for prising the active ingredient adsorbed on an inert inner preparation of delayed release pellets of Nisoldipine com core, a delayed release coat and optionally a separating prises: coat between the inner core and delayed release coat; (a) providing an non pareil seeds; (b) preparing a second portion of matrix granules compris 15 (b) preparing a dispersion comprising hydroxypropyl ing the active ingredient and one or more release modi methyl cellulose, Sodium lauryl Sulfate and talc, fying polymer; (c) adding Nisoldipine into the dispersion of step (b): (c) mixing the delayed release pellets and matrix granules (d) optionally adding simethicone emulsion; and further lubricating the mixture; (e) loading Nisoldipine dispersion of step (c) or step (d) on (d) filling the lubricated mixture into capsule. to the non pareil seeds to form Nisoldipine loaded non According to one embodiment, the invention provides a pareil seeds; process for preparation of multiparticulate modified release (f) optionally seal coating the Nisoldipine loaded non pharmaceutical composition comprising: pareil seeds; (a) preparing a first portion comprising Nisoldipine 25 (g) coating the Nisoldipine loaded non pareil seeds with adsorbed on an inert inner core, a delayed release coat Eudragit FS 30D. and optionally a separating coat between the inner core According to one embodiment, the invention provides a and delayed release coat; process for preparation of Nisoldipine extended release gran (b) preparing a second portion comprising Nisoldipine and ules comprising granulating Nisoldipine with at least one one or more release modifying polymer; 30 release modifying agent by dry granulation or wet granula (c) formulating the first portion and the second portion into tion method to form a granules. multiparticulate dosage form. According to a preferred embodiment, the invention pro According to one embodiment, the invention provides a vides a process for preparation of Nisoldipine extended process for preparation of multiparticulate modified release release granules comprising: pharmaceutical composition comprising: 35 (a) mixing Nisoldipine with hydroxypropyl cellulose, lac (a) preparing a first portion comprising Nisoldipine tose monohydrate and sodium lauryl Sulfate; adsorbed on an inert inner core, a delayed release coat (b) granulating the mixture of step (a) using purified water and optionally a separating coat between the inner core or organic solvents such as isopropyl alcohol, methylene and delayed release coat; chloride to form granulating mass; (b) preparing a second portion comprising Nisoldipine and 40 (c) drying the mass and further milling the mass to form one or more release modifying polymer; granules. (c) formulating the first portion and the second portion into According to one embodiment, the invention provides a multiparticulate tablet: process for preparation of Nisoldipine extended release com wherein said first portion of the active ingredient is released at position comprising granulating Nisoldipine with at least one pH above 5.5 and wherein said wherein the composition 45 release modifying agent to form a granulate mass; character exhibits a dissolution profile such that after about 2 hours, ized in that the granulation of the mixture is carried out by hot from about 5% to about 50% of Nisoldipine is released; after melt granulation at a temperature of 40°C. to 120° C. about 4 hours, from about 20% to about 90% of Nisoldipine The pharmaceutical composition of the invention can also is released; after about 8 hours, from about 40% to about be manufactured by various methods such as by direct com 100% of Nisoldipine is released; after about 12 hours, more 50 pression, dry granulation, wet granulation, double compres than about 80% of Nisoldipine is released. Sion, melt granulation, extrusion spheronization and the like. According to one embodiment, the invention provides a The surfactants which may be used include, but are not process for preparation of multiparticulate composition com limited to, fatty acids, polysorbate 80, alkylsulfates, sodium prising: lauryl Sulfate, sodium dodecyl sulfate, citric acid or mixtures (a) preparing delayed release pellets comprising Nisol 55 thereof and may be present in an amount from about 0.5% to dipine; about 25% by weight of the total composition. (b) preparing extended release granules comprising Nisol Delayed release polymers that may be used in accordance dipine; with the invention includes cellulose acetate phthalate, poly (c) blending the delayed release pellets and extended vinylacetate phthalate, methylcellulose phthalate, ethylhy release granules and 60 droxycellulose phthalate, hydroxypropylmethyl cellulose (d) compressing the blended mixture into multiparticulate phthalate, cellulose acetate Succinate, acetate trimellitate, tablet. polyvinyl butyrate acetate, vinyl acetate-maleic anhydride According to one embodiment, the process for preparation copolymer, styrene-maleic mono-ester copolymer, cellulose of delayed release pellets of Nisoldipine comprises: derivatives, such as ethylcellulose, a cellulose ester, shellac, (a) providing an inert core; 65 polyvinyl alcohol, Sodium alginate, methyl acrylate-meth (b) preparing a dispersion comprising a binder, an anti acrylic acid copolymer, methacrylate-methacrylic acid-octyl foaming agent and Surfactant; acrylate copolymer or shellac. US 8,865,213 B2 15 16 In certain embodiment, a separating coat is present tristearin, rosin, polyvinyl chloride powder or polyethylene between the inner core and delayed release coat. In the prac powder, magnesium or aluminium silicates and the like and tice of the present invention, the separating coat comprises a may be present in an amount from about 10% to about 50% by hydrophilic polymer Such as a cellulose derivative polymer. weight of the total composition. Examples of hydrophilic polymers include hydroxypropyl Water-swellable release-modifying agents that may be methylcelluloses, hydroxypropylcelluloses and other cellu employed for the manufacture of multiparticulate modified lose derivatives. release compositions include, but are not limited to alginic The delayed release pellets may optionally be mixed with acid, carragenan, Xanthan gum, guar gum and the like and conventional tabletting excipients and compressed into a tab may be present in an amount from about 10% to about 50% by let or loaded into a capsule. In certain embodiments, the 10 weight of the total composition. delayed release pellets may be mixed with extended release Mixtures of water soluble and/or water-swellable release granules/pellets and conventional tabletting excipients and modifying agents with water-insoluble release-modifying compressed into tablets or loaded into a capsule. In certain agents may be employed in a weight ratio of about 1:1 to 1:10. embodiments, the core is in the form of pellets, beads, powder Suitable pharmaceutically acceptable excipients that can particles, granules, mini-tablets, micro-tablets, spheroids or 15 be used according to the present invention include, but are not microspheres. limited to diluents, binders, glidants, lubricants, solvents, rate In one embodiment, the drug loaded pellets may optionally controlling polymers, pore formers, plasticizers and like. be coated with an enteric coating polymer. Particularly, said The diluents which may be used include, but are not limited compositions are in the form of a tablet dosage form com to, lactose monohydrate, lactose anhydrous, mannitol, starch, prising of pellets and granules compressed together. The pregelatinised starch, lactitol monohydrate, microcrystalline enteric coating polymers may be pH dependent polymer and/ cellulose, dibasic calcium phosphate or mixtures thereof and or pH independent polymers. is present in an amount from about 10% to about 90% by The pH dependent polymer may be selected from the group weight of the total composition. consisting of a polymethacrylate such as copolymers of meth The binders which may be used include, but are not limited ylmethacrylate-methacrylic acid and polyvinyl acetate phtha 25 to, ethyl cellulose, hydroxypropyl methylcellulose, hydroxy late, a cellulosic ester Such as cellulose acetate phthalate, ethyl cellulose, hydroxyethylmethyl cellulose, hydroxypro hydroxymethylcellulose phthalate and hydroxypropyl meth pyl cellulose, methylcellulose, cellulose acetate, cellulose ylcellulose phthalate. Commercially available pH dependent acetate butyrate, polyvinyl alcohol, polyvinyl acetate, poly polymers include Eudragit L100-55, Eudragit S100, Eudragit acrylate, alginic acid, sodium alginate, gelatin, starch, clays, L 30 D-55 and Eudragit FS 30D. 30 naturally occurring gums, polyvinyl pyrrolidone, copovidone The pH independent polymer may be selected from the or mixtures thereof and may be present in an amount from group consisting of a cellulosic ether such as methyl cellu about 2% to about 20% by weight of the total composition. lose, ethyl cellulose, carboxy methyl cellulose, hydroxy pro The lubricants which may be used include, but are not pyl cellulose, hydroxy ethyl cellulose and hydroxy propyl limited to, magnesium Stearate, colloidal silicon dioxide, methyl cellulose. 35 Stearic acid, talc, hydrogenated castor oil, hydrogenated veg In one embodiment, the invention provides an extended etable oil, sodium stearyl fumarate or mixtures thereof and release portion comprising: (i) Nisoldipine or a pharmaceu may be present in an amount from about 0.5% to about 3% by tically acceptable salt thereof; (ii) at least one of the release weight of the total composition. modifying agents selected from (a) one or more water soluble The plasticizers which may be used include, but are not materials; (b) one or more water insoluble materials; (c) one 40 limited to, dibutyl phthalate, dibutyl sebacate, diethyl phtha or more water swellable materials. late, dimethyl phthalate, glycerin, propylene glycol, triacetin, The release-modifying agents may have different water tributyl citrate and triethyl citrate and may be present in an solubility and permeability. In the practice of the present amount from about 0.5% to about 25% by weight of the total invention, the release-modifying agents may be selected from composition. one or more water-soluble release-modifying agent and/or 45 Solvents that may be employed for the coating include water-insoluble release-modifying agent and/or water isopropyl alcohol, methylene chloride or mixtures thereof. Swellable release-modifying agent. Barrier coating may be performed using Opadry, a ready mix Water soluble release-modifying agents that may be coating material. employed for the manufacture of multiparticulate modified Granulation may be carried out using high shear mixer or release compositions include, but are not limited to polyeth 50 by spray granulation technique. Mixing and granulation can ylene oxide (average molecular weight 1,00,000 to 50.00, be carried out in a conventional rapid mixer granulator and the 000), Sodium alginate, calcium ammonium alginate, potas wet granules can be further dried using fluid bed drier. High sium alginate, calcium alginate, cellulose derivative polymer shear granulation improves the cohesiveness of particles and like cellulose esters and cellulose ethers (eg. Various grades of provides excellent flowability and compression characteris hydroxypropyl methyl cellulose), propylene glycol alginate, 55 tics to the tablet. As the granules exhibit good flow properties, polyvinyl alcohol, povidone, carbomers, Xanthan gum, tri mini tablets produced possess uniformity in weight. ethyl citrate, a co-polymer of vinylacetate and vinylpyrroli In the practice of the present invention, aqueous/non-aque done (Kollidon SR from BASF) and the like. Water-soluble ous granulation is carried out by adding the binder slowly in materials may be present in an amount from about 10% to a thin stream continuously using a peristaltic pump under about 50% by weight of the total composition. 60 high speed mixing with the impeller on and chopper off. Water-insoluble release-modifying agents that may be On completion of binder addition, mixing is continued at high employed for the manufacture of multiparticulate modified impeller speed till cohesive granular mass is obtained. If the release compositions include, but are not limited to Stearic mass is lumpy then chopper may be used at high speed with acid, glyceryl monostearate, glyceryl behenate, glyceryl impeller also at high speed to obtain uniform wet mass. Dry palmitostearate, microcrystalline wax, polymethacrylate, 65 ing of granulated mass may be carried out using fluidized bed Stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydroge drier ortray drier. Granulated mass is dried for sufficient time nated castor oil, polyvinyl acetate phthalate, waxes, shellac, till loss on drying value in the range of about 0.5% to about US 8,865,213 B2 17 18 3.0% is achieved. In a conventional fluid bed processor both EXAMPLES the steps of granulation and drying can be carried out in the same equipment thereby simplifying the process and saving Example 1 the processing time. Compression may be carried out using equipments known 5 Preparation of Delayed Release Pellets in the art such as a rotary tablet press or any suitable tabletting Hydroxypropyl methyl cellulose (Methocel E 5) (47.25 g) machine fitted with Suitable size punches and dies. Coating was added to water. Sodium lauryl sulphate (112.5 g) was may be carried out using equipments known in the art such as added to it and mixed to dissolve completely. Nisoldipine spray coating or coating in conventional coating pan or per (193.26 g) and talc (23 g) was added to this mixture and mixed forated pans. 10 to get a suspension. The Suspension was homogenized and The pharmaceutical compositions of Nisoldipine as simethicone 30% emulsion (9 g) was added to this suspen described herein withstand the accelerated stability condi Sion. The Suspension was strained using 60# sieve. tions of temperature and relative humidity and maintain their 40-60ii sugar spheres (448 g) were coated with the drug physical and chemical integrity at accelerated conditions of 15 suspension in glatt fluid bed coater equipped with 9" bottom stability. spray wurster insert. The drug loaded pellets were dried and According to one embodiment, the present invention pro seal coated with opadry yellow. An aqueous dispersion of vides a method of treating a patient Suffering from hyperten Eudragit FS 30D (266.60 g) and triethyl citrate (17 g) was Sion, comprising administering to a patient in need thereof a prepared and sprayed onto the drug loaded pellets (equivalent therapeutically effective amount of Nisoldipine in multipar to 10,000 tablets) till a weight gain of approx. 20% was ticulate modified release composition as described herein. achieved. The delayed release pellets along with the talc was Advantages of the Present Invention cured at inlet temperature of 50° C. for 1 hr. One advantage of the invention is that it allows the incor Preparation of Granules poration of high amount of active ingredient in the single The active ingredient Nisoldipine (77.30 g) was mixed dosage unit with the different drug release profile. 25 with Hydroxypropyl cellulose (Klucel GXF) (360g), sodium Another advantage of the invention is that it provides com lauryl sulphate (60 g) and lactose monohydrate (134.20 g) positions which have better patient compliance as the fre and granulated using Isopropyl alcohol. The granulated mass quency of dosing is reduced. was dried, sized and milled to get granules of required size. Modified release pharmaceutical composition as described Preparation of Multiparticulate Tablets herein provides the following advantages, 30 (1) flexibility in attaining different release patterns, Pellets (76.5 g) along with the granules (285.75 g) contain (2) low risk of dose dumping, ing active & polymer, Sodium lauryl Sulphate (7.5 g), lactose (3) reduced risk of systemic toxicity and increased drug anhydrous (30 g) were mixed and lubricated with colloidal safety, silicon dioxide (3 g) and magnesium Stearate (3.75 g). The (4) patient compliance due to reduced frequency of dosing, 35 blend was compressed into tablets and further film coated (5) reproducibility. with opadry yellow. (6) increased bioavailability In-Vitro Dissolution Study The process for preparation of the multiparticulate compo Table 1 summarizes the in vitro-dissolution profile of the sitions as described herein is easy, less time consuming and Nisoldipine extended release tablet prepared according to economic in comparison to the prior art processes. 40 Example 1 of the present invention versus Sular(R) (Nisol As used herein, the term “excipient” refers to a pharma dipine extended release tablet by Innovator prepared by Geo ceutically acceptable ingredient that is commonly used in the matrix R technology) (ref. FIG. 1). Dissolution was carried pharmaceutical technology for preparing granules and/or out by USP Type I (basket) method using pH6.8 phosphate Solid oral pharmaceutical dosage forms. buffer with 1% SLS. As used herein the term “multiparticulate” refers to plural 45 ity of particles, pellets, granules, beads or mixtures thereof. TABLE 1 As used herein, the term “modified release' is intended to encompass delayed release, pulsatile release, extended or Drug release (% Sustained release. Time (Hours) (Sular (R) Example 1 50 As used herein, the term “release modifying agent” is O O O intended to encompass enteric coating agents and rate con O.S 2.3 3.6 trolling agents. 1 6.1 14.8 As used herein, the term “separating coat is intended to 2 18.3 41.7 3 36.7 66.2 encompass seal coat, barrier coat or intermediate coat. 4 56.4 85.5 As used herein, the term “loaded' is intended to encompass 55 6 76.7 101.7 Sorption, adsorption or absorption. 8 93.5 102.4 As used herein, the term “active ingredient could be used 10 98 interchangeably with the term “drug’. 12 98.8 As used herein, the term “tablet' is intended to encompass compressed pharmaceutical dosage formulations of all 60 shapes and sizes, whether coated or uncoated. Example 2 The present invention is further illustrated by reference to the following examples which does not limit the scope of the Preparation of Delayed Release Pellets: invention in any way. It will be apparent to those skilled in the Hydroxypropyl methyl cellulose (Methocel E5) (25 g) was art that many modifications, both to the materials and meth 65 added to water, followed by slow addition of Sodium lauryl ods, can be practiced without departing from the purpose and sulphate (90 g) and dissolved completely. Nisoldipine (100 g) Scope of the disclosure. and talc (19 g) was added to it and mixed to forma Suspension. US 8,865,213 B2 19 20 The Suspension was homogenized and simethicone 30% The Summary statistics of pharmacokinetic parameters of emulsion (6 g) was added to it and strained using 60# sieve. Nisoldipine extended release tablets prepared according to Sugar spheres (40-60ii) (239 g) were coated with the drug Example 2 as test and Sular (Nisoldipine extended release suspension in glatt fluid bed coater equipped with 9" bottom tablets 34 mg) manufactured by Sciele Pharmaceutical as spray wurster insert. The drug loaded pellets were dried and 5 reference are as shown below in Table 3. seal coated withopadry yellow. The seal coated pellets were sprayed with an aqueous dispersion of the extended release TABLE 3 polymer membrane Eudragit FS 30D (297.5 g), Talc (48.875 g) and triethylcitrate (10.625 g) till a weight gain of approx. Example 2 Reference 10 Geometric Mean Geometric Mean T.R. 20% is achieved. The delayed release pellets and talc were Parameter (T) (R) ratio (%) cured at inlet temperature of 50° C. for 1 hr. Cmax (ng/ml) 4.45 3.88 114.70 Preparation of Granules AUCo., * (ng * hr/ml) 68.92 69.13 99.70 Nisoldipine (72.8 g) was mixed with Hydroxypropyl cel AUCox * (ng *hri 76.99 71.77 107.27 lulose (Klucel GXF) (120 g), sodium lauryl sulphate (57 g) ml) and lactose monohydrate (261.70 g) and granulated using 15 Isopropyl alcohol. The granulated mass was dried, sized and It will be evident to those skilled in the art that the invention milled to get granules of required size. is not limited to the details of the foregoing illustrative Preparation of Multiparticulate Tablets examples and that the present invention may be embodied in Delayed release pellets (105 g) and Nisoldipine granules other specific forms without departing from the essential (255.75 g) containing active & polymer, sodium lauryl Sul attributes thereof, and it is therefore desired that the present phate (7.50 g), lactose anhydrous (30 g) were mixed and embodiments and examples be considered in all respects as lubricated with colloidal silicon dioxide (3 g) and magnesium illustrative and not restrictive, reference being made to the stearate (3.75 g). The blend was compressed into tablets and appended claims, rather than to the foregoing description, and further film coated with opadry yellow. 25 all changes which come within the meaning and range of In-Vitro Dissolution Study equivalency of the claims are therefore intended to be Table 2 summarizes the in vitro-dissolution profile of the embraced therein. Nisoldipine extended release tablet prepared according to All publications, patents and patent applications are incor Example 2 of the present invention versus Sular(R) (Nisol porated herein by reference. dipine extended release tablet by Innovator prepared by Geo 30 matrix R technology) (ref. FIG. 2). Dissolution was carried We claim: out by USPType I (basket) method using pH6.8 phosphate 1. A multiparticulate modified release pharmaceutical buffer with 1% SLS. composition comprising: a first portion comprising TABLE 2 35 at least one active ingredient comprising a calcium chan Drug release (% nel blocker, at least one surfactant, and Time (Hours) (Sular (R) Example 2 at least one release modifying agent; and O O O a second portion mixed with the first portion, the second O.S 2.3 8 40 portion comprising 1 6.1 22.6 at least one active ingredient comprising a calcium chan 2 18.3 55.6 nel blocker, and 3 36.7 81.2 4 56.4 99.2 optionally, at least one release modifying agent, 6 76.7 106.3 the second portion having a different release profile than 8 93.5 106.7 45 the first portion; 10 98 the first portion having a form comprising a plurality of at 12 98.8 least one selected from pellets, granules, microparticles, nanoparticles, and a combination thereof, the second Bioeduivalence Study portion having a form comprising a plurality of matrix A randomized, open label, two treatment, two-period, two 50 granules, sequence, single dose, crossover bioequivalence study was wherein the active ingredient of the first portion is released conducted on Nisoldipine extended release tablets prepared at pH above about 5.5, and release of the active ingredi according to Example 2 with Sular (Nisoldipine extended ent of the second portion is pH independent. release tablets 34 mg) manufactured by Sciele Pharmaceuti 2. The composition as claimed in claim 1, wherein the cal as reference product. The study was conducted on 9 nor 55 calcium channel blocker is selected from the group consisting mal, healthy, adult, male human Subjects under fasting con of Nisoldipine, Nifedipine, Nitrendipine, Nicardipine, Nimo ditions. dipine, Felodipine, Amlodipine, Aranidipine, AZelnidipine, The parameters C f AUCo., AUCo., were estimated Barnidipine, Benidipine, Cilnidipine, Clevidipine, Efonid during the study. ipine, Lacidipine, Lercanidipine, Manidipine, Nilvadipine, AUCo Area under the plasma concentration versus time 60 Nitrendipine, Pranidipine, and combinations thereof. curve, from time Zero to the last measurable concentration. 3. The composition as claimed in claim 1, wherein the AUCo., Area under the plasma concentration versus time active ingredient present in the first portion and the second curve, from time Zero to infinity. portion are the same. C, maximum plasma concentration. 4. The composition as claimed in claim 1, wherein the first The ratios of log transformed mean values for C and 65 portion provides the release of the active ingredient in a AUC for test and reference (T/R ratio) is a measure of the modified manner and the second portion provides the release bioequivalence between the test and reference product. of the active ingredient in an extended manner. US 8,865,213 B2 21 22 5. The composition as claimed in claim 1, wherein the first thiazolidinedione selected from the group consisting of Tro portion provides the release of the active ingredient in a glitaZone, CiglitaZone, PioglitaZone, RosiglitaZone, and delayed manner and the second portion provides the release combinations thereof; the antidiabetic is a biguanide or an of the active ingredient in an extended manner. insulin sensitizer selected from the group consisting of Tro 6. The composition as claimed in claim 1, wherein the first 5 glitaZone, CiglitaZone, PioglitaZone, RosiglitaZone, and portion of the active ingredient is released in a delayed or combinations thereof, or an insulin secretagogue selected extended manner and the second portion of the active ingre from the group consisting of Glipizide, Glimepiride, Glib dient is released immediately. enclamide, Gliclazide, and combinations thereof. 7. The composition as claimed in claim 1, further compris 15. A multiparticulate modified release tablet comprising: ing an active ingredient present in the second portion selected 10 from the group consisting of an angiotensin-converting a first portion comprising enzyme inhibitor, beta-blocker, angiotensin receptor blocker, at least one active ingredient comprising Nisoldipine, anti-angina agent, anti-arrhythmic agent, anti-ischaemic at least one surfactant, and agent, vasodilator, bronchodilator, hypolipidaemic agent, at least one release modifying agent; and antidiabetic, and combinations thereof. 15 a second portion mixed with the first portion, the second 8. The composition as claimed in claim 1, further compris portion comprising ing an active ingredient in at least one of the first portion or at least one active ingredient comprising Nisoldipine, second portion selected from the group consisting of an and angiotensin-converting enzyme inhibitor, beta-blocker, optionally, at least one release modifying agent, angiotensin receptor blocker, anti-angina agent, anti-arrhyth the second portion having a different release profile than mic agent, anti-ischaemic agent, vasodilator, bronchodilator, the first portion; hypolipidaemic agent, antidiabetic, and combinations the first portion having a form comprising a plurality of at thereof. least one selected from pellets, granules, microparticles, 9. The composition as claimed in claim 1, wherein the first nanoparticles, and a combination thereof, the second portion of the composition is provided in the form of delayed 25 portion having a form comprising a plurality of matrix release pellets and the second portion of the composition is granules, provided in the form of matrix granules. wherein the active ingredient of the first portion is released 10. The composition as claimed in claim 1, wherein the at pH above about 5.5, and release of the active ingredi active ingredient present in the first portion and the second ent of the second portion is pH independent. portion is Nisoldipine. 30 16. A multiparticulate modified release pharmaceutical 11. The composition as claimed in claim 10, wherein the composition comprising: composition is in the form of multiparticulate tablet or cap a first portion comprising Sule. at least one active ingredient comprising a calcium chan 12. The composition as claimed in claim 10, wherein the nel blocker loaded on an inert inner core, first portion of the composition is provided in the form of 35 a delayed release coat, and delayed release pellets and the second portion of the compo optionally, a separating coat between the inner core and sition is provided in the form of matrix granules and said delayed release coat, and composition exhibits a dissolution profile Such that a second portion mixed with the first portion, the second after about 2 hours, about 5% to about 50% of Nisoldipine portion comprising is released, 40 at least one active ingredient comprising a calcium chan after about 4 hours, about 20% to about 90% of Nisoldipine nel blocker, and is released, one or more release modifying polymers, after about 8 hours, about 40% to about 100% of Nisol the second portion having a different release profile than dipine is released, and the first portion; after about 12 hours, more than about 80% of Nisoldipine 45 the first portion having a form comprising a plurality of at is released. least one selected from pellets, granules, microparticles, 13. The composition as claimed in claim 10, wherein the nanoparticles, and a combination thereof, the second composition comprises about 2.0% to about 20% by weight portion having a form comprising a plurality of matrix of Nisoldipine, about 10% to about 50% by weight of release granules, modifying agents, 2% to about 90% by weight of diluents, 50 wherein the active ingredient of the first portion is released about 2% to about 20% by weight of binders, about 0.2% to at pH above about 5.5, and release of the active ingredi about 3.0% by weight of lubricants, about 0.2% to about 5% ent of the second portion is pH independent. by weight of glidants, about 2.0 to about 20% by weight of 17. A multiparticulate modified release pharmaceutical coating agents. composition comprising: 14. The composition as claimed in claim 7, wherein the 55 a first portion comprising beta-blocker is selected from the group consisting of Acebu at least one active ingredient comprising Nisoldipine tolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Esmolol. loaded on an inert inner core, Labetalol, Metoprolol, Timolol, Nadolol, Oxprenolol, Penb a delayed release coat, and utolol, Pindolol, Propranolol, Sotalol, and combinations optionally, a separating coat between the inner core and thereof; the angiotensin receptor blocker is selected from the 60 delayed release coat, and group consisting of Valsartan, Telmisartan, Irbesartan, Losa a second portion mixed with the first portion, the second rtan, Candesartan, Olmesartan, and combinations thereof the portion comprising angiotensin-converting enzyme inhibitor is selected from the at least one active ingredient comprising Nisoldipine, group consisting of benazepril, captopril, cilaZapril, enala and pril, fosinopril, lisinopril, moexipril, perindopril, quinapril, 65 optionally, at least one release modifying agent, ramipril, trandolapril, pharmaceutically acceptable salts the second portion having a different release profile than thereof, and combinations thereof; the insulin sensitizer is a the first portion; US 8,865,213 B2 23 24 the first portion having a form comprising a plurality of at 21. The process as claimed in claim 20, wherein the inert least one selected from pellets, granules, microparticles, inner core is non-pareil seeds. Sugar spheres, or a combination nanoparticles, and a combination thereof, the second thereof. portion having a form comprising a plurality of matrix 22. The process as claimed in claim 20, wherein the granules, delayed release coat comprises enteric coating polymers. wherein said composition exhibits a dissolution profile 23. The process as claimed in claim 22, wherein the enteric Such that coating polymer is a pH dependent polymer, pH independent after about 2 hours, about 5% to about 50% of Nisol polymer, or combinations thereof. dipine is released, 24. The process as claimed in claim 20, wherein the com after about 4 hours, about 20% to about 90% of Nisol 10 dipine is released, position is in the form of a multiparticulate tablet. after about 8 hours, about 40% to about 100% of Nisol 25. A multiparticulate modified release pharmaceutical dipine is released, and composition comprising: after about 12 hours, more than about 80% of Nisol a first portion comprising dipine is released, 15 at least one active ingredient comprising a calcium chan wherein the active ingredient of the first portion is released nel blocker, at pH above about 5.5, and release of the active ingredi at least one surfactant, and ent of the second portion is pH independent. at least one release modifying agent; and 18. The composition as claimed in claim 1, wherein the a second portion mixed with the first portion, the second Surfactant is selected from the group consisting offatty acids, portion comprising polysorbate 80, alkyl sulfates, sodium lauryl sulfate, sodium at least one active ingredient selected from the group dodecyl sulfate, citric acid, and mixtures thereof. consisting of calcium channel blocker, angiotensin 19. The composition as claimed in claim 1, wherein the converting enzyme inhibitor, beta-blocker, angio release modifying agent is selected from (a) one or more tensin receptor blocker, anti-angina agent, anti-ar water soluble materials, (b) one or more water insoluble 25 rhythmic agent, anti-ischaemic agent, vasodilator, materials, (c) one or more water Swellable materials, and bronchodilator, hypolipidaemic agent, antidiabetic, combinations thereof. and combinations thereof, and 20. A process for preparation of the multiparticulate modi optionally, at least one release modifying agent, fied release pharmaceutical composition as claimed in claim the second portion having a different release profile than 16, comprising: 30 the first portion; preparing the first portion comprising the active ingredient the first and second portion each independently having a loaded on the inert inner core, the delayed release coat form comprising a plurality of at least one selected from and optionally the separating coat between the inner pellets, granules, microparticles, nanoparticles and a core and delayed release coat; combination thereof, preparing the second portion comprising the active ingre 35 wherein the active ingredient of the first portion is released dient and one or more release modifying polymers; and at pH above about 5.5, and release of the active ingredi formulating the first portion and the second portion into the ent of the second portion is pH independent. multiparticulate dosage form. ck ck ck ck ck