EXTENDED RELEASE DOSAGE FORMS OF QUETIAPINE SALTS

FIELD OF THE INVENTION

The present invention relates to extended release dosage forms of quetiapine or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Quetiapine is chemically known as 2-[2-(4-dibenzo[b,fJ[l,4]thiazepin-ll-yl-l- piperazinyl) ethoxyjethanol. Quetiapine has been employed as an antipsychotic or neuroleptic agent in the treatment of schizophrenia and bipolar mania, due to its antidopaminergic activity, as well as depressive episodes associated with bipolar disorder. As a combined serotonin (5HTz) and dopamine (Di) receptor antagonist, quetiapine, including its fumarate salt, is also known for the effective treatment of psychiatric conditions. Quetiapine is a drug of the dibenzothiazepine class and belongs to a group of drugs known as '"atypical" or second generation antipsychotics which have become increasingly popular alternatives to "typical" antipsychotics.

Quetiapine molecule is first described in United States Patent No. 4,879,288 (corresponds to European Patent No. 0240228). Later on many references have been published describing various formulations of quetiapine in which certain drawbacks exist in light of the poor dissolution properties of this medicament and the uncontrolled release profile provided by said formulations.

There are many arts describing the modified release or sustained release of extended release dosage form of quetiapine. There are various formulations available, which have been developed with quetiapine.

WO2012147100 discloses a pharmaceutical composition of quetiapine, more particularly extended release compositions of quetiapine or its pharmaceutically acceptable salts comprising carboxymethyl ethyl cellulose, a non-gelling, hydrophobic release controlling polymer, and processes for preparing the same. WO2010001413 discloses a formulation comprising quetiapine and a non-gelling controlled- release polymer, as well as one or more excipients. Said formulation further comprises a controlled-release coating. WO2010082220 describes a sustained release pharmaceutical composition of quetiapine, and process for preparing such composition. More particularly, it relates to sustained release pharmaceutical composition of quetiapine comprising a non- gelling agent and pharmaceutically acceptable excipients. US20090220593 discloses a multiple unit extended release dosage forms of quetiapine for oral administration, wherein each unit comprises a core containing quetiapine and one or more of pharmaceutically acceptable excipients coated with a rate-controlling coating and process for the preparation thereof. WO2005/041935 describes quetiapine formulations which do not provide a constant or substantially constant level of quetiapine, such that the patient can, at certain time intervals, receive therapeutic amounts of quetiapine exceeding the recommended doses, whereas at other times the amount may be below the therapeutically effective limits. It discloses a novel dosage form of quetiapine and its salts, particularly quetiapine hemifumarate including wax dosage forms, press-coat dosage forms, and sprinkle dosage forms, and other novel dosage forms. The invention also provides sustained release and pulsed release dosage forms of quetiapine and its salts.

W01997/45124 describes the use of matrices with a gelling agent. However, in the latter application, the use of water-soluble active ingredients, such as quetiapine or its pharmaceutically acceptable salts, combined with gelling agents such as hydroxypropyl- methylcelluloses, can give rise to a phenomenon known as dumping in which the release of the active ingredient is delayed, but once initiated the release occurs at very high rates. EP 1218009 describes the preparation of granules containing quetiapine and a freely or very water-soluble binder for their use in suspensions or solutions. WO2003/039516 describes methods for improving the dissolution of poorly dispersible medicaments, including, for example, quetiapine. The dissolution is improved by means of preparing granules in which a floating agent is added to the medicament. Unfortunately, there is no indication about the release profile of these medicaments in the granulate formulations.

US 2007/0244093 describes a controlled release dosage form comprising quetiapine and at least one excipient, exhibiting a dissolution profile such that at 4 hours after combining the dosage form with a dissolution media 50 to 95% of the quetiapine, or the pharmaceutically acceptable salt thereof, is released. Examples 10, 12 and 13 are formulations of quetiapine where stearic acid is used as a lubricant and wherein the tablets may further be coated with ethylcellulose.

US 2008/0287418 describes a formulation comprising quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is about 9.6% to about 10.4% by weight and wherein the formulation comprises about 30% hydroxypropyl methyl cellulose by weight and about 7.2% sodium citrate dehydrate by weight. The formulation further comprises 25.1% lactose monohydrate by weight, about 25.1% microcrystalline cellulose and about 1% magnesium stearate by weight. US 2009/0035370 describes an orally deliverable pharmaceutical dosage form comprising quetiapine and at least one pharmaceutically acceptable excipient, wherein quetiapine is in a form of free base and/or pharmaceutically acceptable salt thereof and comprising a major component in immediate release form and one or more minor components in delayed extended release or delayed pulsed-release form.

WO2007/058593 relates to the a method of treating a patient suffering from or susceptible to a mood disorder or an anxiety disorder comprising administering a sustained release pharmaceutical composition comprising a pharmaceutically effective amount of quetiapine, or a pharmaceutically acceptable salt thereof, to the patieiit in need thereof. The compositions claimed display a particular mean C _ma x characteristics. The proposed method to obtain controlled release of the active ingredient uses the conventional Methocel ^(R) excipients. WO2008/098969 describes a granule for the preparation of pharmaceutical compositions comprising a core that contains quetiapine or pharmaceutically acceptable salt thereof as active ingredient and a binder, and a coating layer comprising a lubricant. It is said that the presence of a lubricant in an amount ranging from 5 to 10 % would be sufficient to achieve me goal of the invention. The application suggests the use of lubricants from the glyceryl behenate, glyceryl palmitostearate and macrogol groups.

However there are various problems associated with quetiapine and other weakly basic drugs to provide controlled release or extended release formulations.

One of the problems associated with the extended release systems for the weakly basic drug is the difficulty in achieving control over the release profiles. Weakly basic drugs exhibits pH dependent solubility and due to varying the solubility according to pH of environment, it> seems very difficult to prepare sustained or extended release dosage form with controlled manner release profile. Particularly the dose dumping may lead to undesired outcomes in terms of sudden increase in the concentration of the active ingredients. Dose dumping is one of the most significant drawbacks of extended-release dosage forms. The most significant event of dose dumping under in vitro conditions is the amount of the active agent released at an earlier time point which may lead to increase in the side effects or adverse events.

Producing extended release formulation of weekly basic drug and having low solubility like quetiapine and similar active agents, and providing desired release profiles in such formulations are quite difficult. Providing appropriate release amounts at desired intervals is at most important for the treatment of the symptoms of patients. Obtaining a desired release profile at desired time is very critical and can be achieved by selection of proper dosage form and proper excipients in specific amount.

However still there exist needs in the society to provide an extended release dosage form of weakly basic drugs like quetiapine which can provide extended release profile with better control over the release profile. The inventors of the present invention have surprisingly arrived to an extended release composition of quetiapine in the form of capsule dosage form which provide extended release profile with better controlled release over a period of time.

SUMMARY OF THE INVENTION

An extended release dosage form of a weakly basic drug comprising a capsule comprising at least two units each comprising weakly basic drug, a release retarding agent, an acidifier only if the unit is tablet and pharmaceutically acceptable excipients wherein at least one unit is enteric coated.

One aspect of the present invention is to provide an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising at least two units each comprising quetiapine or pharmaceutically acceptable salts thereof, a release retarding agent, an acidifier only if the unit is tablet and pharmaceutically acceptable excipients wherein at least one unit is enteric coated.

Another aspect of the present invention is . an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising two tablets each comprising quetiapine or pharmaceutically acceptable salts thereof, a release retarding agent, an acidifier and pharmaceutically acceptable excipients wherein one tablet is enteric coated.

Yet another aspect of the present invention is an extended release dosage form of qiietiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising one tablet and granules each comprising quetiapine or pharmaceutically acceptable salts thereof, a release retarding agent and pharmaceutically acceptable excipients wherein the tablet contains an acidifier and either tablet or granules are enteric coated.

One more aspect of the present invention is an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising two types of pellets or granules each comprising quetiapine or pharmaceutically acceptable salts thereof, a release retarding agent and pharmaceutically acceptable excipients wherein one type of pellets or granules are enteric coated. Yet another aspect of the present invention is to provide an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising one tablet and pellets each comprising quetiapine or pharmaceutically acceptable salts thereof, a release retarding agent pharmaceutically acceptable excipients wherein either tablet or pellets are enteric coated and tablet contains an acidifier.

In one more aspect of the invention is to provide an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising granules and pellets each comprising quetiapine or pharmaceutically acceptable salts thereof, a release retarding agent pharmaceutically acceptable excipients wherein either granules or pellets are enteric coated.

Yet another aspect of the invention is to provide a use of an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof for the treatment of schizophrenia:

The invention will be illustrated in detail below. Other features, objects, and advantages of the invention will be apparent from the specification and the claims.

DETAIL DESCRIPTION OF THE INVENTION

In accordance with the above-mentioned objects and others, the present invention in one embodiments is directed to an extended release dosage form of weakly basic drug comprising a capsule comprising at least two units each comprising weakly basic drug, a release retarding agent, an acidifier only if the unit is tablet and pharmaceutically acceptable excipients wherein at least one unit is enteric coated. Weakly basic active pharmaceutical ingredient which can be used for the dosage form of the present invention can refer to a compound having a pKa of less than 14. In another embodiment, the weakly basic active pharmaceutical ingredient has a solubility of not more than about 20 mg/mL at pH 6.8. Preferred active pharmaceutical ingredient for the present invention is having weakly basic nature. Weakly basic drug for the present invention can be selected from the group consisting of abciximab, abiraterone acetate, acarbose, acebutolol, aceclofcnac, acemetacin, acetaminophen, acetazolamide, acetohexamide, aclidinium bromide, actinomycin, acyclovir, adalimumab, albuterol, aldosterone, alfaxalone, alfuzosin hydrochloride, alosetron hydrochloride, alprazolam, alprenolol, amantadine, ambenonium chloride, amifloxacin, amitriptyline, amlodipine besylate, amoxiprin, amphetamine aspartate, amphetamine mixed salts, amphotericin b, ampicillin, armodafinil, aspirin, atenolol, atorvastatin, calcium, auranofin, azacitidine, azathioprine, azidovudine, azithromycin, azithromycin, aztreonam, bacampicillin hydrochloride, baclofen, beclamide, beclomethasonc, bendamustine hydrochloride, benorilate, benztropine mesylate, besifloxacin hydrochloride, betamethasone, betaxolol, biperiden, bisoprolol, bleomycin, bortezomib, bosentan, brimonidine tartrate, brivaracetam, bromfenac, bromocriptine, buprenoφhine, bupropion hydrochloride, bupropion hydrobromide, buspirone, butaxemine, butenafine, hydrochloride, butylscopalamine bromide, cabergoline, caffeine, carbamazepine, carbenicillin, carbidopa/levodopa, carisoprodol, carprofen, carteolol, carvedilol, caspofungin acetate, celiprolol, cefazolin, cefditoren pivoxil, celecoxib, cerivastatin, carvedilol phosphate, cevimeline hydrochloride, cetrizine hydrochloride, chlorambucil, chlordiazepoxide, chlorhexidine, chloroquine, chlorpheniramine maleate, chlorpheniramine polistirex, chlorpromazine, chlorpropamide, chlorzoxazone, cidofovir, cinacalcet hydrochloride, ciprofloxacin, citalopram, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clobazam, clonazepam, clonidine, clopidogrel, clorazepate dipotassium, clorezepate, clozapine, codeine, colesevelam hydrochloride, cotrimoxazole, cyclobenzaprine, cyclosporine, d- penicillamine, dactinomycin, dalfampridine, dalfopristin, dantrolene, darifenacin hydrobromide, daunorubicin, decitabine,, delavirdine mesylate, desirudin, desloratadine, desvenlafaxine succinate, dexadrine, dexamethasone, dexfenfluramine, dexmethylphenidate hydrochloride, dexrazoxane, dextroamphetamine saccharate, dextroamphetamine sulphate, dextromethorphan hydrobromide, dextromethorphan polistirex, diamo hine, diazepam, dibucaine, diclofenac, dicumarol, dicyclomine, didanosine (dideoxyinosine, ddl), diethylpropion hydrochloride, difenoxin, hydrochloride, difloxacin hydrochloride, diflunisal, diltiazem hydrochloride, diphenhydramine, dipyridamole, dolasetron, donepezil, dopamine, doripenem, dorphenadrine, doxazosin, doxorubicin, doxycyline hyclate, disopyramide phosphate, echinomycin, econazole, eflornithine hydrochloride, eletriptan hydrobromide, enfuvirtide, enoxacin, epirubicin, eptifibatide, erythromycin, esmolol, eszopiclone, etanercept, ethadione, ethopropazine, ethosuximide, ethotoin, etodolac, etomidate, etoricoxib, exanatide, ezogabine, faislamine, felbamate, felodipine, fenfluramine, fentanyl, fingolimod, fleroxacin, fesoterodine fumarate, fexofenadine hydrochloride, fluconazole, fluoxetine, fluphenazine, flurbiprofen, fluspirilene, fluvastatin, fluvoxamine maleate, fluvoxamine, fomepizole, fosphenytoin, frovatriptan succinate, gabapentin, gadopentetic acid, galantamine, gatifloxacin, gentamicin, gliclazide, glimepiride, glipizide, glyburide, granisetron, griseofulvin, haloperidol, heparin, hydrocodone polistirex, hydrocodone, hydrocortisone, hydromorphone, hydroxychloroquine, hydroxyzine, ilopcridone, imidacloprid, imipenem, imipramine, indanylsodium, indinavir, indomethacin, infliximab, isocarboxazid, isradipine, itraconazole, ketoconazole, ketorolac, ketotifen fumarate, labetalol, lacosamide, lamifiban, lamivudine (epivir, 3TC), lamotrigine, leflunomide, lercanidipine, leuprolide acetate, levetiracetam, levobunolol, levodopa, lidocaine, linezolid, lodoxamide tromethamine, lomefloxacin, lomustine, loiatidine, lorazepam, lornoxicam, lovastatin, loxapine, lumiricoxib, lurasidone Hydrochloride, matamizole, mefenamic acid, meloxicam, melphalan hydrochloride, memantine hydrochloride, mepenzolate bromide, mephenytoin, mepindolol, meprobamate, mesuximide, metformin, methadone, methotrexate, methylphenidate hydrochloride, methylphenidate, methylphenobarbital, methylprednisolone, metipranolol hydrochloride, metipranolol, metoprolol, metronidazole, mevastatin, midazolam hydrochloride, mifepristone, miglitol, milrinone lactate, minocycline, mirabegron, mirtazepine, mitomycin, mitoxantrone, molindone, montelukast sodium, morantel, morphine, mupirocin, nabumetone, nadolol, nafcillin, nalbuphine hydrochloride, nalidixic acid, naltrexone, nateglinide, nebivolol, nefazodone, nelarabine, nelfinavir, nevirapine, niacin, nicardipine hydrochloride, nietaxalone, nifedipine, nilutamide, nimesulide, nisoldipine, nitazoxanide, nitrazepam, norfloxacin, nortriptyline, nystatin, octriotide, ofloxacin, olanzepine, ondansetron, orlistat, orphenadrine, oxazepam, oxcarbezepine, oxfendazole, . oxiconazole nitrate, oxprenolol, oxtriphylline, oxybutynin chloride, oxycodone, oxymorphone, oxyphenbutazone, oxytetracycline, paliperidone, palonosetron, pancuronium, paramethadione, parecoxib, paroxetine, pazepam, pefloxacin, penbutolol, penciclovir, penfluridole, penicillin g, pentostatin, pentoxifylline, pergolide, pethidine, phenacemide, phendimetrazine tartrate, phenelzine, pheneturide, phenformin, phenobarbital, phensuximide, phentermine, phenylbutazone, phenylpropanolamine, phenytoin, physostigmine, pilocarpine, pimecrolimus, pindolol, pioglitazone, pirbuterol acetate, piroxicam, pitavastatin, plerixafor, plicamycin, pralatrexate, pramipexole, pravastatin, prazosin, prednisolone, prednisone, pregabalin, primidone, procainamide hydrochloride, prochlorperizine, procyclidine, progabide, propafenon hydrochloride, propazone, propranolol, pseudoephedrine, pyridostigmine bromide, quetiapine, quinacrine, quinidine, quinine, quinupristin, ranolazine, regorafenib, remifentanil hydrochloride, repaglinide, rifampin, rifapentine, rimonabant, risperidone, ritonavir, rivastigmine, rofecoxib, roflumilast, romifidine hydrochloride, ropinirole, rosiglitazone, rosuvastatin, saxagliptin, saquinavir, selegiline, seletracetam, sertaconazole nitrate, sertraline, sildenafil, simvastatin,- sincalide, sitagliptin, sodium aurothiomalate, sodium valproate, sotalol, sparfloxacin, spiramycin, streptozocin, sulbactam, sulfamethoxazole, sulfasalazine, sulfinprazone, sulindac, tacrine, tapentadole hydrochloride, tenoxicam, telcoplanin, telithromycin, tenofovir disoproxil fumarate, terconazole, teriflunomide, temafloxacin, tetrabenazine, theophylline, thiabendazole, thioridazine, thiothixene, tiagabine, ticlopidine, timolol, tirofiban, tizanidine, tolazamide, tolbutamide, tolmetin, tolterodine tartrate, tolvaptan, topiramate, toremifene citrate, tosufloxacin, tramadol, trandolapril, tranylcypromine, trazodone, triamcinolone, trifluoperazine hydrochloride, trihexyphenidyl, trimazosin, trimethadione, trimethoprim, troglitazone, troleandomycin, tropisetron, trospium chloride, tubulazole, ulipristal acetate, valdecoxib, valnoctamide, valpromide, vancomycin, vardenafil hydrochloride, venlafaxine, verapamil hydrochloride, vigabatrin, vildagliptin, vincristine, vinblastine, virazole, voriconazole, warfarin, zalcitabine (dideoxycytosine, ^' ddc), zileuton, zipras ^' idone, Zolpidem tartrate, zonisamide, [R-(R*S*)]-5-chloro-N-[2-hydroxy-3- {methoxymethylamino}-3-oxo-l - (phenylmethyl)propyl-l H-indole-2-carboxamide, 5-chloro- 1 H-indole-2-carboxylic acid [(1 S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-l- yl-)-3-o- xypropyl] amide, [2R,4S] 4-[(3,5-bis- trifluoromethyl-benzyl)-methoxycarbonyl- amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- quinoline-l-carboxylic acid ethyl ester, [2R,4S] 4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)- amino]-2-ethyl-6-trifluoromethyl-3,4- dihydro-2H-quinoline- 1 -carboxylic acid isopropyl ester, [2R, 4S] 4-[(3,5-Bis- trifluoromethyl-benzyl)-methoxycarbonyl-amino] -2-eth-yl-6- trifluoromethyl-3 ,4-dihydro- 2H-quinoline-l -carboxylic acid isopropyl ester; (+)-N-{4-[3- (4-fluorophenoxy)phenoxy]-2- cyclopenten-1 -yl}-N-hyroxyurca.Preferred active pharmaceutical ingredient is quetiapine. Each listed active pharmaceutical ingredient should be understood to include the free base of the API, as well as pharmaceutically acceptable salts, complexes, polymorphs, solvates, hydrates, esters, enantiomers, steroisomers and prodrugs thereof. The term "Quetiapine", as used herein, means quetiapine or a pharmaceutically acceptable form of quetiapine, including its free base form, and all pharmaceutically acceptable salts, complexes, stereoisomers, enantiomer, solvates, hydrates, and polymorphs thereof. Preferably quetiapine is in the form of its fumarate or hemifumarate salt.

In accordance with the above-mentioned objects and others, the present invention, one embodiments is directed to an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof comprises a capsule comprising at least two units each comprising quetiapine or pharmaceutically acceptable salts thereof, a release retarding agent, an acidifier and pharmaceutically acceptable excipients wherein at least one unit is enteric coated.

The term "unit", as used herein, includes individual dosage form which may be coated or uncoated and may be designed as tablets, granules, pellets, compacts, beads, spheroids, and the like.

The term "extended release", as used herein can be used interchangeably with term "controlled release", "modified release" or "sustained release" and refers to a means of releasing an active agent from the dosage form thereof such that it is available to the site of absorption by the body over a period of time.

The term "release retarding agent" as used herein means an agent that plays a role to retard the release of active ingredient or quetiapine from the dosage form so that the quetiapine can be released for extended period of time at therapeutic effective amount to the body.

In one embodiment of the invention, an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising at least two tablets, each comprising quetiapine or pharmaceutically acceptable salts thereof, hydrogenated castor oil as a release retarding agent in the range from 2 to 50% w/w, citric acid anhydrous in the range from 5 to 40% w/w and pharmaceutically acceptable excipients wherein at least one tablet is enteric coated. • In another embodiment of the invention, an extended release dosage form of q ₁ ietiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising at least two type of pellets, each comprising quetiapine or pharmaceutically acceptable salts thereof, hydrogenated castor oil as a release retarding agent in the range from 15 to 70% w/w and pharmaceutically acceptable excipients wherein at least one type of pellets are enteric coated.

In yet another embodiment of the invention, an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising at least one tablet and granules or pellets, wherein tablet comprises quetiapine or pharmaceutically acceptable salts thereof, hydrogenated castor oil as a release retarding agent in the range from 2 to 50% w/w, citric acid anhydrous in the range from 5 to 40% w/w and pharmaceutically and granules or pellets comprises quetiapine or pharmaceutically acceptable salts thereof, hydrogenated- castor oil as a release retarding agent in the range from 15 to 70% w/w and pharmaceutically acceptable excipients and wherein either granules or pellets or tablets are enteric coated.

In yet another embodiment of the invention, an extended release dosage form of quetiapine or pharmaceutically acceptable salts thereof comprising a capsule comprising granules and pellets, each granules and pellets comprises quetiapine or pharmaceutically acceptable salts thereof, hydrogenated castor oil as a release retarding agent in the range from 15 to 70% w/w and pharmaceutically acceptable excipients and either granules or pellets are enteric coated.

Release retarding agent may include one or more hydrophobic or hydrophilic polymers or mixtures thereof. Hydrophobic polymers that can be used for the present invention is selected from the group consisting of but not limited to bees wax, glycol wax, carnauba wax, hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenatd soyabean oil, cetyl alcohol, cetostearyl alcohol, lauryl alcohol, palmityl alcohol, tribehenin, fatty acids, fatty acid triglycerides, stearicc acid, ethyl cellulose, glycerol palmitostearate, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, polyacrylates, polymethacrylates and combinations thereof. Hydrophilic polymers that can be used for the present invention is selected from the group consisting of but not limited to polyethylene oxides; polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, cellulosic polymers/copolymers or its derivatives including methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose;, polyalcohols derivatives and combinations thereof.

Preferably, the release retarding agent is hydrophobic polymer. More preferably the hydrophobic polymer of choice is hydrogenated castor oil.

Release retarding agent to be used for the present invention is in the ranges from 2 to 70%' w/w of the dosage form. Preferably when the unit is tablet the release retarding agent 'should be preferred in the range from 2 to 60% w/w of the dosage form. Preferably when the unit is granules or pellets, the release retarding agent should be preferred in the range from 15 to 70% w/w of the dosage form. More preferably when the unit is tablet the release retarding agent should be preferred in the range from 5 to .45 % w/w of the dosage form. More preferably when the unit is granules or pellets, the release retarding agent should be preferred in the range from 20 to 65% w/w of the dosage form.

Acidifier is selected from the group consisting of but not limited to citric acid (anhydrous or hydrous), sodium citrate, tartaric acid, succinic acid, fumaric acid, aspartic acid, adipic acid, sodium citrate, malic acid, glycolic acid, lactic acid, ascorbic acid, pamoic acid, hydroxymalic acid, glutamic acid, benzoic acid, alginic acid, maleic acid, oxalic acid and corresponding alkali metals salts thereof, and combinations thereof. Preferably the acidifier for the present invention is citric acid anhydrous. The acidifier is used only when the unit is in the form of tablet. Preferred range is from 2 to 50% w/w of dosage form, more preferably 5 to 40 % w/w. When the unit is either pellet or granules an acidifier is not required.

The unit in form of tablet, granules or pellets is optionally film-coated following art known for coating procedures. Further when the unit is enteric coated, the film coating is to be applied before applying enteric coating. The film coating can be carried out by polymers selected from the group consisting of but not limited to hydroxypropyl methyl cellulose, polyvinyl acetate, polyvinyl alcohol, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl methylcellulose, cellulose acetate, ammonium alginate, carboxymethyl cellulose, cellulose triacetate, zein, and combination thereof.

The term "enteric coating", as used herein means any pharmaceutically acceptable coating preventing the release of the active agent in the stomach environment and dissolve the coating in the intestine tract.

More specifically, the term "enteric coating" as used herein refers to a coating which remains intact for at least 2 hours, in contact with artificial gastric juices such as HQ of pH 1 at 36 to 38° C. and preferably thereafter coating gets dissolved within 60 minutes in artificial intestinal juices buffered solution of pH above 4.0.

The enteric coating may be carried out in conventional manner, e.g. so that the units are sprayed with a solution of the enteric-coating. The % of enteric coating can be in the range of 3 to 30% w/w. Enteric polymer can be selected from the group consisting of but not limited to hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylic acid and acrylic acid based polymers, shellac, hypromellose acetate succinate, Poly (methyl vinyl ether/ maleic acid) based polymers known as brand name Gantrez ^® and cellulose acetate trimelliate. Preferable enteric polymer for the present invention is either hydroxypropyl methylcellulose phthalate (HP 50) or Poly (methyl vinyl ether/ maleic acid) monoethyl ester (Gantrez ^® ES 225).

Suitable solvents for film coating and enteric-coating are for example water or organic solvents, e.g. an alcohol such as ethanol, a ketone such as acetone, halogenated hydrocarbons such as CH2C12 or mixtures of such solvents. Plasticizer to be used for film coating and/or enteric coating can be selected from the group consisting of but not limited to propylene glycol, polyethylene glycols, 1,2-propylene glycols, acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, triacetin, acetylated monoglycerides, phthalate esters, castor oil, dibutylphthalate, chlorbutanol, dextrin, diethyl phthalate, dimethyl phthalate, glycerin, glycerin monostearate, mannitol, mineral oil and lanolin alcohols, palmitic acid, 2- pyrrolidone, sorbitol, stearic acid, tributyl citrate, triethanolamine, butyl phthalybutyl glycolate, dibutyl tartrate, ethyl phthalylethyl glycolate, triacetin citrate, tripropionin, diacetin, glyceryl triacetate and combinations thereof.

Conveniently the cores are treated at room temperature or warmed up to 40° C. e.g. by means of warm air of 40° up to 70° C, before spraying. To avoid a sticking, of the cores the spray procedure is preferably interrupted at certain time intervals and the cores then wanned up again. It is, however, also possible to proceed without interruption of the spray procedure, e.g. by automatic regulation of the spray amount taking into account the temperature of exhaust air and/or cores.

Pharmaceutically acceptable excipients are selected from one or more from the group consisting of diluent, binder and lubricant.

The diluent can be selected from the group consisting of but not limited to microcrystalline cellulose, lactose monohydrate, lactose anhydrous, spray dried lactose, di-calcium phosphate, tri-calcium phosphate, di-calcium phosophate dihydrate, starch, mannitol, sorbitol, powdered cellulose, sugars, sugar alcohol, glucose, fructose, sucrose, mannose, dextrose, galactose, xylitol, gelatin, acacia, mono-calcium phosphate, sodium phosphate, sodium carbonate, ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, powdered cellulose, silicified microcrystalline, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, erythritol, ethylcellulose, isomalt, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, tragacanth, trehalose and combinations thereof. Lactose monohydrate is preferred diluents for the present invention. The binder can be used and can be selected from the group consisting of but not limited to cellulose per se (such as sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose), polymers (such as polyvinylpyrrolidone, polyethylene glycol), gelatins (such as hydrolysed gelatin), and traditional binders (such as starch, natural gums) and combnations thereof.

The lubricant for the present invention can be selected from the group consisting of but not limited to magnesium stearate, stearic acid, calcium stearate, PEGs (polyethylene glycols), sodium lauryl sulfate, sodium stearyl fumarate, glyceryl behenate, talc, hydrogenated castor oil (HCO), zinc stearate, silicon dioxide and combination thereof. Preferable lubricants are hydrogenated castor oil (HCO) and magnesium stearate.

Tablets may be prepared by using suitable hot melt extrusion/granulation techniques, mentioned in the literature. The process steps include, dry blending the ingredients, melt granulation, milling of the granules, adding extra granular ingredients, lubrication, compression and optional coating followed by optional enteric coating. When the tablet is to be enteric coated, before enteric coating, a film coating is to be applied. Granules may be prepared by using suitable hot melt extrusion/granulation techniques, mentioned in the literature. The process steps include, dry blending the ingredients, melt granulation and milling of the granules.

Pellets may be prepared by using suitable hot melt extrusion/granulation techniques, mentioned in the literature. The process steps include, dry blending the ingredients, melt extrusion spheronization drying and sieving.

The capsule as used herein which is a final dosage form, preferably uses a gelatin or non- gelatin hard capsule shell formed mainly of a polysaccharide. The polysaccharides include but mot limited to water-soluble cellulose derivatives, pullulan, hemicellulose, corn starch, and chitosan. Exemplary water-soluble cellulose derivatives are carboxymethyl cellulose and water-soluble salts thereof such as sodium salts, and preferably cellulose esters in which some or all of the hydroxyl groups are replaced by alkyl groups, especially lower alkyl groups and/or hydroxy lower-alkyl groups. Illustrative examples are hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxyethyl methyl cellulose, with the hydroxypropyl methyl cellulose being most preferred for film-forming ability and mechanical strength at low water contents. Preferably gelatin based hard capsules to be used.

Capsule filling can be performed by any known conventional method available in the art manually or automatically.

Dissolution of the final dosage form (Capsule) is performed as per below mentioned criteria;

EXAMPLES

Below provided examples are representing particular strength, however the other strengths can be prepared in dose proportional manner and/or with minor modification which is known by person skilled in the art.

Example 1 (Tablet-Tablet)

Core tablets

1. Quetiapine hemifumarate, lactose monohydrate, anhydrous citric acid and hydrogenated castor oil are passed through 40 # sieve.

2. The ingredients of step 1 are mixed for 15 minutes in a blender.

3. The mixer of step 2 is loaded in hot melt extruder at temperature range of 70-95 °C.

4. The agglomerates coming out of the extruder are cooled to room temperature.

5. The agglomerates are milled/passed through 30 # sieve.

6. The extra granular materials (HCO and magnesium stearate) are passed through 60 # sieve and mixed with the granules of step 5 in a blender for 5 minutes.

7. The blended mixture of step 6 is then compressed to produce tablets.

Film coating:

8. Film coating is carried using Opdary® readymade solution in aqueous system.

Enteric Coating (Only for unit 2): .*

9. Enteric coating is carried out by using HPMC Phathalate HP 50 by using acetone and alcohol based system.

Capsule filling

10. One tablet of unit 1 and one tablet of unit 2 to be filled in empty hard gelatin capsule of appropriate size.

% Drug release

Example 1.1 (Comparative example)

Ingredients mg/Tablet (unit 1) mg/Tablet (unit 2)

Quetiapine hemifumarate 28.75 28.75

Lactose monohydrate 4.17 4.17

Citric acid (anhydrous) - -

HCO (intra granular) 10.38 10.38

HCO (extra granular) 4.38 4.38

Magnesium stearate 0.63 0.63

Film coating

(HPMC E5- Opadry® ) 1.50 1.50

Enteric coating

(HPMC phthalate HP 50) 7.12

Total weight 49.81 56.93 Procedure as per example 1.

% Drug release Example 2 (Granules-Tablet)

Tablets of unit 2 can be prepared as per Example 1.

Granules

1. Quetiapine hemifumarate and hydrogenated castor oil are passed through 40 # sieve.

2. The ingredients of step 1 are mixed for 15 minutes in a blender.

3. The mixer of step 2 is loaded in hot melt extruder at temperature range of 70-95 °C.

4. The agglomerates coming out of the extruder are cooled to room temperature.

5. The agglomerates are milled/passed through 16 # sieve and retained over 22 # sieves. The granules fraction between 16 to 22 # is used in further use.

Capsule filling

6. Granules (162 mg) from unit 1 and one tablet of unit 2 to be filled in empty hard gelatin capsule of appropriate size. Drug release

Example 3 (Pellets-Tablet)

Tablets of unit 2 can be prepared as per Example 1.

Pellets

1. Quetiapine hemifumarate and hydrogenated castor oil are passed through 40 # sieve.

2. The ingredients of step 1 are mixed for 15 minutes in a blender.

3. The mixer of step 2 is loaded in hot melt extruder at temperature range of 70-95 °C.

4. The extrudes are spheronized in a spheronizer at elevated temperature (65-80 °C) and then cooled to room temperature.

5. The pellets are passed through 16 # sieve and retained over 22 # sieve. The pellet- fraction between 16 to 22 # are used for further use.

Capsule filling

6. Pellets (155.25 mg) from unit 1 and one tablet of unit 2 to be filled in empty hard gelatin capsule of appropriate size.

% Drug release Example 4 (Pellets-Pellets)

Pellets can be prepared as per Example 3 and further film coating and enteric coating of unit 2 pellets can be done in fluid bed coater.

Capsule filling

Pellets (415 mg) from unit 1 and pellets (479 mg) of unit 2 to be filled in empty hard gelatin capsule of appropriate size.

% Drug release

EXAMPLE 5 (Tablet-Tablet)

Unit 1 and unit 2 tablets are prepared as per Example Capsule filling

One tablet of unit 1 and one tablet of unit 2 to be filled in empty hard gelatin capsule of appropriate size.

% Drug release

Example 6 (Pellets-Granules)

Pellets can be prepared as per Example 3 and Example 2 respectively.

Capsule filling

Pellets (179.7 mg) from unit 1 and granules (162 mg) of unit 2 to be filled in empty hard gelatin capsule of appropriate size.

% Drug release

Example 7 (Granules-Granules)

Granules (unit 1) Granules (Unit 2)

Ingredients

Quantity in mg

Quetiapine hemifumarate 115 1 15

HCO (Intragranular) 100 100

Film coating

(opadry clear) 6

Enteric coating

(GANTREZ® ES 225) 28

Total weight 215 249 Granules can be prepared as per Example 2 and further film coating and enteric coating of unit 2 granules can be done in fluid bed coater.

Capsule filling

Granules (215 mg) from unit 1 and granules (249 mg) of unit 2 to be filled in empty hard gelatin capsule of appropriate size.

% Drug release