FORM 2
The Patents Act, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Prevention of Alcohol Induced Dose Dumping for Modified Release
Pharmaceutical Compositions
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall,
Ahmedabad 380 009, Gujarat, India
The following specification describes the invention:

FIELD OF THE INVENTION
The present invention relates to prevention of alcohol induced dose dumping in modified release pharmaceutical compositions intended for oral administration. Preferably, the present invention relates to modified release pharmaceutical compositions whose release profile is not substantially affected in alcoholic solution.
BACKGROUND OF THE INVENTION
A modified release (MR) pharmaceutical composition for the oral administration of a drug is well known. They provide a better cover of the therapeutic need since the useful plasma concentration can be maintained longer than in case of immediate release pharmaceutical compositions. A MR composition is particularly more suitable for an active pharmaceutical ingredient (API) which has a narrow therapeutic window, in case of these APIs, MR dosage compositions avoid the magnitude and number of peaks of excessive plasma API concentration, thereby reducing the toxicity of the drug and its side effects. Furthermore, due to the increased duration of action of MR compositions, they improve patient compliance.
However, it has recently become apparent that, MR compositions may cause accidental immediate release (dose dumping) of the bulk of the API when it is ingested concomitantly with alcohol. Thus, in the USA in October 2005, the Food and Drug Administration expressed the idea that s study of the resistance of MR compositions to the dose dumping potentially induced by alcohol would be worth conducting for drugs.
In fact, recent studies have shown that the presence of alcohol can accelerate the release of an API contained in a MR pharmaceutical composition, in a first analysis, this alcohol effect can be explained by a degradation of the MR system or by a modification of the solubility of the API in presence of a significant amount of alcohol. This situation is all the more likely to be encountered and the Consequences are likely to be all the more serious, if a large amount of alcoholic drink is ingested, if the drink has a high alcoholic strength and if the subject has an empty stomach. In fact, In this last case, the stomach will essentially contain the ingested drink mixed with a small amount of gastric juice. In practice, therefore, the ingestion of alcohol concomitantly with the administration of an MR pharmaceutical composition can result in the accelerateq and potentially dangerous release of the API in the patient. Depending on the type of API, this accelerated release of the API at best renders the MR pharmaceutical composition totally ineffective, and at worst jeopardizes the patient's vital prognosis.
This harmful acceleration of the release can result in a loss of activity of the drug, as would

be the case, for example, of proton pump inhibitors, whose excessively early release in an acidic gastric medium would lead to their degradation and hence to the inefficacy of the treatment.
Conversely, a more dangerous case is that of certain tranquilizers, antidepressants or opiate analgesics, where it is the vital prognosis which would be in question because of the seriousness of the side effects following an overdose.
One particular group of drugs for which a massive release of API would be particularly harmful is the group of products which have an unfavorable pharmacological interaction with alcohol, an incompatibility or an exacerbation of the side effects. Thus, for example, an undesirable effect of the opiate analgesic group of drugs is that they are capable of inducing respiratory depression; this can be aggravated by the concomitant consumption of alcohol because of the false routes and the swallowing pneumopathies conventionally caused by alcohol abuse. Likewise, very widely used drugs such as tranquilizers and antidepressants have effects on the central nervous system (loss of vigilance, risks of somnolence) which are exacerbated by the simultaneous consumption of alcohol. Interactions of alcohol with antihistamines (potentiation of the sedative effect, somnolence and loss of attention, giddiness) and with non-steroidal anti-inflammatory drugs (potentiation of the risk of digestive bleeding) may also be mentioned.
US20070264346 A1 application discloses a multimicroparticulate pharmaceutical form for the modified release of at least an API whose in vitro dissolution profile is not significantly affected in presence of alcohol. The pharmaceutical form comprises micro-particles of the reservoir type and at least one agent which is a pharmaceutically acceptable compound whose hydration or solvation rate or capacity is greater in an alcohol-free aqueous medium than in alcoholic solution. The reservoir micro-particles have a mean diameter preferably of less than 2000 μm, particularly preferably of between 50 and 800 urn and very particularly preferably of between 100 and 600 urn. Also, the reservoir micro-particles individually consist of a core which comprises the API and is covered with a coating comprising at least one polymer that is insoluble in the fluids of the digestive tract, at least one plasticizer, and optionally at least one surfactant.
We have surprisingly found that if a modified release pharmaceutical composition comprising at least one API is coated with a solution/dispersion comprising sodium alginate or carrageenan then such coating prevents dose dumping in presence of alcohol.

SUMMARY OF THE INVENTION
One embodiment discloses a modified release pharmaceutical composition comprising:
i) a core comprising at least an active pharmaceutical ingredient (API) and one or
more pharmaceutically acceptable excipients, and
ii) a coat comprising alginate or its salts and optionally one or more
pharmaceutically acceptable excipients characterized in that the dissolution profile of the composition is not affected substantially in presence of alcohol.
Another embodiment discloses a modified release pharmaceutical composition comprising:
i) a core comprising at least an active pharmaceutical ingredient (API) and
one or more pharmaceutically acceptable excipients, and ii) a coat comprising carrageenan and optionally one or more pharmaceutically acceptable excipients characterized in that the dissolution profile of the composition is not affected substantially in presence of alcohol.
Another embodiment provides a process for preparation of a modified release pharmaceutical composition comprising API or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition coated with alginate or its salts or carrageenan.
Yet another embodiment discloses a modified release pharmaceutical composition characterized in that the time taken to release 50 % of API in an alcoholic solution is not reduced more than 2 fold relative to the time taken to release 50 % of API in an alcohol free aqueous medium; is preferably not reduced more than 1.5 fold relative to the time taken to release 50 % of API in an alcohol free aqueous medium; is preferably similar to the time taken in an alcohol free aqueous medium according to the similarity factor f2 or is longer than the time taken to release 50 % of API in an alcohol free aqueous medium.
In one of the aspect such coating of alginate or carrageenan in a pharmaceutical dosage form may additionally prevent alcohol induced degradation and subsequent impurity formation in GIT after ingestion of dosage form.

DETAILED DESCRIPTION OF THE INVENTION
The term "modified release pharmaceutical composition" (MR) as used herein in relation to the composition according to the invention means release, which is not immediate release and is taken to encompass controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release. The term "modified release pharmaceutical composition" as used herein can be described as dosage forms whose drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or immediate release dosage form. The term "modified release pharmaceutical composition" is well known in the field of Pharmaceutics; cf. for example, Remington: The Science and Practice of Pharmacy, 19th Ed., Mack Publishing Co., Pennsylvania, USA.
The term "active pharmaceutical ingredient" (API) refers to an agent, active ingredient compound or other substances, or compositions and mixtures thereof that provide some pharmacological, often beneficial, effect. It denotes a single and a mixture of several active ingredients. API can be in the form of a salt, an ester, a hydrate, a solvate, a polymorph, isomers or other pharmaceutically acceptable forms.
The term "immediate release pharmaceutical composition" means that the release is not of the modified type and the major part of the API is released over a relatively short period. The term "immediate release pharmaceutical composition" is well known in the field of Pharmaceutics; cf. for example, Remington; The Science and Practice of Pharmacy, 19th Ed., Mack Publishing Co., Pennsylvania, USA.
The term "dose dumping" is understood as meaning an immediate and unwanted release of the dose after oral ingestion in presence of alcoholic solution.
The term "alcoholic solution" as used herein means aqueous solution of ethanol.
The similarity between two dissolution profiles is evaluated using the similarity factor f2 as defined in the document "Qualite des produits a liberation modifiee" ("Quality of modified-release products") of the European Drug Evaluation Agency, document reference CPMP/QWP/604/96 (Annex 3). An f2 value of between 50 and 100 indicates that the two dissolution profiles are similar.
The present invention relates to prevention of alcohol induced dose dumping in pharmaceutical compositions intended for oral administration. Preferably the invention

relates to the development of MR pharmaceutical compositions which have a resistance to alcohol-induced dose dumping. This advantageous property can be demonstrated in particular under conditions that reproduce the physicochemical characteristics expected in vivo. Binge drinking, a form of alcoholism characterized by bouts of high consumption, typically at the end of the week, alternating with long periods of abstinence or moderation, has become an increasingly widespread social activity in certain spheres, and there has been a parallel increase in the risk represented by an accidental release of the dose of API contained in an MR pharmaceutical composition in a subject who has also ingested a large amount of alcohol, or an accidental increase.
The sensitivity of various MR pharmaceutical compositions in the presence of alcohol has been studied. The approach chosen for measuring the resistance of the MR pharmaceutical compositions to alcohol-induced dose dumping consists of modification of the conventional dissolution tests for MR pharmaceutical compositions by introducing ethanol into the dissolution medium, at a. concentration of 40% (v/v). Alternate approach chosen for measuring the resistance of the MR tablet compositions to afcohof-i'nducecf dose dumping consists of modification of the conventional disintegration test in which MR tablets compositions are tested for two hours by introducing ethanol into the 0.1 N HCI, at a concentration of 40%(v/v).
The invention relates to the development of oral pharmaceutical compositions which have a resistance to alcohol-induced impurities. This advantageous property can be demonstrated in particular under conditions that reproduce the physicochemical characteristics expected in vivo. Binge drinking, a form of alcoholism characterized by bouts of high consumption, typically at the end of the week, alternating with long periods of abstinence or moderation, has become an increasingly widespread social activity in certain spheres, and there has been a parallel increase in the risk represented by an accidental release of the dose of API contained in an MR pharmaceutical composition in a subject who has also ingested a large amount of alcohol.
Alginic acid and its various inorganic salt forms such as sodium, potassium or calcium are derived from brown seaweeds (Phaeophyceae). The monovalent salts, often referred to as alginates, are hydrophilic colloids widely used in the food industry. It is sold in filamentous, granular or powdered forms. Different grades of alginate are available in market by FMC Biopolymer under trade- names such as Protacid®, Protanaj®.

Carrageenan is a naturally occurring family of polysaccharides extracted from certain types of red seaweed belonging to the Rhodophyceae family. It is a high molecular weight polysaccharide made up of repeating galactose and 3, 6 anhydrogalactose units, both sulfated and nonsulfated. The units are joined by alternating α1-3 and β1-4 glycosidic linkages. Carrageenan is basically of three types: Iota, Kappa and Lambda. Preferably, carrageenan as used herein is the lambda grade of carrageenan, such as the grade marketed under trade name such as Viscarin GP®.
The pharmaceutical compositions as described herein may comprise one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, buffering agent, glidant, surfactants, lubricant, plasticizer, opacifying agent, pore forming agent and anti-tacking agent.
Diluent may be selected from a group consisting of powdered cellulose, microcrystalline cellulose, starch, sugars such as lactose, sucrose, dextrose, dextrin, and the like; sugar alcohols such as mannitol, sorbitol or erythritol; calcium phosphate, calcium carbonate, calcium sulphate; and mixtures thereof.
Disintegrant may be selected from a group consisting of carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium alginate; or mixtures thereof.
Buffering agent may be selected from a group consisting of organic acids and its salts, mineral acids, alkali metal phosphates, carbonates, hydroxides, oxides, base and the like; and mixtures thereof. Preferably, buffering agent is selected from benzoic acid, citric acid, tartaric acid, succinic acid, sodium carbonate, sodium citrate, sodium or potassium hydroxide, dibasic sodium phosphate, disodium hydrogen ortho phosphate, and the like; or mixtures thereof. Preferably, the buffering agent is sodium citrate.
Lubricant or glidant may be selected from a group consisting of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl paImitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate; or mixtures thereof.

Surfactant may be selected from a group consisting of polysorbates, pluronics, alkali metal salts of fatty alcohol sulfates, such as sodium lauryl sulfate,, salts of fatty acids such as sodium oleate and triethanolamine oleate, and the like,
Plasticizer may be selected from a group consisting of glycerin and esters thereof, propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate; or mixtures thereof. Plasticizer is generally used in the coating to increase the flexibility and strength of the coat.
Anti-tacking agent may be selected from a group consisting of talc, finely divided silicon dioxide, glyceryl monostearate, and the like. The anti-tacking agent may be used in the coating to aid bulk build-up and form a smooth surface.
Opacifying agent may be selected from a group consisting of titanium dioxide, iron oxides, and the like.
Pore-forming agent is selected from a group consisting of potassium bitartrate, creatine,
aspargine, glutamine, aspartic acid, glutamic acid, leucin, neroleucine, inosine, isoleucine,
magnesium .citrate, magnesium phosphate, magnesium carbonate, magnesium hydroxide,
magnesium oxide, cellulose derivatives such as hydroxypropyl methyl cellulose,
hydroxypropyl cellulose or mixture thereof.
The MR pharmaceutical formulation as described herein may be in the form of a tablet or a
capsule. The compositions may be prepared by techniques such as wet granulation, dry
granulation, drug layering, and the like. For example, an API may be mixed with one or more
pharmaceutically acceptable excipients and the mixture may be granulated either by wet
granulation or by dry granulation techniques. The granules may be coated with one or more
pharmaceutically acceptable excipients. The uncoated or coated granules may be coated
further with sodium alginate and one or more pharmaceutically acceptable excipients or with
carrageenan and one or more pharmaceutically acceptable excipients to prevent dose
dumping in the alcoholic solution. The coated granules may be filled in a capsule.
Alternatively, the coated or uncoated granules, as obtained above may be compressed into
tablets. The tablets may be coated with one or more pharmaceutically acceptable excipients.
The uncoated or coated tablets may be coated further with sodium alginate and one or more
pharmaceutically acceptable excipients or with carrageenan and one or more
pharmaceutically acceptable excipients to prevent dose dumping in the alcoholic solution.

The coating of the tablet and/or granules with a solution and/or dispersion comprising sodium alginate or carrageenan is such that the weight of the tablet/granule increases by an amount of 1 to 10 percent compared to that of the uncoated or coated tablet.
The present inventior also provides a useful property of prevention of alcohol induced degradation of oral pharmaceutical composition in GIT by coating the said pharmaceutical composition with alginate or carrageenan. Preferably the prevention of alcohol induced degradation in GIT may be achieved in MR pharmaceutical compositions coated with alginate or carrageenan.
Example 1 and 2 show quetiapine SR tablets coated with a dispersion comprising carrageenan and quetiapine SR tablets coated with a dispersion comprising sodium alginate, respectively. The dissolution profiles of the tablets as prepared in the examples 1 and 2 are shown in Table 1. It clearly shows that the tablets are having matching dissolution profiles in 0.1 N HCI and 0.1 N MCl containing 40 % alcohol. This result confirms that dose dumping in presence of alcohol can be prevented by a 3 - 5 % coating of either sodium alginate and other pharmaceutically acceptable excipients or carrageenan and other pharmaceutically acceptable excipients. Table 2 shows the dissolution data of uncoated and coated tablets of quetiapine prepared as per example 2, This clearly demonstrates the fact that the dissolution profile of the uncoated tablets matches with that of the coated tablets. Hence it can be concluded that the coating of the present invention only prevents alcohol induced dose dumping, but it does not affect the dissolution profile of quetiapine SR tablets.
Example 3 and 4 show paliperidone ER tablets without and with a 3 % coating comprising sodium alginate, respectively. The dissolution profiles of these tablets were studied in USP II dissolution apparatus at 100 rpm and 37.0 ± 0.5 °C in 0.1 N HCI containing 40 % ethanol. The results are illustrated in table 3. It shows that the tablets with coating comprising sodium alginate show substantially retarded release profile than the tablets without coating. This proves that coating comprising sodium alginate is effective against dose dumping.
Example 5 and 6 show levetiracetam ER tablets and example 7 and 8 shows pregablin SR tablets, without and with a 3 % coating comprising sodium alginate, respectively. The disintegration of these tablets was studied in disintegration apparatus USP by raising and lowering the basket in the immersion fluid at a constant frequency rate between 29 and 32 cycles per minute through a distance of not less than 5.3 cm and not more than 5.7 cm and immersion media containing 0.1 N HCI and 40 % ethanol having a temperature 37.0 ± 2 °C.

The results illustrated in table 4 indicate that integrity of coat was not compromised. This proves that coating comprising sodium alginate is effective against dose dumping.
Example 9 shows Duloxetine DR Capsules - Cymbalta. Cymbalta trade/brand name of Duloxetine DR capsules. The dissolution profiles of these capsules were studied in USP I dissolution apparatus at 100 rpm and 37.0 ± 0.5 °C in 0.1 N HCI containing 40 % ethanol. The results are illustrated in table 5. It shows that the capsule with coated beads/ pellets and which does not comprising sodium alginate or carrageenan show substantially increase in impurities. This suggests that coating comprising sodium alginate or carrageen may also be effective against drugs which produce impurities in presence of alcohol.
The API according to the invention is advantageously selected from at least one of the following families of active substances: agents for treating alcohol abuse, agents for treating Alzheimer's disease, anesthetics, agents for treating acromegaly, analgesics, antiasthmatics, agents for treating allergies, anticancer agents, muscarinic receptor inhibitors, anti-inflammatories, anticoagulants and antithrombotics, anticonvulsants, antiepileptics, antidiabetics, antiemetics, antiglaucoma agents, antihistamines, anti-infectives, antiparkinsonians, anti-cholinergics, antitussives, carbonic anhydrase inhibitors, cardiovascular agents: hypolipemics, antiardythmics, vasodilators, antianginals, antihypertensives, vasoprotectors and cholinesterase inhibitors, agents for treating central nervous system disorders, central nervous system stimulants, contraceptives, fertility promoters, labor inducers and inhibitors, agents for treating cystic fibrosis, dopamine receptor agonists, agents for treating endometriosis, agents for treating erectile dysfunctions, agents for treating fertility, agents for treating gastrointestinal disorders, immuno-modulators and immunosuppressants, agents for treating memory disorders, anti-migraines, muscle relaxants, nucleoside analogs, agents for treating osteoporosis, parasympathomimetics, prostaglandins, psychotherapeutic agents: sedatives, hypnotics, tranquilizers, neuroleptics, anxiolytics, psychostimulants and anti-depressants, agents for dermatological treatments, steroids and hormones, amphetamines, anorexigenics, non-analgesic painkillers, antiepilepties, barbiturates, benzodiazepines, hypnotics, laxatives and psychotropics.
Examples of agents for- treating alcohol abuse are chlorazepate, chlordiazepoxide, diazepam, disulfiram, hydroxyzine, naltrexone and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of anesthetics are lidocaine, midazolam and salts, esters, hydrates, polymorphs and isomers thereof.

Examples of analgesics and/or anti-inflammatories are paracetamol, aspirin, buprenorphine, butorphanol, celecoxib, clofenadol, choline, clonidine, codeine, diclofenac, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, ethylmorphine, etodolac, eletriptan, eptazocine, ergotamine, fentanyl, fenoprofen, hyaluronic acid, hydrocodone, hydromorphone, hylan, ibuprofen, indomethacin, ketorolac, ketotifen, levomethadone, levallorphan, levorphanol, lidocaine, mefenamic acid, meloxicam, meperidine, methadone, morphine, nabumetone, nefopam, naloxone, naltrexone, naproxen, naratriptan, nefazodone, normethadone, oxaprozin, oxycodone, oxymorphone, pentazocin, pethidine, phenpyramide, piritramide, piroxicam, propoxyphen, rizatriptan, ketoprofen, sulindac, sumatriptan, tebacone, tilidine, tolmetine, tramadol, zolmitriptan and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of antiasthmatics are ablukast, azelastine, bunaprolast, cinalukast, cromitrile, cromolyn, enofelast, isambxole, ketotifen, levcromakalim, lodoxamide, montelukast, ontazolast, oxarbazoie, oxatomide, piriprost potassium, pirolate, pobilukast, edamine, pranlukast, quazolast, repirinast, ritolukast, sulukast, tetrazolast meglumine, tiaramide, tibenelast, tomelukast, tranilast, verlukast, verofylline, zarirlukast and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of anticancer agents are adriamycin, aldesleukin, allopurinol, altretamine, amifostine, anastrozole, asparaginase, betamethasone, bexaroten, bicalutamide, bleomycin, busulfan, capecitabin, carboplatin, cannustine, chlorambucil, cisptatin, cladribine, conjugated estrogen, cortisone, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, dactinomycin, denil^ukin, dexamethasone, discodermolide, docetaxel, doxorubicin, eloposidem, epirubicin, epoetin, epothilones, estramustine, esterified estrogen, ethynylestradiol, etoposide, exemestane, flavopirdol, fluconazole, fludarabine, fluorouracil, flutamide, floxuridine, gemcitabine, hexamethylmelamine, hydrocortisone, hydroxyurea, ifosfamide, lemiposide, letrozole, leuprolide, levamisole, levothyroxin, lomustine, mechlorethmine, melphalan, mercaptopurine, megestrol, methotrexate, methylprednisolone, methyltestosterone, mithramycin, mitomycin, mitotane, mitoxantrone, mitozolomide, mutamycin, nilutamige, pamidronate, pentostatin, plicamycin, porfimer, prednisolone, procarbazine, semustjne, streptozocin, tamoxifen, temozolamide, teniposide, testolactone, thioguanie, tomudex, toireifen, tretinoin, semustine, streptozolocin, verteprofin, vinblastine, . vincristine, vindesine, vinorelbine and salts, esters, hydrates, polymorphs and isomers thereof.

Examples of anticoagulants and antithrombotics are warfarin, danaparoid, alprostadil, anagrelide, araob, ataprost, betaprost, camonagrel, cilostazol, clinprost, clopidogrei, prasugrel, cloricromen, dermatan, desirudine, domitroban, drotaverine, epoprostenol, fradafiban, Gabe ate, iloprost, isbogrel, lamifiban, lefradafiban, lepirudin, levosimendan, lexipafant, melagatran, nafagrel, nafamostat, nizofenone, orbifiban, ozagrel, pamicogrel, quinobendan, sarpognilate, satigrel, simendan, ticlopidine, vapiprost, tirofiban, xemilofiban, and salts, esters, hydrates, polymorphs and isomers thereof.
Example of antidepressants are Agomelatine, Amitriptyline, Amoxapine, Atomoxetine, Bupropion, Buspirone, Butriptyline, Citalopram, Clomipramine, Desipramine, Dosulepin, Doxepin, Duloxetine, Etoperidone, Femoxetine, Fluoxetine, Fluvoxamine, Imipramine, Lofepramine, Maprotiline, Mazindol, Mianserin, Milnacipran, Mirtazapine, Nefazodone, Nisoxetine, Nomifensine, Nortriptyline, Oxaprotiline, Paroxetine, Protriptyline, Reboxetine, Sertraline, Trazodone, Trimipramine, Venlafaxine, Viloxazine, Zimelidine, and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of muscarinic receptor inhibitors are darifenacin, solifenacin, tolterodine and salts, ester, hydrates, polymorphs and isomers thereof.
Examples of anticonvulsants are carbamazepine, clonazepam, clorazepine, diazepam, divalproex, ethosuximide, ethotion, felbamate, fosphenytoin, gabapentine, lamotrigine, levetiracetam, lorazepam, mephenytoin, mephobarbital, metharbital, methsuximtde, oxcarbazepine, phenobarbital, phenytoin, pregabaline, primidone, tiagabine, topiramate, valproic acid, vigabatrine, zonisamide and salts, ester, hydrates, polymorphs and isomers thereof.
Examples of antidiabetics are acarbose, acetohexamide, carbutamide, chlorpropamide, epaloretat, glibonuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, glyburide, glyhexamide, metformin, miglitol, nateglinide, orlistat, phenbutamide, pioglitazone, repaglinide, rosiglitazone, tolazainde, tolbutsmide, tolcyclamide, tolrestat, troglitazone, voglibose and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of antimetics are alprazolam, benquimamide, benztropine, betahistine, chlorpromazine, dexamethasone, difenidol, dimenhydrinate, diphenhydramine, dolasetron, domperidone, dronabinol, droperidol, gransetron, haloperidol, lorazepam, meclizine, methylprednisolone, metoclopramide, ondansetron, perphenazine, prochlorperazine, promethazine, scopolamine, tributine, triethylperazine, trifluptomazine, trimethobenamide,

tropisetron and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of antiglaucoma agents are alprenoxime, dapiprazole, dipivefrine, latanoprost, naboctate, pimabine and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of antihistamines or beta-agonists are acepromazine, acrivastine, activastine, albuterol, alimemazine, antazoline, azelastin, bitolterol, amlexanox, benzydamine, bromphenirime, cetirizine, chlorpheniramine, cimetidine, cinnarizine, clemastine, clofedanol, cycloheptazine, cyprheptadine, difencloxazine, diphenhydramine, dotarizine, ephedrine, epinastine, epinephrine, ethylnorepinephhne, fenpentadiol, fenpoterol, fexofenadine, flurbiprofen, hydroxyzine, isoetherine, isoproterenol, ketorolac, levocetirizine, levomepromazine, loratidine, mequitazine, metaproterenol niaprazine, oxatomide, oxomemazine, phenylephrine, phenylpropanolamine, pirbuterol, promethazine, pseudoephedrine, pyhlamine, ranitidine, salmeterot, terbutaline, terfenadine, tranilast, xanthine derivatives and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of anti-infectives, especially antibiotics, antifungals and antivirals, are abacavir, acyclovir, albendazole, amantadine, amphotericin, amikacin, amiosalicylic acid, amoxicillin, ampicillin, amprenavir, atovaquine, azithiomycin, aztreonam, cefaclor, cefadroxil, cefazolin, cefdinir, cefexime, cefpodoxime proxetil, cefprozil, ceftibuten, cephalexine, chloroquine, cidofovir, cilastatin, ciprofloxacin, claithromycin, clavulanic acid, clindamycin, dalfopristine, dapsone, delavirdine, demeclocycline, didanosine, doxycycline, efavirenz, enoxacin, erythromycin, ethambutol, ethionamide, famcyclovir, fluconazole, fluctosine, foscamet, ganciclovir, gatifloxacin, griseofulvin, hydroxychloroquine, indinavir, isoniazide, itraconazole, ivermectil, ketoconazole, lamivudine, levofloxacin, linizolide, lomefloxacin, loracarbef, mebendazole, mefloquine, methanamine, metronidazole, minocycline, moxefloxacin, nalidixic acid, nelfinavir, neomycin, nevirapine, nitrofurantoin, norfloxacin, ofloxacin, oseltarrwir, oxytetracyclihe, penicillin V, perfloxacin, praziquantel, pyrznamide, pyrimediamine, quinidine, quinupristine, retonavir, ribavirin, rifabutin, rifampicin, rimantadine, saquinavir, sparfloxacin, stavudine, streptomycin, sulfamethoxazole, tetramycin, terbinafine, tetracycline, thiabendazole, tobramycin, trinmethoprinm, troleandomycin, trovafloxacin, valacyclovir, vancomycin, zalcitabine, zanamivir, zidovudine and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of antiparkinsonians are amantadine, adrogolide, altinicline, benzatropine, biperiden, brasofensine, bromocriptine, budipine, cabergoline, CHF-1301, dihydrexidine, entacapone, etilevodopa, idazoxane, iometopane, lazabemide, melevodopa, carbidopa,

levodopa, mofegiline, moxiraprine, pergolide, pramipexole, quinelorane, rasagiline, ropinirole, seligiline, talipexole, tolcapone, trihexyphenidyl and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of antirheumatics are azathioprine, betamethasone, celecoxib, cyclosporin, diclofenac, hydroxychmoroquine, indomethacin, mercaptobutanedioic acid, methylprednisolone, naproxen, penicillamine, piroxicam, prednisolone, sulfasalazine and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of platelet aggregation inhibitors are anagrelide, aspirin, cilostazol, clopidogrel, dipyridamole, epoprostenol, eptifibatide, ticlopidine, tinofiban and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of antispasmodics and anticholinergics are aspirin, atropine, diclofenac, hyoscyamine, mesoprostol, methocaramol phenobarbital, scopolamine and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of antitussives are parazetamol, acnivastine, benzonatate, beractant, brompheniramine, caffeine, calfactant, carbetapetane, chlorpheniramine, codeine, colfuscerine, dextromethorphan, doxylamine, fexofenadine, guaphenesine, metaproterenol, montelukast pentoxiphylline, phenylephrine, phenylproparolamine, pirbuterol, pseudoephedrine, pyrilamine, terbutaline, theophylline, zafirlukast, zileuton and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of carbonic anhydrase inhibitors are acetazolamide, dichlorphenamide, dorzolamide, methazolamide, sezolamide and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of cardiovascular agents, especially hypolipemics, antiarrythmics, vasodilators, antianginals, antihypertensives and vasoprotectors, are acebutolol, adenosine, amidarone, amiloride, amlodipine, amyl nitrate, atenolol, atorvastatin, benzepril, bepiridil, betaxalol, bisoprolol, candesartan, captopril, cartenolol, carvedilol, cerivastatin, chorthalidone, chlorthmiazole, clofibrate, clonidine, colestipol, colosevelam, digoxin, diltiazem, disopyramide, dobutamine, dofetilide, doxazosin, enalapiril, epoprostenol, eprosartan, esmolol, ethacirynate, erythrityl, felodipine, fenoidapam, fosinopril, flecainide, furosemide, fluvastatin, gemfibrozil, hydrochlorthiazide, hydroflumethiazine, ibutilide, indapamide, isosorbide, irbesartan, labetolol, lacidipine, lisinopril, losartan, lovastatin, mecamyiamine,

metoprolol, metaminol, metazolone, methylchlothiazide, methyldopa, metyrosine, mexiletine, midrodine, milrinone, moexipril, nadolol, niacin, nicardipine, nicorandil, nifedipine, nimodipine, nisoldipine, nitroglycerin, phenoxybenzamin perindopril, polythiazide, pravastatin, prazosin, procainamide, propafenone, propranolol, quanfacin, quinapril, quinidine, raniprfl, simvastatin, sotalol, spironolactone, telmisartan, terazosin, timolol, tocainamide, torsemide, trandolapril, triamterene, trapidil, valsartan and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of vasodilators are adenosine, alverine, caffeine, dihydroergocomine, enalapril, enoximone, iloprost, kalleone, lidoflazine, nicardipine, nimodipine, nicotinic acid, papaverine, pilocarpine, salbutamol, theophytline, trandolapril, uradipil, vincamine and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of cholinesterase inhibitors are donepezil, neostigmine, pyridostigmine, rivastigmine, tacrine and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of central nervous system stimulants arc caffeine, doxapram, dexoamphetamine, donepezil, methamphetamine, methylphenidate, modafinil, neostigmine, pemoline, phentermine, pyndostigmine, rivastigmine, tacrine and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of contraceptives are desogestral, ethynylestradiol, ethynodiol, levonorgestrel, medroxyprogesterone, mestranol, norgestimate, norethindrone, norgestrel and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of agents for treating cystic fibrosis are pancrelipase, tobramycin and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of dopamine receptor agonists are amantadine, cabergoline, fenoldopam,
pergolide, pramipezal, ropinirole and salts, esters, hydrates, polymorphs and isomers
thereof.
Examples of agents for treating endometriosis are danazol norethindrone and salts, esters,
hydrates, polymorphs and isomers thereof.
Examples of agents for treating erectile dysfunctions are sildenafil, tadalafil vardenafil, yohimbine and salts, esters, hydrates, polymorphs and isomers thereof.

Examples of agents for treating fertility are clomiphene, progesterone and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of agents for treating gastrointestinal disorders are alosetron, bisacodyl, bismuth subsalicylate, celecoxib, cimetidine, difoxine, diphenoxylate, docusate, esomeprazole, famotidine, glycopyrrolate, lansoprazole, loperamide, metoclopramide, nizatidine, omeprazole, pantoprazole, rabeprazole, ranitidine, simethicone, sucralfate and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of immunomodulators and immunosuppressants are azathioprine, ceftizoxime, cyclosporin, leflunomide, levamisol, mycophenolate, phthalidomide, ribavirin, sirolimus, tacrolimus and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of agents for treating Alzheimer's disease are donepezil, galanthamine, metrifonate, revastigmine, tacrine, and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of antimigraines are paracetamol, dihydroergotamine, divalproex, ergotamine, propranolol, risatriptan, sumatriptan, trimetrexate and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of muscle relaxants are azapropazone, baclofen, carisoprodol, quinine derivatives, chloromezanone, chlorphenesin carbamate, chlorozoxazone, cyclobenzaprin, dantrolene, dimethyltabocurarinium chloride, fenyramidol, guaiphenesin, memantin, mephenesin, meprobamate, metamisol, metaxalone, methocarbamol, orphenadrine, phenazone, phenprobamate, tetrazepam, tizanidine, tybamate and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of nucleoside analogs are abacavir, acyclovir, didanosine, gamciclovir, gemcitabine, lamivudine, ribavirin, stavudine, zalcitabine and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of agents for treating osteoporosis are alendronate, calcitonin, estradiol, estropipate, medroxyprogesterone, norethindrone, norgestimate, pamidronate, raloxifen, risdronate, zoledronate and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of parasympathomimetics are bethanechol, biperidine, edrophonium,

glycopyrrolate, hyosycyamine, pilocarpine, tacrine, yohimbine and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of prostaglandins are alprostadil, epoprostenol, misoprostol and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of psychotherapeutic agents are acetophenazine, alentemol, alpertine, alprazolam, amitriptyline, apripmazole, azaperone, batelapine, befipiride, benperidol, benzindopyrine, bimithil, biriperone, brofoxine, bromperidol, broniperidol, bupropione, buspirone, butaclamol, butaperzine, carphenazine, carvotroline, chlorazepine, chlordiazepoxide, chlorpromazine, chlorprothixen, cinperene, cintriamide, citalopram, clomacran, clonazepam, clopenthixol, clopimozide, clopipazan, cloroperonec clothespins, clothixamide, clozapine, cyclophenazine, dapiprazole, dapoxetine, desipramine, divalproex, dipyridamole, doxepine, droperidol, duloxetine, eltoprazine, eptipirone, etazolate, fenimide, flibanserine, flucindole, fiumezapine, fluoxetine, fluphenazine, fluspiperone, fluspirilene, flutro/ine, fluvoxamine, gepirone, gevotroline, halopemide, haloperido/, hydroxyzine, hydroxynortriptyline, iloperidone, imidoline, lamotrigine, loxapine, enperone, mazapine, mephobarbital, meprobamate, mesoridazine, mesoridazine, milnacipran, mirtazepine, metiapine, milenperone, milipertine, molindone, nafadotride, naranol, nefazodone, neflumozide, ocaperidone, odapipatn, olanzapine, oxethiazine, oxiperomide, pagoclone, paliperidone, paroxitene, penfluridol, pentiapine, peiphenazine, phenelzine, pimozide, pinoxepine, pipamperone, piperacetazine, pipotiazine, piquindone, piracetm, pirlindole, pivagabine, pramipexole, prochlorperazine, promazine, quetiapine, reboxetine, remoxipride, risperidone, rimcazole, robolzotan, selegiline, seperidol, sertraline, sertindole, seteptiline, setoperone, spiperone, sunipitrone, tepirindole, thiordazine, thiothixen, tiapride, tioperidone, tiospirone, topiramate, tranycypromine, trifluoperazine, trflperidol, triflupromauzine, trimipramine, venlafaxine, ziprasidone and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of sedatives, hypnotics and tranquilizers are bromazepam, buspirone, clazolam, clobazam, chlorazepate, diazepam, demoxepam, dexmedetomidine, diphenyhydtenine, doxylamine, enciprazine, estrazolam, hydroxyzine, ketazoiam, lorazatone, larazepam, loxapine, medazepam, meperidine, methobarbital, midazolam, nabilone, nisobamate, oxazepam, pentobarbital, promethazine, propofol, triazolam, zaleplon, Zolpidem and salts, esters, hydrates, polymers and isomers thereof.

Examples of agents for dermatological treatments are acitretin, alclometasone, alitretinoin, betamethasone, calcipotriene, clobetasol, clocortolone, ctotrimazole, cyclosporin, desonide, difluorosone, doxepine, eflomithine, finasteride, flurandrenolide, hydrochloroquine, hydroquinone, hydroxyzine, ketoconazole, mafenide, malathion, menobenzone, neostigmine, nystatin, podophyllotoxin, povidone, tazarotene, tretinoin and salts, esters, hydrates, polymorphs and isomers thereof.
Examples of steroids and hormones are alclometasone, betamethasone, citrorelix, clobetasol, clocortolone, cortisones, danazol, desonide, desogestrel, desoximetasone, dexamethasone, diflorasone, estradiol, estrogens, estropipate, ethynylestradiol, fluocinolone, flurandrenolide, fluticasone, halobetasol, hydrocortisone, leuprolide, levonorgestrel, levothyroxin, medroxyprogesterone, methylprednisolone, methyltestosterone, mometasone, norethrndrone, norgestrel, oxandrolone, oxymetholone, prednisolone, progesterone, stanozolol, testosterone and salts, esters, hydrates, polymorphs and isomers thereof.
The modified release pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
EXAMPLE 1

SrNo. Composition mg/tab % w/w
Core
1 Quetiapine Fumarate 230.26 36.55
2 Lactose Monohydrate 29.87 4.74
3 Microcrystalline Cellulose (AvicelPH 101) 29.87 4.74
4 Magnesium oxide (Light) 90.00 14.29
5 PVP K 30 20.00 3.17
6 Carrageenan (Viscarin GP 209) 150.00 23.81
7 Methylene Dichloride — —
8 PVP K 30 40.00 6.35
9 Magnesium stearate 10.00 1.59
600.00 95.24
Coatin(
10 Carrageenan (Viscarin GP 209) 16.17 2.57
11 PEG 400 5.38 0.85
12 Titanium dioxide 7.70 1.22
13 Iron oxide Yellow 0.75 0.12
14 P. Water — —
15 Isopropyl alcohol — ~
Coated tablet weight 630.00 100.00

PROCEDURE:
Quetiapine fumarate, Lactose, Microcrystalline cellulose, Carrageenan and magnesium oxide were mixed and sieved through suitable sieve. Granulation was carried out using PVP K 30 (of binder addition step) in Methylene chloride and the granules obtained were dried. Quantity of PVP K 30 and magnesium stearate was calculated according to yield, dispensed, sifted through suitable sieve and mixed with granules of above step. The lubricated was compressed into tablets using suitable punches.
Carrageenan (Viscarin GP 209) was slowly added in isopropyl alcohol in beaker with stirring with stirrer. Polyethylene Glycol 400 was added to the above dispersion and stirred continuously. Titanium dioxide and Ferric oxide yellow was dispersed separately in water and passed through colloid mill for sufficient time with recirculation. Both the dispersion were mixed together to form the coating dispersion. The tablets were coated using the coating dispersion until the tablets gained 5 % by weight.
EXAMPLE 2

Sr No. Composition mg/tab %w/w
Core
1 Quetiapine Fumarate 230.26 37.28
2 Lactose Monohydrate 29.87 4.83
3 Microcrystalline Cellulose (AvicelPH 101) 29.87 4.83
4 Magnesium oxide (Light) 90.00 14.57
5 PVP K 30 20.00 3.23
6 Carrageenan (Viscarin GP 209) 150.00 24.29
7 Methylene Dichioride — —
8 PVP K 30 40.00 6.48
9 Magnesium stearate 10,00 1.62
600,00 95.24
Coating
10 Sodium alginate 4.95 0.80
11 HPMC 4.95 0.80
12 Glycerin 2.97 0.48
13 Titanium dioxide 4.62 0.75
14 P. Water — —
Coated tablet weight 617.5 100.00

PROCEDURE:
Quetiapine fumarate, Lactose, Microcrystalline cellulose, Carrageenan and magnesium oxide were mixed and sieved through suitable sieve. Granulation was carried out using PVP K 30 (of binder addition step) in Methylene chloride and the granules obtained were dried. Quantity of PVP K 30 and magnesium stearate was calculated according to yield, dispensed, sifted through suitable sieve and mixed with granules of above step. The lubricated was compressed into tablets using suitable punches.
Sodium alginate and HMPC was dissolved in water and glycerin was added to the solution under stirring. Titanium dioxide was dispersed separately in water and passed through colloid mill for sufficient time with recirculation. The solution of sodium alginate and HPMC was added to the dispersion of titanium dioxide and stirred. The tablets were coated using the coating dispersion until the tablets gained 3 % by weight.
The dissolution profiles of the tablets of Example 1 and 2 are shown in table 1.
Table 1

% Drug dissolved (Example 1) % Drug dissolved (Example 2)
Time (Min.) Media Media

0.1 N HCI 0.1 N HCLEthanol (60:40) 0.1 N HCI 0.1 N HCkEthanol (60:40)
30 2.5 2.3 7.4 4.3
60 26.8 5.6 13.8 8.0
90 10.9 8.5 19.3 11.6
120 14.4 11 24 14.8
(Dissolution Apparatus: USP I; Volume: 900 ml; Rotation: 200 rpm; Temperature: 37±0.5 °C)
Dissolution profiles of the uncoated and coated tablets of Example 2 are shown in table 2.
Table 2

Tablet Time Points (hrs)

1 2 4 6 8 10 12 16 20
Uncoated 5.9 16.4 34.6 48.7 63.3 77.2 83.7 92.8 94.5
Coated 2.9 11.9 29.8 43.7 56,7 69.8 79.1 90.1 92.9
(Media: pH 6.5 Citro Phosphate buffer, Dissolution Apparatus: USP II; Volume; 1000 mL; Rotation: 100 rpm; Temperature: 37.0 ±0.5 °C)

EXAMPLE 3

Sr. No. Ingredients Qty/Mg
1 Paliperidone 6.00
2 Lactose Anhydrous (DCL-21) 25.00
3 MCCPH102 65.54
4 BHT 0.40
5 PVP K 30 5.00
6 Sodium hydroxide 0.06
7 Water q.s.
8 Polyox WSR 303 35.00
9 EudragitL100 55 20.00
10 HPMC K 4 M 75.00
11 Carrageenan 15.00
12 Magnesim Stearate 3.00
13 Eudragit RLPO 15.16
14 PEG 400 2.27
15 Talc 7.57
16 Acetone 166.00
17 Isopropyl alcohol 166.00
Net weight 275.00
PROCEDURE:
Paliperidone, lactose, microcrystalline cellulose, and BHT were sieved through 30# sieve, mix in RMG and granulate with PVP solution in water. Add 0.1N Sodium hydroxide to this wet mass. The granules were dried. Polyox, Eudgragit L 100 55, carrageenan and HPMC were sieved through 30# sieve and mix with the dried granules. Magnesium stearate was mixed with the blend and the lubricated granules were compressed into tablets.
Eudragit RLPO and PEG 400 were dissolved into IPA-acetone mixture talc was added into this solution. This solution was sprayed over the core tablet to get the desired weight gain.

EXAMPLE 4

Sr. No. Ingredients Qty/Mg
1 Paliperidone 6.00
2 Lactose Anhydrous (DCL-21) 25.00
3 MCCPH 102 65.54
4 BHT 0.40
5 PVP K 30 5.00
6 Sodium hydroxide 0.06
7 Water q-s.
8 Polyox WSR 303 35.00
9 Eudraqit L100 55 20.00
10 HPMCK4M 75.00
11 Carrageenan 15.00
12 Magnesim Stearate 3.00
13 Eudragjt RLPO 15.16
14 PEG 400 2.27
15 Talc 7.57
16 Acetone 166.00
17 Isopropyl alcohol 166.00
18 Sodium Alginate 2.33
19 Hypromellose 2910 (6cps) 2.33
20 Glycerin 1.40
21 Titanium dioxide 2.18
22 Water q-s.
Net weight 283.24
PROCEDURE:
Paliperidone, lactose, microcrystalline cellulose, and BHT were sieved through 30#
sieve, mix in RMG and granulate with PVP solution in water. Add 0.1N Sodium hydroxide
to this wet mass. The granules were dried. Polyox, Eudgragit L 100 55, carrageenan and
HPMC were sieved through 30# sieve and mix with the dried granules. Magnesium
stearate was mixed with the blend and the lubricated granules were compressed into
tablets.
Eudragit RLPO and PEG 400 were dissolved into IPA-acetone mixture talc was added
into this solution. This solution was sprayed over the core tablet to get the desired weight
gain.
Sodium alginate, HPMC, glycerin was dissolved in water and titanium dioxide was added
to this solution. This suspension was sprayed onto the coated tablets until the tablets
gained 3 % weight.
The dissolution profiles of the tablets of Example 3 and 4 are shown in table 3.

Table 3

Time (Min) % of drug dissolved (Example 3) % of drug dissolved (Example 4)
30 7.4 2.6
60 18.8 9.1
90 27.9 15.9
120 35.7 22.2
(Media: 40 % Alcohol in 0.1 N HCI; Dissolution Apparatus: USP II; Volume: 1000 mL; Rotation: 100 rpm; Temperature: 37.0 ± 0.5 °C)
EXAMPLE 5

Sr. No. Ingredients Qty/Mg
1 Levetiracetam 750.00
2 Microcrystalline Cellulose 41.54
3 Acetone q.s.
4 Ammonio Methacrylate copolymer 71.77
5 Colloidal Silicon Dioxide 9.33
6 Glyceryl Behanate 18.36
7 Ammonio Methacrylate Copolymer Type A 9.56
8 Ammonio Methacrylate Copolymer Type B 12.18
9 Talc 10.95
10 Titanium Dioxide 2.98
11 Triethyl Citrate 4.33
12 Water q.s.
13 Hydroxy Propyl Methyl Cellulose 12.45
14 PEG-6000 1.55
15 Water q.s.
Net weight 945.00
PROCEDURE:
Levetiracetam and microcrystalline cellulose were sieved through 30# sieve, mix in RMG
and granulate with amino methycrylate co-polymer type B solution in acetone. Add The
granules were dried. Colloidal silicon dioxide and Glyceryl behanate were mixed with the
blend and the lubricated granules were compressed into tablets.
Ammonio methycrylate co-polymer type B, Ammino methycrylate co-polymer type A, talc,
titanium dioxide, triethyl citrate were dissolved into water. This solution was sprayed over
the core tablet to get the desired weight gain.
Hydroxy propyl methyl cellulose and polyethylene glycol were dissolved into water, This
solution was sprayed over the core tablet to get the desired weight gain.

EXAMPLE 6

Sr. No. Ingredients Qty/Mg
1 Levetiracetam 750.00
2 Microcrystafline Cellulose 41.54
3 Acetone q.s.
4 Ammonio Methacrylate copolymer 71.77
5 Colloidal Silicon Dioxide 9.33
6 Glyceryl Behanate 18.36
7 Ammonio Methacrylate Copolymer Type A 9.56
8 Ammonio Methacrylate Copolymer Type B 12.18
9 Talc 10.95
10 Titanium Dioxide 2.98
11 Triethyl Citrate 4.33
12 Water q.s.
13 Hydroxy Propyl Methyl Cellulose 12.45
14 PEG-6000 1.55
15 Water q.s.
16 Hydroxypropylmethyl cellulose 8.02
17 Sodium alginate 8.02
18 ■ Glycerine 4.82
19 Titanium dioxide 7.49
20 Water q.s.
Net weight 973.35
PROCEDURE:
Levetiracetam and microcrystalline cellulose were sieved through 30# sieve, mix in RMG
and granulate with amino methycrylate co-polymer type B solution in acetone. Add The
granules were dried. Colloidal silicon dioxide and Glyceryl behanate were mixed with the
blend and the lubricated granules were compressed into tablets.
Ammonio methycrylate co-polymer type B, Ammino methycrylate co-polymer type A, talc,
titanium dioxide, triethyl citrate were dissolved into water. This solution was sprayed over
the core tablet to get the desired weight gain.
Hydroxy propyl methyl cellulose and polyethylene glycol were dissolved into water. This
solution was sprayed over the core tablet to get the desired weight gain.
Sodium alginate, HPMC, glycerin was dissolved in water and titanium dioxide was added
to this solution. This suspension was sprayed onto the coated tablets until the tablets
gained 3 % weight.

EXAMPLE 7

Sr. No. Ingredients Qty/Mg
1 Pregablin 300.00
2 Microcrystalline Cellulose 116.00
3 Mannitol 88.00
4 Ammonio methycrylate copolymer B 12.00
5 Ethylcellulose 20 cps 16.00
6 Methyl chloride q.s.
7 Acetone q.s.
8 Talc 16.00
9 Magnesium stearate 12.00
Net weight 560.00
PROCEDURE:
Pregablin, Microcrystalline cellulose, Mannitol and Ammonio methycrylate copolymer B were sieved through 30# sieve, mix in RMG and granulate with ethylcellulose solution in methylene chloride:Acetone (1:1). The granules were dried. Talc and Magnesium stearate were mixed with the blend and the lubricated granules were compressed into tablets.
EXAMPLE 8

Sr. No. Ingredients Qty/Mg
1 Pregablin 300.00
2 Microcrystalline Cellulose 116.00
3 Mannitol 88.00
4 Ammonio methycrylate copolymer B 12.00
5 Ethylcellulose 20 cps 16.00
6 Methyl chloride q.s.
7 Acetone q.s.
8 Talc 16.00
9 Magnesium stearate 12.00
10 Hydroxypropylmethyl cellulose 4.75
11 Sodium alginate 4.75
12 Glycerine 2.86
13 Titanium dioxide 4.44
14 Water q.s.
Net weight 577.00
PROCEDURE:

Pregablin, Microcrystalline cellulose, Mannitol and Ammonio methycrylate copolymer B were sieved through'30# sieve, mix in RMG and granulate with ethylcellulose solution in methylene chloride:Acetone (1:1). The granules were dried. Talc and Magnesium stearate were mixed with the blend and the lubricated granules were compressed into tablets.
Sodium alginate, HPMG, glycerin was dissolved in water and titanium dioxide was added to this solution. This suspension was sprayed onto the coated tablets until the tablets gained 3 % weight.
The disintegration test result of the tablets of Example 3, 4, 5, 6, 7 and 8 are shown in table 4.
Table 4

Time (Min) Physical
observati
on of
tablet
(Example
3) Physical
observatio
n oftabfet
(Example
4) Physical
observatio
n of tablet
(Example
S) Physical
observatio
n of tablet
(Example
6) Physical observation
of tablet (Example 7) Physical
observatio
n of tablet
(Example
8)
05 Tablets
break into
3 to 4
parts Film coating was intact Slight pore formation Film coating was intact Surface erosion observed Film coating was intact
10 Almost all tablet disintegrat ed Film coating was intact Reduction in tablet size due to
erosion Film coating was intact More
erosion Film coating was intact
15 Tablet disintegrat
ed Film coating was intact Reduction in tablet size due to erosion Film coating was intact Further disinteg ratio n by erosion Film coating was intact
20 Tablet
disintegrat
ed Film coating was intact Tablet
disintegrate
d Film coating was intact Reduction in tablet size due to erosion Film coating was intact
120 Tablet
disintegrat
ed Film coating was intact Tablet
disintegrate
d Film coating was intact Reduction in tablet size due to erosion Film coating was intact
(Media: 40 % Alcohol in 0.1 N HCI; Disintegration Apparatus: USP; Volume: 700 ml_; temperature: 37.0 ± 2 °C, basket cycle strokes 30 ± 2)

EXAMPLE 9
The impurity profiles of the duloxetine DR capsules- Cymbalta. Cymbalta is trade name of duloxetine DR capsules. The impurity profile of Cymbalta is studied with the help dissolution apparatus USP type I. The impurity profiles of Cymbalta with and without alcohol are shown in table 5.
Table 5

Time (Minutes) Impurity E profile {4-[3-(methylamino)-1 -(2-thienyi)propyl]-1 -napthol} Impurity D profile (1-Napthol)

Media: 0.1 N HCI Media: 40 % Alcohol in 0.1 NHCI Media: 0.1 NHCI Media: 40 % Alcohol in 0.1 NHCI
0 0.0 0.0 0.0 0.0
15 0.0 0.0 0.0 0.1
30 0.0 0.5 0.0 0.6
45 0.0 0.9 0.0 1.2
60 0.0 1.3 0.0 1.8
75 0.0 1.7 0.0 2.3
90 0.0 2.0 0.0 2.9
105 0.0 2.4 0.0 3.4
120 0.0 2.7 0.0 3.9
(Dissolutio n Apparatus: US P I; Volume: 1000 mL; Rota tion: 100 rpm Temperature: 37.0 ±
0.5 °C)
It shows that the capsule with coated beads/ pellets and which does not comprising sodium alginate or carragenan show substantially increase in impurities. This suggests that coating comprising sodium alginate or carrageen may also be effective against drugs which produce impurities in presence of alcohol.

We Claim:
1) An oral modified release pharmaceutical composition comprising
i) a core comprising at least an active pharmaceutical ingredient (API) and
one or more pharmaceutically acceptable excipients, and
ii) a coat comprising alginate or its salts and optionally one or more
pharmaceutically acceptable excipients characterized in that the dissolution profile of the composition is not affected substantially in presence of alcohol.
2) An oral modified release pharmaceutical composition comprising
i) a core comprising at least an active pharmaceutical ingredient (API) and
one or more pharmaceuticaily acceptable excipients, and
ii) a coat comprising carrageenan, and optionally one or more
pharmaceutically acceptable excipients characterized in that the dissolution profile of the composition is not affected substantially in presence of alcohol.
3) The modified release pharmaceutical composition of claims 1 and 2, characterized in that the time taken to release 50 % of API in an alcoholic solution is not reduced more than 2 fold relative to the time taken to release 50 % of API in an alcohol free aqueous medium; is preferably not reduced more than 1.5 fold relative to the time taken to release 50 % of API in an alcohol free aqueous medium; is preferably similar to the time taken in an a)coho\ free aqueous medium according to the similarity factor f2 or is longer than the time taken to release 50 % of API in an alcohol free aqueous medium,
4) The modified release pharmaceutical composition of claims 1 and 2, wherein the coat comprises one or more pharmaceuticaily acceptable plasticizer, pore forming agent and opacifying agent.
5) The modified release pharmaceutical composition of claims 1 and 2. wherein plasticizer is
selected from a group consisting of glycerin and esters thereof, propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate or mixture thereof.
6) The modified release pharmaceutical composition of claims 1 and 2, wherein pore-forming
agent is selected from a group consisting of potassium bitartrate, creatine, aspargine, glutamine, aspartic acid, glutamic acid, leucin, neroleucine, inosine, isoleucine,

magnesium citrate, magnesium phosphate, magnesium carbonate, magnesium hydroxide, magnesium oxide, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose or mixture thereof.
7) The modified release pharmaceutical composition of claims 1 and 2, wherein opacifying agent is selected from a group consisting of titanium dioxide, iron oxide or mixture thereof.
8) A process for preparation of a modified release pharmaceutical composition comprising API or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable exciptents, wherein the pharmaceutical composition coated with alginate or its salts or carrageenan.