US008O12496 B2

(12) United States Patent (10) Patent No.: US 8,012.496 B2 Dudhara et al. (45) Date of Patent: *Sep. 6, 2011

(54) GASTRIC RETENTION CONTROLLED 26.6 A 3. 3. Shah etC DELIVERY SYSTEM 5,091, 184 A 2f1992 Khanna 5,096,714 A 3, 1992 Kuhrt (75) Inventors: Kamlesh Mohanlal Dudhara, Baroda 5,651,985 A 7/1997 RNis et al. (IN); Nitin Bhalachandra 5,654,005 A 8, 1997 Chen et al. 6,261,601 B1 7/2001 Talwar et al. After Mybi SN). Vaishali 6,340.475 B2 1/2002 Shell et al. ijay Dhavse, Mumbai (IN) 6,960,356 B1 1 1/2005 Talwar et al. 7,109,239 B2 9/2006 Gallop et al. (73) Assignee: Sun Pharma Advanced Research 7,776,345 B2 * 8/2010 Dudhara et al...... 424/400 Company Ltd., Andheri (IN) 2007/0265343 A1 11/2007 Dharmadhikari et al. (*) Notice: Subject to any disclaimer, the term of this EP Fores print M.Nis past its, G adjusted under 35 JP 630.14715. A 1, 1988 .S.C. 154(b) by 0 days. WO 98.51408 11, 1998 This patent is Subject to a terminal dis- WO 99.47OOf 15198 128 A1 9,3, 20001999 claimer. WO OO15198 A1 3f2000 WO OO,23045 4/2000 (21) Appl. No.: 12/856,097 WO 00-386.50 T 2000 WO OO,386.50 T 2000 (22) Filed: Aug. 13, 2010 WO 01/08670 A2 2, 2001 WO O1 10417 A1 2, 2001 (65) Prior Publication Data WO O1 10419 A1 2/2001 US 2010/0305208 A1 Dec. 2, 2010 OTHER PUBLICATIONS M. Merino et al.; “Evidence of a Specialized Transport Mechanism Related U.S. Application Data for the Intestinal Absorption of ': Biopharmaceutics & Drug (63) Continuation of application No. 10/482,770, filed as Disposition; Apr. 26, 1988; vol. 10; pp. 279-297: John Wiley & Sons, s s Ltd.; c. 1989. application No. PCT/IN02/00144 on Jul. 4, 2002, now M. Merino et al.; "Evidence of Specialized Absorption Mechanism Pat. No. 7,776,345. for Baclofen': Department of Pharmacology and Pharmaceutics, University of Valencia, Valencia, Spain; pp. 564-573, 1987. (30) Foreign Application Priority Data * cited by examiner Jul. 4, 2001 (IN) ...... 612AMUMA2001 Primary Examiner — Robert A Wax (51) Int. Cl. Assistant Examiner — Aradhana Sasan A6 IK9/00 (2006.01) (74) Attorney, Agent, or Firm — Sughrue Mion, PLLC A6 IK9/24 (2006.01) A 6LX3L/95 (2006.01) (57) ABSTRACT A6IP 7/00 (2006.01) The present invention provides a gastric retention controlled (52) U.S. Cl...... 424/400; 424/471; 514/567 drug delivery system comprising: (58) Field of Classification Search ...... 424/400 (a) a controlled release core comprising a drug, a highly 424/471: 51474 67 Swellable polymer and a gas generating agent, said core See application file for complete search history being cap able of swelling and achieving floatation rap idly while maintaining its physical integrity in gas (56) References Cited trointestinal fluids for prolonged periods, and (b) a rapidly releasing coat composition comprising the U.S. PATENT DOCUMENTS same drug as in the core and pharmaceutically accept able excipients, wherein the coating composition Sur $49.59 A 38. E. rounds the core such that the system provides a biphasic 4,777.033 A 10, 1988 Ikura et al. release of the drug in gastrointestinal fluids. 4,824,678 A 4, 1989 Lindahl et al. 4,844.905 A 7, 1989 Ichikawa et al. 1 Claim, 1 Drawing Sheet U.S. Patent Sep. 6, 2011 US 8,012,496 B2

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time (hours) US 8,012,496 B2 1. 2 GASTRC RETENTION CONTROLLED DRUG Sustained or controlled drug delivery systems by using a DELIVERY SYSTEM composition containing highly Swellable polymers in admix ture with a gas-generating agent to form systems that are large CROSS REFERENCE in size as well as capable of floating on gastric fluids. It has now become well recognized by those particularly skilled in This is a Continuation of U.S. patent application Ser. No. the art that systems containing Swellable polymers will 10/482,770, filed on Dec. 31, 2003, which is a 371 of PCT instantly float on gastric fluids because the gas generated and Application No. PCT/IN02/00144 filed Jul. 4, 2002, which entrapped within the system decreases the density. Swelling claims priority from Indian Patent Application No. 612/ to a large size is an important factor in gastric retention of the MUM/2001 filed Jul. 4, 2001, all of which applications are 10 system. Solids having a size less than 5 to 7 mm show delayed incorporated herein by references. gastric emptying in fed conditions but they can still be emp tied from the stomach because their size is smaller than the FIELD OF THE INVENTION pyloric sphincter. Even floating systems of size less than 5 to 7 mm can be emptied if the patient is in Supine position. The The present invention relates to a gastric retention con 15 mean resting pyloric diameter is approx. 13+7 mm and it has trolled drug delivery system having a biphasic release pattern. been reported that dosage forms with a size of approx. 12-18 mm diameter in their expanded State would generally be BACKGROUND OF THE INVENTION excluded from the passage of the pyloric sphincter. The sys tem should also be capable of retaining this size in the gastric Controlled drug delivery systems deliver drug to the body fluids for long periods under agitational conditions created by so as to establish therapeutically effective blood levels of the gastric motility. Such large intact systems cannot be emptied active ingredient and once these blood levels are achieved until the arrival of the interdigestive migrating motor complex they continue to maintain constant blood levels for long dura at the beginning of the interdigestive phase. The combination tions by delivering the drug to the body at the same rate as the of increase in size and floatation results in increased gastric body eliminates the drug. By avoiding peaks and troughs in 25 retention of the system. The prior art resulting in this current blood levels associated with conventional dosage forms, con state of the art is described below. trolled drug delivery systems lower the incidence of adverse U.S. Pat. No. 4,101,650 (650) assigned to Zaidan Hojin effects or side effects. Very importantly controlled drug deliv Biseibutsu Kagaku Kenkyu Kai discloses a formulation in ery systems reduce the frequency of dosing leading to con which granules containing sodium bicarbonate, lactose and Venience to the patient in terms of dosing and compliance to 30 polyvinylpyrrolidone are coated with a layer of hydroxypro the specified dosage regimens. pyl methylcellulose. These are then further coated with a It is generally known that the rate at which an oral con suspension containing the active ingredient pepstatin and trolled drug delivery system delivers the drug into the blood is hydroxypropyl methylcellulose to form floating minicap not the same as the rate at which it releases the drug into a test sules of a diameter in the range of 0.1 to 2 mm. The drawback aqueous fluid because the gastrointestinal fluids pH, compo 35 of this system is that the minicapsules are much smaller in sition and agitation intensity change with the specific location size than required for long durations of retention in the stom of the drug delivery system in the gastrointestinal tract i.e. ach. from the stomach to the colon, fasted versus fed State, type U.S. Pat. No. 4,777.033 (033) assigned to Teijin Limited, and amount of food ingested, and also vary from individual to discloses an oral Sustained release pharmaceutical prepara individual. In addition, the drug may not be absorbed in the 40 tion comprising a lower alkyl ether of cellulose, polyacrylic same manner and propensity we move from the stomach to acid or its pharmaceutically acceptable salt, a drug, and an the colon. Some have an “absorption window’ i.e. they effective amount of effervescent foaming agent. Tablets made are absorbed only from the upper parts of the gastrointestinal from the composition however still retained the above-cited tract, whereas there are others whose absorption from the major disadvantages associated with the 650 prior art in that colon is not uniform or complete. Thus, the location of the 45 the tablets of the 033 system did not remain intact when controlled drug delivery system in the gastrointestinal tract as Subjected to dissolution testing. well as the rate at which the controlled drug delivery system U.S. Pat. No. 4,844.905 assigned to Eisai Co. discloses moves from the stomach to the colon represent important granules comprising a drug containing core; a middle gas factors that need to be considered in the design of an oral generating layer comprising sodium carbonate and organic controlled drug delivery system. It is thus known to those 50 acid; and an outer coat of an expandable polymer film. skilled in the art that an oral controlled delivery should be Although intended for remaining in the stomach, the granules designed not only with a control on the rate at which it have the disadvantage of Small size. releases the drug over the drug delivery time period (temporal Japanese Patent No. 6301,4715 assigned to Zeria Shinyaku control) but also a control on the location from which it is Kogyo KK discloses a slow releasing composition compris delivered (spatial control). The spatial control can be 55 ing (A) a high-viscosity water-soluble polymer, preferably achieved by prolonging the period of retention of the system cellulose ether or polyvinyl , (B) crosslinked insoluble in the stomach. Gastric retention systems are also beneficial polyvinyl pyrrolidone, and (C) a component to foam in con when the drug is effective locally in the stomach. Drugs tact with gastric juice, preferably carbonate, especially cal absorbed in the upper part of the gastrointestinal tract may cium carbonate or precipitated calcium carbonate. The sys exhibit variability in absorption due to inter and intra-indi 60 tem does not however contain a part of the drug in immediate vidual variability in gastric emptying and gastrointestinal release formanda partin controlled release form and does not motility. This variation in absorption may be addressed by provide a biphasic release pattern. Thus, even at the start of administering a dosage form comprising the drug such that a the dosage regimen when there is no drug available in the Small part of the drug is available as immediate release, and a body, the system may begin with a relatively slow rate of large part is available as Sustained or controlled release. 65 release as compared to that from an immediate release com One of the approaches that has been used for achieving position. Another disadvantage is that whereas polymers that spatial control involves increasing the gastric retention of are highly swellable as well as rapidly swellable may be US 8,012,496 B2 3 4 desirable for achieving gastric retention, we have found that of WO 01/10417 uses the non-active phase to achieve floata several cellulose ethers do not conform to these requirements. tion, which is achieved by a low density resulting from U.S. Pat. No. 5,651,985 assigned to Bayer AG, claims a entrapment of carbon dioxide in the non-active phase matrix. pharmacologically active composition comprising a pharma cologically active compound dispersed in a homogenous OBJECT OF THE INVENTION mixture on the molecular level of polyvinylpyrrolidone and a methacrylic acid polymer having an acidic number between It is an object of the present invention to provide a gastric 100 and 1,200 mg of KOH/g of polymer solid substance, and retention controlled drug delivery system comprising: optionally a gas-forming additive. The system does not how a. a controlled release core comprising a drug, a highly ever contain a part of the drug in immediate release form and 10 Swellable polymer and a gas generating agent, said core a part in controlled release form and does not provide a being capable of Swelling and achieving flotation rapidly biphasic release pattern. The rate of swelling of these systems while maintaining its physical integrity in gastrointestinal is also slow so that they do not achieve the desired large size fluids for prolonged periods, and in a short period of 15 to 30 minutes. Moreover in order to b. a rapidly releasing coat composition comprising the same achieve homogeneity of the two polymers on the molecular 15 level a cumbersome and expensive process such as freeze drug as in the core and pharmaceutically acceptable excipi drying is required. ents, wherein the coating composition Surrounds the core PCT publication No. WO 00/15198 assigned to Ranbaxy Such that the system provides a biphasic release of the drug Laboratories relates to a pharmaceutical composition com in gastrointestinal fluids. prising a drug, a gas-generating component, a Swelling agent, Yet another specific object of the present invention is to a Viscolyzing agent, and optionally a gel-forming polymer. provide a gastric retention controlled drug delivery system for The gas generating agents used are carbonates or bicarbon baclofen. ates. The Swelling agent is a Superdisintegrant such as cross linked polyvinylpyrrolidone, cross-linked carboxymethyl SUMMARY OF THE INVENTION cellulose and Sodium starch glycolate. The Viscolyzing agent 25 is a carbohydrate gum that viscolyzes instantly. The system The present invention provides a gastric retention con does not however contain a part of the drug in immediate trolled drug delivery system comprising: release form and a partin controlled release form and does not (a) a controlled release core comprising a drug, a highly provide a biphasic release pattern. Swellable polymer and a gas generating compound, said PCT publication No. WO 01/10419 assigned to Ranbaxy 30 core being capable of Swelling and achieving floatation Laboratories relates to a pharmaceutical composition com rapidly while maintaining its physical integrity in gas prising a drug, a Sugar, a diluent and a gas generating agent, trointestinal fluids for prolonged periods, and and PCT publication No. WO 01/10405 also assigned to (b) a rapidly releasing coat composition comprising the same Ranbaxy Laboratories relates to a pharmaceutical composi drug as in the core and pharmaceutically acceptable excipi tion comprising a drug, inert oil, a Sugar, a diluent and a 35 ents, wherein the coating composition Surrounds the core gas-generating agent. These systems however are not capable Such that the system provides a biphasic release of the drug of Swelling to a desirable large size Suitable for gastric reten in gastrointestinal fluids. tion, as they do not contain any Swellable Substance. The present invention further provides a gastric retention PCT publication No. WO 00/23045 assigned to Sanofi controlled drug delivery system wherein the controlled Synthelabo discloses a pharmaceutical composition contain 40 release core is capable of swelling rapidly to at least about two ing two or three layers and contains an active principle in times its original Volume, and maintaining its physical integ association with an excipient modifying its release and a rity in gastrointestinal fluids for prolonged periods. system capable of generating carbon dioxide in a Swelling The present invention also provides a gastric retention polymer hydrophilic matrix. Examples are provided where controlled drug delivery system comprising baclofen or its the active principle is in one layer containing Swellable poly 45 pharmaceutically acceptable salt. mers as the excipient modifying its release and the second layer contains Swellable polymer in association with a car BRIEF DESCRIPTION OF THE DRAWING bonate. The composition is in the form of bilayer or trilayer tablets. The system does not however contain a part of the FIG. 1 shows the plasma concentration vs time profile drug in immediate release form and a part in controlled 50 obtained upon administration of one embodiment of the gas release form and does not provide a biphasic release pattern. tric retention controlled drug delivery system of the present PCT publication No. WO 01/10417 assigned to Galenix invention having 30 mg baclofen. Development discloses and claims a pharmaceutical compo sition containing at least one phase comprising an active DESCRIPTION OF THE INVENTION principle in association with one or many excipients and a 55 second phase called non-active, consisting of at least one The present invention provides a gastric retention con gas-generating system and at least one hydrophilic polymer trolled drug delivery system comprising: or a porous mineral compound; and wherein the active phase (a) a controlled release core comprising a drug, a highly comprises at least 80% active principle. The limitation of Swellable polymer and a gas generating compound, said using not more than 20% of a release rate controlling excipi 60 core being capable of Swelling and achieving floatation ent limits the flexibility that a formulator has for obtaining the rapidly while maintaining its physical integrity in gas desired rate of release while providing a higher level of assur trointestinal fluids for prolonged periods, and ance of reproducibility of the release profile from batch-to (b) a rapidly releasing coat composition comprising the same batch. On the other hand when rate-controlling excipients are drug as in the core and pharmaceutically acceptable excipi chosen judiciously such that they provide a highly reproduc 65 ents, wherein the coating composition Surrounds the core ible release profile even when used in Small amounts they may Such that the system provides a biphasic release of the drug not be rapidly and highly swellable themselves. The system in gastrointestinal fluids. US 8,012,496 B2 5 6 The gastric retention controlled drug delivery system of the sole, , lomustine, mechlorethamine, mel present invention is useful in providing improved drug deliv phalan, mercaptopurine mechlorethamine, megesterol, ery. Drugs that may be used in the gastric retention controlled methotrexate, methylprednisolone, methyltestosterone, drug delivery system of the present invention may be selected mithramycin, mitomycin, mitotane, mitoxantrone, mitoZolo from the following, viz. alcohol abuse preparations, drugs mide, mutamycin, nilutamide, paclitaxel, pamidronate, used for alzheimer's disease, anaesthetics, acromegaly pegaspargase, pentostatin, plicamycin, porfimer, predniso agents, , antiasthmatics, anticancer agents, antico lone, procarbazine, rituximab, SargramoStim, Semustine, agulants and antithrombotic agents, , antidia streptozocin, tamoxifien, temozolamide, teniposide, testolac betics antiemetics, antiglaucoma, , anti-infec tone, thioguanine, thiotepa, tomudex, topotecan, toremifene, tive agents, antiparkinsons, antiplatelet agents, antirheumatic 10 trastumuZab, tretinoin, Semustine, streptozolocin, valrubicin, agents, antispasmodics and agents, antitus verteprofin, vinblastine, Vincristine, vindesine, vinorelbine sives, carbonic anhydrase inhibitors, cardiovascular agents, and their salts. inhibitors, treatment of CNS disorders, CNS Examples of anticoagulants and antithrombic agents are stimulants, contraceptives, cystic fibrosis management, warfarin, dalteparin, heparin, tinzaparin, enoxaparin, danap , endometriosis management, 15 aroid, abciximab, alprostadil, altiplase, anagralide, anistre erectile dysfunction therapy, fertility agents, gastrointestinal plase, argatroban, ataprost, beraprost, camonagreel, cilosta agents, immunomodulators and immunosuppressives, Zol, climprost, clopidogrel, cloricromen, dermatan, desirudin, memory enhancers, preparations, muscle relaxants, domitroban, drotaverine, epoprostenol, eptifibatide, nucleoside analogues, osteoporosis management, parasym fradafiban, gabexate, iloprost, isbogrel, lamifiban, lam pathomimetics, , psychotherapeutic agents, oteplase, lefradafiban, lepirudin, levosimendan, lexipafant, , and tranquilizers, drugs used for skin melagatran, nafagrel, nafamost sat, niZofenone, orbifiban, ailments, steroids and hormones. OZagrel, pamicogrel, parnaparin, quinobendan, reteplase, Sar Examples of acromegaly agents are octreotide, laureotide pogralate, satigrel, silteplase, Simendan, ticlopidine, and pegVisomant. vapiprost, tirofiban, xemilofiban, Y20811 and their salts. Examples of alcohol abuse preparations are chloraZepate, 25 Examples of anticonvulsants are , clon , , disulfuram, , naltr azepam, clorazepine, diazepam, divalproex, , exone and their salts. ethotion, , fosphenyloin, , , Examples of anaesthetics are , , , , mephenyloin, mephobarbital, , , , , , methSuximide, , , , , , and their salts. 30 phenyloin, , , , valproic acid, Examples of analgesics are acetaminophen, , bupi vigabatrin, , and their salts. vacain, , butorphanol, celecoxib, clofenadol, Examples of antidiabetic agents are acarbose, acetohexa , , codeine, diflunisal, dihydrocodeine, dihy mide, , , epalrestat, , droergotamine, dihydromorphine, ethylmorphine, etodolac, , , , , glisoxepid, , eptazocine, , fentanyl, fentoprofen, 35 glyburide, glyhexamide, metformin, miglitol, , hyaluronic acid, hydrocodon, hydromorphon, hylan, ibupro orlistat, phenbutamide, pioglitaZone, , rosiglita fen, lindomethacin, ketorolac, , levomethadon, Zone, , , tolcyclamide, tolrestat, trogli levallorphan, levorphanol, lidocaine, , taZone, Voglibose and their salts. meloxicam, meperidine, , morphine, nabumetone, Examples of antiemetics are benzquinamide, nalbuphin, , nalorphine, naloxone, naltrexone, 40 benztropine, betahistine, , dexamethasone, naproxen, , , mormethadon, oxapozin, difenidol, , , , oxycodone, oxymorphon, pentazocin, , pehnpyra , dronabinol, , , haloperi mid, piritramid, piroXicam, propoxyphene, refecoxib, riza dol, lorazepam, , methylprednisolone, metoclopra , Salsalaketoprofen, Sulindac, , tebacon, mide, , , , promet tilidin, tolmetin, , and their salts. 45 hazine, Scopolamine, tributine, triethylperazine, Examples of antiasthmatics are ablukast, , , , and their bunaprolast, cinalukast, cromitrile, cromolyn, enofelast, salts. isamoxole, ketotifen, levcromekalin, lodoxamide, mon Examples of antiglaucoma agents are alprenoXime, telukast, ontazolast, oxarbazole, , piriprost potas , diplivefrin, , naboctate, pirnabine and sium, , pobilukast edamine, quaZolast, repirinast, 50 their salts. ritolukast, Sulukast, tetraZolastmeglumine, tiaramide, Examples of antihistamines are acrivastine, activastine, tibenelast, tomelukast, tranilast, Verlukast, Verofylline, Zar albuterol, azelastine, , , amlexanox, irlukast. aZelastine, benzydamine, brompheniramine, , chlo Examples of anticancer agents are adriamycin, aldesleu rpheniramine, cimetidine, clemastine, cycloheptazine, kin, allopurinol, altretamine, amifostine, anastroZole, aspara 55 , diclofenac, diphenhydramine, , ginase, betamethasone, bexarotene, bicalutamide, bleomy , , epinephrine, ethylnorepinephrine, fen cin, buSulfan, capecitabine, carboplatin, carmustine, poterol, fexofenadine, flurbiprofen, hydroxyzine, , chlorambucil, cisplatin, cladribine, conjugated estrogen, cor isoetharine, isoproterenol, ipratropium , ketorolac, tisone, cyclophosphamide, cytarabine, dacarbazine, dauno levocetirizine, loratidine, meduitazine, metaproterenol, phe rubicin, dactinomycin, denileukin, dexamethasone, discoder 60 nylephrine, , , , mollide, docetaxel, doxorubicin, eloposidem, epirubicin, pseudoepedrine, pyrilamine, , , tra epoetin, epothilones, estramustine, esterified estrogen, ethi nilast, Xanthine derivatives, and their salts. nyl estradiol, etoposide, exemestane, flavopirdol, flucona Examples of anti-infective agents are abacavir, albenda Zole, fludarabine, fluorouracil, flutamide, floxuridine, gem Zole, , amphotericin, amikacin, aminosalicylic citabine, gemtuzumab, goserelin, hexamethylmelamine, 65 acid, amoxycillin, amplicillin, amprenavir, atovaquin, hydrocortisone, hydroxyurea, idarubicin, ifosfamide, inter azithromycin, aztreonam, carbenicillin, cefaclor, cefadroxil, feron, irinotecan, lemiposide, letrozole, leuprolide, levami cefamandole, cefazolin, cefdinir, cefepime, cefexime, cefop US 8,012,496 B2 7 8 eraZone, cefotaxime, cefotitam, cefoperaZone, cefoxitin, cef astatin, , metaprolol, metaminol, metazolone, podoxine, cefprozil, ceftazidime, ceftibuten, ceftizoxime, methylchlothaizide, , metyrosine, , ceftriaxone, cefuroxime, cephalexin, chloroquine, cidofovir, midrodine, milrinonr, moexipril, , , , , , , clavulinic acid, clin , nifidepine, , , nitroglyc damycin, colistimethate, dalfopristine, dapsone, daunorubi erin, , perindopril, polythiazide, pravasta cin, delavirdin, demeclocycline, didanosine, doxycycline, tin, , , , , quan doxorubicin, , enoxacin, , ethambutol, facine, quinapril, , ranipril, reteplase, simvastatin, ethionamide, famsiflovir, fluconazole, flucytocin, foscarnet, , Spironolactone, Streptokinase, telmisartan, , fosfomycin, ganciclavir, gatifloxacin, griseofulvin, hydroxy , tocainamide, torsemide, trandolapril, , chloroquine, imipenem, , interferon, isoniazide, itra 10 trapidil, Valsartan and their salts. conazole, ivermectil, , lamivudine, levofloxa Examples of cholinesterase inhibitors are , edro cin, linizolid, lomefloxacin, lovacarbef mebendazole, phonium, , pyridostigmine, rivastigmine, tacrine , meropenem, methanamine, metronidazole, and their salts. , moxefloxacin, naldixic acid, nelfinavir, neomy Examples of CNS stimulants are caffeine, doxapram, cin, nevirapine, nitorfurantoin, norfloxacin, ofloxacin, osel 15 deXoamphetamine, donepezil, edorphonium, methamphet tamivir, oxytetracycline, palivizumab, penicillins, perfloxa amine, methylphenidate, , neostigmine, pemoline, cin, piperacillin, praziquantel, pyrazinamide, phentermine, pyriodstigmine, rivastigmine, tacrin and their pyrimethamine, quinidine, quinupristine, retonavir, ribavirin, salts. rifabutine, rifampicin, , saquinavir, sparfloxacin, Examples of contraceptives are desogestral, ethinyl estra stavudine, Streptomycin, Sulfamethoxazole, teramycin, ter diol, ethynodiol, levonorgestrel, medroxyprogesterone, binafine, tetracycline, ticarcillin, thiabendazole, tobramycin, mestranol, norgestimate, norethindrone, norgestrel and their trimethoprim, trimetraxate, troleandomycin, trovafloxacin, salts. Valacyclovir, Vancomycin, Zalcitabine, Zanamivir, zidovudine Examples of cystic fibrosis management are dornase alpha, and their salts. pancrelipase, tobramycin and their salts. Examples of antiparkinsons are amantadine, adrogolide, 25 Examples of agonists are amantadine, , benztropine, biperiden, , bromocrip , , , pramipezal, tine, budipine, cabergoline, CHF-1301, , enta and their salts. capone, , , iometopane, lazabemide, Examples of drugs used for endometriosis management are , carbidopa/levodopa, mofegiline, moxiraprine, danazol, goserelin, leuprolide, nafarelin, norethindrone and pergolide, , , rasagiline, ropinirole, 30 their salts. Seligiline, , tolcapone, trihexyphenidyl and their Examples of drugs used for erectile dysfunction therapy salts. are alprostadil, , and their salts. Examples of antirheumatic agents are azathiprine, Examples of fertility agents are citrorelix, clomiphen, fol betamethasone, celecoxib, cyclosporin, diclofenac, hydroxy litropin, ganirelix, gonadotropin, menotropin, , chloroquine, indomethacin, infliximab, mercaptobutanedioic 35 urofollitropin and their salts. acid, methylprednisolone, naproxen, penicillamine, piroxi Examples of gastrointestinal agents are , bisa cam, prednisolone, SulfaSalazine and their salts. codyl, bismuth Subsalicylate, celecoxib, difoxin, dipheoxy Examples of platelet agents are abciximab, anagrelide, late, docusate, famotidine, glycopyrrolate, infliximab, lanSo aspirin, cilostazol, clopidogrel, dipyridamole, epoprostenol, prazole, , metaclopramide, nizatidine, eptifibatide, ticlopidine, tinofiban and their salts. 40 omeprazole, pantoprazole, rabeprazole, ranitidine, simethi Examples of antispasmodics and anticholinergic agents are cone. Sucralfate, and their salts. aspirin, , diclofenac, hyoscyamine, mesoprostol, Examples of immunomodulators and immunosupressives , phenobarbital, Scopolamine and their salts. are azathioprin, ceftizoxine, cyclosporin, daclizumab, glati Examples of antitussives are acetaminophen, acrivastin, ramer, immunoglobulin, interferon, leflunomide, levamisol, albuterol, benzonatate, beractant, brompheniramine, caf 45 mycophenolate, mausomanab, phthalidomide, ribavirine, feine, calfactant, carbetapentane, chlorpheniramine, codeine, Sirolimus and their salts. collfuscerin, dextromethorpham, dornase alpha, , Examples of drugs used in alzheimer's disease are CP epinephrine, fexofenadine, guaphenesin, ipratropium, leval 118954, donepezil, galanthamine, metrifonate, revastigmine, buterol, metaproterenol, , pentoxyphyline, phe tacrine, TAK-147 and their salts. nylephrine, phenylpropanolamine, pirbuterol, poractant 50 Examples of drugs used for migraine preparations are alpha, , pyrilamine, Salbuterol, salmeterol, acetaminophen, dihyroergotamine, divalproex, ergotamine, terbutaline, theophylline, , and their salts. propranolol, risatiriptan, Sumitriptan, trimetrexate and their Examples of carbonic anhydrase inhibitors are acetazola salts. Examples of muscle relaxants are alcuronium-chloride, mide, dichlorphenamide, , , aZapropazon, atracurium, baclofen, , seZolamide and their salts. 55 derivatives, chloromeZanon, chlorophenesincarbamate, chlo Examples of cardiovascular agents are abciximab, acebu roZOxazon, , dantrolen, decamethoniumbro tolol, activase, adenosine, adrenaline, amidarone, , mide, dimethyltubocurariniumchloride, doxacurium, fenyra , amyl nitrate, , atorvastatin, benzepril, midol, gallamintriethiodide, guaiphensine, bepiridil, betaxalol, , candesartan, , hexafluoreniumbromide, hexacarbacholinbromide, meman cartenolol, , cerivastatin, chlorthalidone, chlorthia 60 tin, , , metamisol, metaxalon, Zole, clofibrate, clonidine, colestipol, colosevelam, digOX methocarbamol, mivacurium, orphenadrin, pancuronium, inm, , , , dolfetilide, phenazon, , pipecuronium, rapacuronium, aZosin, enalapril, epoprostenol, eprosartan, esmolol. rocuronium, Succinylcholine, suxamethoniumchloride, tet ethacrynate, erythrityl, , fenoidapam, , razepam, , , , vecu flecamide, fluorosemide, fluvastatin, gemfibrozil, hydrochlo 65 ronium and their salts. rthiazide, hydroflumethazine, , indapamide, isosor In preferred embodiments of the gastric retention con bide, irbesartan, labetolol, , lisinopril, losartan, lov trolled drug delivery system the used is US 8,012,496 B2 10 baclofen or its pharmaceutically acceptable salt. A baclofen Examples of drugs used for treatment of skin ailments are gastric retention controlled drug delivery system is not known acitretin, alclometaSone, allitretinoin, betamethasone, cal or disclosed or Suggested prior to the present invention. ciprotrine, chlorhexidine, clobetasol, clocortolone, clotri Baclofen may be used in the system in an amount ranging amozole, collagenase, cyclosporin, desonide, difluorosone, from about 15 mg to about 80 mg. In the gastric retention doxepine, eflornithine, finasteride, fluocinolone, flurandre controlled drug delivery system of the present invention, nolide, fluticasone, halobetasol, hydrochloroquine, hydro baclofen is used in an amount of 30 mg. The system is quinone, hydroxy Zine, ketoconazole, mafenide, malathion, designed Such that a large part of the 30 mg dose of baclofen menobenzone, neostigmine, nystatin, podofilox, povidone, is present in the core, and is available as controlled release, taZorotene, tretinoin and their salts. 10 Examples of Steroids and hormones are alclometasone, while a small part of the drug is present in the coat, and is betamethasone, calcitonin, citrorelix, clobetasol, clocor available as immediate release. Thus, a biphasic release of tolone, cortisones, danazol, desmopressin, desonide, baclofen is provided by the delivery system of the present desogestrel, desoximetasone, dexamethasone, diflorasone, invention. estradiol, estrogens, estropipate, ethynlestradiol, fluocino Examples of nucleoside analogues are abacavir, acyclovir, 15 lone, flurandrenolide, fluticasone, glucagon, gonadotropin, didanosine, gamciclovir, gemcitabine, lamivudine, ribavirin, goserelin, halobetasol, hydrocortisone, leuprolide, levonorg stavudine, Zalcitabine and their salts. estrel, levothyroxine, medroxyprogesterone, menotropins, Examples of drugs used for osteoporosis management are methylprednisolone, methyltestosterone, mometaSone, alendronate, calcitonin, estradiol, estropipate, medroX naferelin, norditropin, norethindrone, norgestrel, octreolide, yprogesterone, norethindrone, norgestimate, pamidronate, Oxandrolone, oxymetholone, polytropin, prednicarbate, raloxifen, risdronate, Zoledronate and their salts. prednisolone, progesterone, sermorelin, Somatropin, stano Examples of parasympathomimetics are bethanechol, pip Zolol, , urofolitropin and their salts. eridine, edrophonium, glycopyrolate, hyoscyamine, pilo In accordance with this invention the core achieves a high carpine, tacrine, yohimbine and their salts. degree of Swelling in a short time. This high degree of Swell Examples of prostaglandins are alprostadil, epoprostenol, 25 ing may be achieved by using highly and rapidly Swellable misoprostol and their salts. polymers, or by avoiding a high pressure of compaction of the Examples of psychotherapeutic agents are , swellable polymers, or by use of highly swellable polymers , alpertine, alprazolam, , apriprazole, that inherently compress to a low density. When the core that , , befipiride, , benzindopy is compressed has a low density, the core has sufficient rine, bimithil, biriperone, brofoxine; ; bromperi 30 strength such that if it has to be further coated by compression dol, , , , ; then it can be transferred mechanically from the first com butaperazin, carphenazine, carvotroline, cericlamine, chlo pression station, where it is compressed, to the second com razepine, chlordiazepoxide, chlorpromazine; chlorprothix pression station, where the compression coat is formed; or if ene, cinperene, cintriamide, , clomacran, clon it is to be further coated by spraying, then it can withstand the azepam, , , clopipazan, cloroperone, 35 rigors of agitation in the coating equipment. clothiapine, clothixamide, ; cyclophenazine, Examples of the highly swellable polymers that may be dapiprazole, dapoxetine, , divalproex, dipy used in the present invention include: ridamole, , droperidol, dulloxetine, , highly swellable grades of cellulose ethers such as hydroxy eptipirone, , fenimide, , , Calkyl Calkyl celluloses, carboxyalkyl celluloses, , , , fluspiperone, fluspir 40 hydroxy C. alkyl celluloses preferably hydroxyethyl ilene, flutroline, , , , cellulose, hydroxypropylcellulose, hydroxypropyl halopemide, , hydroxy Zine, hydroxynortriptyline, methylcellulose, more preferably a high viscosity grade , imidoline, lamotrigine, , enperone, of hydroxyethylcellulose; maZapertine, mephobarbital, meprobamate, , gums of plant, animal, mineral or synthetic origin such as mesoridazine, , mirtazepine, , milen 45 (i)agar, alginates, carrageenan, furcellaran derived from perone, millipertine, , , naranol, nefaZ marine plants, (ii) guar gum, gum arabic, gum traga odone, neflumozide, , odapipam, , canth, karayagum, locustbean gum, pectin derived from oxethiazine, oxiperomide, , , paroX terrestrial plants, (iii) microbial polysaccharides such as itene, , pentiapine perphenazine, , dextran, gellan gum, rhamsangum, Welangum, Xanthan , , , , pipotiaz 50 gum, and (iv) synthetic or semi-synthetic gums such as ine, , , pivagabine, pramipexole, propylene glycol alginate, hydroxypropyl guar and prochlorperazine, prochlorperazine, , , modified Starches like sodium starch glycolate; , , remoxipride, , rimca a Superdisintegrant polymer Such as cross-linked polyvi Zole, robolzotan, , Seperidol, , ; nylpyrrolidone, cross-linked sodium carboxymethylcel Seteptiline, , , Sunipitron, tepirindole, 55 lulose, carboxymethyl starch, Sodium carboxymethyl , thiothixene, , tioperidone, , starch, potassium methacrylate-divinylbenzene copoly topiramate, , , . mer, polyvinyl , amylose, cross-linked amylose, triflupromazine, triflupromazine, , , starch derivatives, microcrystalline cellulose and cellu and their salts. lose derivatives, alpha-, beta- and gamma-cyclodextrin Examples of sedatives, hypnotics and tranquilisers are bro 60 and dextrin derivatives; mazepam, buspirone, , , chloraZepate, an acrylic acid polymer Such as cross-linked polymer avail diazepam, , dexmedetomitine, diphenyhy able under the tradename Carbopol R; dramine, doxylamine, , estraZolam, hydroxy Zine, a vinyl pyrrolidone polymer Such as crosslinked polyvi , loraZatone, lorazepam, loxapine, , nylpyrrolidone or crospovidone; copolymers of vinyl meperidine, methobarbital, midazolam, nabilone, nisobam 65 pyrrolidone and vinyl acetate; or mixtures thereof. ate, , , promethazine, propofol, triaz In preferred embodiments the highly swellable polymer is olam, , and their salts. a mixture of a Superdisintegrant and one or more binding US 8,012,496 B2 11 12 agents, the binding agent being selected from hydrophilic alone or in combination with an acid source as a gas gener polymers, preferably highly swellable polymers. In preferred ating couple. The acid source may be an edible organic acid, embodiments, the hydrophilic polymer used is a high viscos a salt of an edible organic acid, or mixtures thereof. Examples ity cellulose derivative having aqueous solution viscosity of organic acids that may be used include citric acid, malic ranging from about 500 mPas to about 1,20,000 mPas. A acid, Succinic acid, tartaric acid, fumaric acid, maleic acid, mixture of sodium starch glycolate and high viscosity grade ascorbic acid, glutamic acid, and their salts, and mixtures hydroxyethyl cellulose is used as the preferred swellable thereof. The gas generating agent is used in an amount rang polymer in one embodiment of the present invention. In yet ing from about 1% to about 50% by weight of the core, more another embodiment, the highly swellable polymer used is a preferably from about 1% to about 15% by weight of the core. mixture of Sodium starch glycolate, high viscosity grade 10 Sodium bicarbonate is used as the preferred gas generating hydroxyethyl cellulose and hydroxypropyl methylcellulose. agent. Sodium starch glycolate is a Sodium salt of carboxymethyl The highly swellable polymer may further comprise an ether of starch having a molecular weight in the range of excipient that increases the rate of swelling of the delivery 500,000 to 1,000,000 Daltons, and is commercially available system. This excipient may be a water-soluble compound that as Explotab(R) and Primoel R. Sodium starch glycolate causes 15 induces osmosis, or a wicking agent Such as microcrystalline disintegration by rapid uptake of water, followed by rapid and cellulose, that promotes the influx of water into the system. enormous Swelling. The advantage of using sodium starch Water-soluble compounds Suitable for inducing osmosis, i.e. glycolate as the Superdisintegrant is that its effectiveness is osmotic agents or osmogents, include all pharmaceutically not affected by the presence of hydrophobic excipients, such acceptable and pharmacologically inert water-soluble com as lubricants, or by increased compression pressure. It is pounds referred to in the pharmacopoeias Such as United capable of swelling to 300 times its volume in water. Sodium States Pharmacopoeia, as well as in Remington: The Science starch glycolate is used as the preferred Superdisintegrant in and Practice of Pharmacy. Pharmaceutically acceptable the present invention in an amount ranging from about 5% to water-soluble salts of inorganic or organic acids, or non-ionic about 50% by weight of the core, preferably from about 10% organic compounds with high water Solubility, e.g. carbohy to about 40% by weight of the core, more preferably from 25 drates such as Sugar, or amino acids, are generally preferred. about 15% to about 30% by weight of the core. The examples of agents used for inducing osmosis include Hydroxyethyl cellulose is a non-ionic, water soluble poly inorganic salts such as chloride or magnesium mer, which is a partially substituted poly(hydroxyethyl)ether Sulfate, , Sodium or potassium chloride, lithium, of cellulose, and is available in different grades that vary in Sodium or potassium hydrogen phosphate, lithium, sodium or Viscosity and degree of substitution. It is commercially avail 30 potassium dihydrogen phosphate, salts of organic acids Such able as Cellosize from Amerchol Corp., and Natrosol (R) from as sodium or potassium acetate, magnesium Succinate, Aqualon. Preferably, hydroxyethyl cellulose having aqueous sodium benzoate, sodium citrate or sodium ascorbate; carbo solution viscosity ranging from 9000 mPas to 30,000 mPas hydrates such as mannitol, Sorbitol, arabinose, ribose, Xylose, for a 2% w/v aqueous solution is used as the hydrophilic glucose, fructose, mannose, galactose, Sucrose, maltose, lac polymer in the present invention. It is used in an amount 35 tose, raffinose; water-soluble amino acids such as glycine, ranging from about 5% to about 50% by weight of the core, leucine, alanine, or methionine; urea and the like, and mix preferably from about 10% to about 40% by weight of the tures thereof. In preferred embodiments, the core of the gas core, more preferably from about 15% to about 30% by tric retention controlled drug delivery system includes one or weight of the core. more osmotic agents that increase the rate of Swelling of the Hydroxypropyl methylcellulose (HPMC) is a partly O-me 40 system. Preferably, the osmotic agent is used in an amount thylated and O-(2-hydroxypropylated) cellulose, available in ranging from about 0.5% to about 50% by weight of the core, different grades that vary in viscosity. The molecular weight more preferably from about 2% to about 40% by weight of the of HPMC ranges between 10,000 and 1,500,000. It is com COC. mercially available as Benecel MHPC, Methocel and Meto The gastric retention controlled drug delivery system of the lose. In one embodiment of the present invention, HPMC 45 present invention may also include various pharmaceutically K4M grade is used as the Swelling polymer in an amount acceptable excipients, for example disintegrants such as ranging from about 5% to about 25% by weight of the core, starch, cellulose derivatives, gums, crosslinked polymers and more preferably from about 10% to about 15% by weight of the like; binders such as starch, gelatin, Sugars, cellulose the core. derivatives, polyvinyl pyrrolidone and the like; lubricants In preferred embodiments the mixture of high viscosity 50 Such as talc, magnesium Stearate, colloidal silicon dioxide, grade hydroxyethyl cellulose and Sodium starch glycolate is polyethylene glycol, cellulose derivatives and the like; and used as the highly swellable polymer, preferably in a weight mixtures thereof. ratio lying in the range of 1:9 to 9:1, more preferably 3:7 to 7:3 In preferred embodiments, hydroxypropyl methylcellulose and still more preferably 4:6 to 6:4, of hydroxyethyl cellulo (HPMC) is used as the binder. Preferably, HPMC K4M is se: sodium starch glycolate. The cores formed with this mix 55 used as the binder in an amount ranging from about 0.2% to ture are capable of Swelling rapidly and achieving floatation about 5% by weight of the core, more preferably from about while maintaining their physical integrity over prolonged 0.2% to about 2% by weight of the core. periods of time. Examples of lubricants that may be used in the present The gas generating agent used in the core of the gastric invention include talc, magnesium Stearate, calcium Stearate, retention controlled drug delivery system of the present 60 aluminum Stearate, Stearic acid, hydrogenated vegetable oils, invention may include a single component that generates gas colloidal silicon dioxide, polyethylene glycol, cellulose upon contact with the gastric fluid, or may include a gas derivatives such as carboxyalkyl cellulose and its alkali salts, generating couple. Gas generating components that may be or mixtures thereof. In preferred embodiments, the lubricant used in the present invention include carbonates such as cal used is a mixture of silicified microcrystalline cellulose, talc cium carbonate, bicarbonates Such as sodium or potassium 65 and polyethylene glycol. Silicified microcrystalline cellulose bicarbonate, sulfites such as sodium sulfite, sodium bisulfite, is a synergistic, intimate physical mixture of microcrystalline or sodium metabisulfite, and the like. These salts may be used cellulose and colloidal silicon dioxide, having a particle size US 8,012,496 B2 13 14 in the range of 20 to 200 um, and generally contains 2% by Example 1 weight of colloidal silicon dioxide. It is commercially avail able as Prosolv(R) SMCC, and has an improved compaction The gastric retention controlled drug delivery system was property as compared to microcrystalline cellulose. The poly obtained as per Table 1 below. glycol (PEG) used is PEG 8000. The mixture is used 5 as the lubricant in an amount ranging from about 0.5% to about 40% by weight of the core, preferably from about 5% to TABLE 1 about 30% by weight of the core, more preferably from about 10% to about 25% by weight of the core. Ingredients Quantity (mg tablet) The core of the gastric retention controlled drug delivery 10 system is Surrounded by a rapidly releasing coat composition Core comprising the same drug as in the core, and pharmaceuti Intragranular cally acceptable excipients. In a preferred embodiment of the present invention, the coat composition comprises baclofen Baclofen 2O.O and pharmaceutically acceptable excipients, such as film 15 Lactose 3O.O forming agents, plasticisers and the like. The film forming agents are selected from a group comprising cellulose ethers Hydroxyethyl cellulose (HEC 250 H) 4OOO and esters such as methyl cellulose, ethyl cellulose, hydrox Sodium starch glycolate 1SO.O ypropyl cellulose, hydroxypropyl methylcellulose (HPMC); Sodium bicarbonate 40.0 acrylic acid polymers such as methacrylate and methyl meth Hydroxypropyl methylcellulose (HPMC K4M) 136.0 acrylate copolymers, and the like, and mixtures thereof. In Extragranular preferred embodiments hydroxypropyl methylcellulose is used as the film forming agent in an amount ranging from Silicified microcrystalline cellulose 90.0 about 0.5% to about 5% by weight of the core, preferably (Prosolv SMCC 90) from about 1% to about 3% by weight of the core. The rapidly 25 Talc 24.O releasing composition may further contain one or more plas Polyethylene glycol (PEG 8000) 1O.O ticisers selected from a group comprising glycerin, propylene glycol, polyethylene glycols, acetylated monoglyceride, cit Hydroxypropyl methylcellulose (HPMC K4M) 1OOO rate esters such as triethylcitrate, and phthalate esters such as Coat diethyl phthalate. In preferred embodiments propylene glycol 30 is used as the plasticiser. Alternatively, hydroxypropyl meth Baclofen 1O.O ylcellulose coating solution, commercially available as Hydroxypropyl methylcellulose (Opadry II) 45.O Opadry(R) II from Colorcon, may be mixed with the drug and used to coat the controlled release cores. The manufacture of coated tablets may be performed in 35 The core of the gastric retention controlled drug delivery two steps. In the first manufacturing step the core composi system was obtained by passing baclofen, lactose, hydroxy tion is added to the die cavity at a first compression station, ethyl cellulose, Sodium starch glycolate, sodium bicarbonate compressed and ejected with the aid of a lower punch. The and a part of HPMC K4M through ASTM (American Society second step consists of applying a coat on the core by con for Testing and Materials) sieve #40 and mixing the ingredi ventional methods such as spray coating or compression coat 40 ents to obtain a dry powder blend. An aqueous Solution of ing. Spray coating comprises exposing the Surfaces of the HPMC K4M was then used to granulate the dry powder core by rolling it in a suitable coating vessel or by fluidizing blend. The granules thus obtained were passed through a them in a fluidizing equipment; and applying coating com suitable sieve and dried. The dry granules were lubricated positions containing drug and coating polymers. The drug is with a mixture of Prosolv SMCC 90, talc, PEG 8000 and incorporated either in the same composition containing the 45 coating polymer in a liquid vehicle or is layered as a powder. HPMC K4M, and compressed to obtain the cores. The cores Compression coating comprises filling the coating composi were then coated with an aqueous Solution containing tion for the lower half of the tablet into the die at a second baclofen and Opadry II to obtain the gastric retention con compression station, transfer of the core from the first com trolled drug delivery system of the present invention. pression station to the second compression station and its 50 The tablets thus obtained were subjected to dissolution placement in the center of the coating composition already testing at 37° C. using United States Pharmacopoeia Type II filled into the die, filling of the upper half of the coating (paddle) dissolution apparatus at 50 rpm. The dissolution composition into the die, a compression phase to form the medium used was 1000 ml of 0.1N HC1. The tablets achieved coated tablet, and an ejection phase that serves to remove the floatation in about 10 minutes. The results of the dissolution compression coated tablet from the die with the aid of the 55 test are recorded in Table 2 below. lower punch. The gastric retention controlled drug delivery system of the TABLE 2 present invention rapidly Swells while maintaining its physi cal integrity in gastrointestinal fluids for prolonged periods. A Time % drug released in 0.1N HCl low density is achieved by entrapment of the gas generated by 60 O the gas generating agent such that the system floats in gastric 39 fluids. The Swelling and gas entrapment can occur rapidly 44 Such that the system is capable of achieving floatation in a 53 60 dissolution bath containing 0.1N HCl in 15 minutes, prefer 66 ably in less than 10 minutes. 65 77 The following examples do not limit the scope of the inven tion and are used as illustrations. US 8,012,496 B2 15 16 Example 2 Example 3

The gastric retention controlled drug delivery system was The gastric retention controlled drug delivery system of the obtained as per Table 3 below— 5 present invention was obtained as given in Table 5 below. TABLE 3 TABLE 5

Ingredients Quantity (mg tablet) Ingredients Quantity (mg tab) 10 Baclofen 3O.O Core Hydroxyethyl cellulose (Natrosol 250 H) 197.5 Intragranular Sodium starch glycolate 217.5 Microcrystalline cellulose (Avicel PH 101) 435.0 Baclofen 22.5 Sodium bicarbonate 1O.O Mannitol 60 26O.O Polyvinylpyrrollidone (PVP K-30) 22.0 Hydroxyethyl cellulose (HEC 250 HX Pharma) 2OO.O 15 Talc 9.0 Magnesium stearate 9.0 Sodium starch glycolate 2SO.O Sodium bicarbonate 80.0 Hydroxypropyl methylcellulose (HPMC K4M) 4SO A part of baclofen, hydroxyethylcellulose, apart of sodium Extragranular starch glycolate, a part of microcrystalline cellulose and apart Silicified microcrystalline cellulose 90.0 of polyvinylpyrrolidone, were mixed together and granulated (Prosolv SMCC 90) with isopropanol and lubricated with talc and magnesium Talc 24.O Stearate to form the core granulation. The remaining parts of Polyethylene glycol (PEG 8000) 1O.O baclofen, microcrystalline cellulose, polyvinylpyrrolidone 25 and sodium starch glycolate were mixed together and granu Coat lated with water to form the coat granulation. The core granu lations were compressed and the coat was applied on the core Baclofen 7.5 using compression coating. The gastric retention controlled Hydroxypropyl methylcellulose (HPMC E5) 24.O drug delivery system thus obtained in the form of coated Talc 1O.O 30 tablets shows a high degree of swellability in a short time, has Propylene glycol S.O sufficient strength for handling as well as remaining intact in Titanium dioxide 11.0 aqueous fluids, and is capable of providing a biphasic con trolled release profile. The core of the gastric retention controlled drug delivery 35 system was obtained by passingbaclofen, mannitol, hydroxy Example 4 ethyl cellulose, Sodium starch glycolate and sodium bicar bonate through ASTM (American Society for Testing and The of baclofen after administration of Materials) sieve #40 and mixing the ingredients to obtain a the gastric retention controlled drug delivery system compris dry powder blend. An aqueous solution of HPMC K4M was 40 ing 30 mg baclofen (Example 2) was studied. A multiple-dose then used to granulate the dry powder blend. The granules and single-dose, open label, randomized, comparative and thus obtained were passed through a suitable sieve and dried. two-way crossover study was undertaken for the same. The dry granules were lubricated with a mixture of Prosolv SMCC 90, talc and PEG 8000, and compressed to obtain the The pharmacokinetic assessment was based on the plasma cores. The cores were then coated with a hydroalcoholic 45 levels of baclofen measured by blood sampling. Blood solution of a mixture of baclofen, HPMC E5, talc, propylene samples were obtained before dosing and at the following glycol and titanium dioxide to obtain the gastric retention times after administration of the test 0.25, 0.5, controlled drug delivery system of the present invention. 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 16, 20 and 24 hours. The tablets thus obtained were subjected to dissolution 50 testing at 37° C. using United States Pharmacopoeia Type II Twelve healthy male volunteers were enrolled for the study (paddle) dissolution apparatus at 50 rpm. The dissolution and all of them completed the study. The subjects were fasted medium used was 1000 ml of 0.1N HC1. The tablets achieved overnight and were given a high fat breakfast before dosing. floatation in about 6 minutes. The results of the dissolution Drinking water was prohibited 2 hours before dosing and 2 test are recorded in Table 4 below. 55 hours thereafter, but was allowed ad lib at all other times. Standard meals were provided at 4 hours and 8 hours after TABLE 4 dosing and at appropriate times thereafter. Meal plans were identical for both the periods. Time % drug released in 0.1N HCl Subjects received a single gastric retention controlled O 60 release tablet of baclofen (30 mg) with 240 ml of water at 55 63 ambient temperature after the fast, for five days. 75 The plasma concentration of baclofen was determined for 83 91 samples collected at different time points and averaged over 99 65 the twelve volunteers. The data is given in Table 6 below. The plasma concentration versus time profile is illustrated in FIG 1. US 8,012,496 B2 17 18 TABLE 6 TABLE 6-continued

Mean Plasma concentration Mean Plasma concentration Time (ng/ml) of baclofen gastric retention Time (ngi ml) of baclofen gastric retention (hours) controlled release tablet (30 mg) (hours) controlled release tablet (30 mg) O O 16.0 40.07 O.25 0.97 2O.O 28.03 O.S 12.95 24.0 18.87 1.O 81.57 1.5 117.42 2.0 141.46 10 The gastric retention controlled drug delivery system was 2.5 154.1 Suitable for once daily administration. 3.0 157.67 The invention claimed is: 4.0 172.88 6.O 155.77 1. An oral controlled drug delivery system for once-a-day 8.0 119.55 therapy comprising baclofen and release rate controlling 12.O 67.38 15 excipients, wherein the said system is adapted to release 12.5 65.28 baclofen in a controlled manner so as to provide control over 13.0 6O20 the plasma levels, such that the plasma levels of baclofen are 13.5 57.01 within a desirable range over a 24-hour period for said once 14.O 52.26 a-day therapy. 1S.O 48.18