ABSTRACT
Mouth dissolving pharmaceutical or neutraceutical composition comprising 1 to 70% by weight of at least one pharmaceutical or neutraceutical active and 30 to 99% by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as super disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at least one pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of the pharmaceutically acceptable excipients. Potassium salt of crosslinked acrylic polymer as superdisintegrant is preferably Indion 414. The partially pre-gelatinized starch and the modified polysaccharide as softening agent are preferably Starch 1500 and Avicel RC 591 respectively. The water soluble channelizing agent is preferably selected from polysorbates or sodium lauryl sulfate or water soluble sugars such as dextrose, mannitol including xylitol or sucrose. The composition can be in the form of pellets, granules or tablets. Also methods of making the composition as pellets, granules or tablets are also disclosed.

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005
COMPLETE SPECIFICATION (See section 10 and rule 13)
TITLE OF THE INVENTION
Mouth dissolving pharmaceutical or nutraceutical composition
INVENTORS
1) Name : Amin Purnima Dhanraj
Address : B-207 Sahayog Apartment, L T Raod, Vazira Naka, Borivli, (West), Mumbai - 400 091, Maharashtra, India
Nationality : an Indian National
2) Name : Pirthi Pal Singh Partap Singh
Address : Building No 13, Flat No 616, G T B Nagar, Sion Koliwada, Mumbai -400 037, Maharashtra, India
Nationality : an Indian National
3) Name : Rajadhyaksha Namita Sham
Address : B-27, Kanta Apartment, Pantnagar, Ghatkopar (East), Mumbai - 400 075, Maharashtra, India
Nationality : an Indian National
4) Name : Jain Satishkumar Pannalal
Address : F (Archit), 403 Kanchan Puhpa Complex, Ghodbundar road, Kavesar, Thane (W) 400 607, Maharashtra, India +
Nationality : an Indian National
5) Name : Mehta Vinam Bharatbhai
Address : C/60, Gunatit Nagar, Near Motibaug, Junagadh 362 001, Gujarat, India Nationality : an Indian National
APPLICANTS
Name : Bajaj Healthcare Limited
Address : 202-204, Faiz-E-Qutbi, 2nd Floor, 375 Narshi Natha Street, Mumbai
400009, Maharashtra, India
Nationality : an Indian Company
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
This invention relates to a mouth dissolving pharmaceutical or nutraceutical composition. The composition is formulated into various dosage forms such as pellets, granules or tablets. This invention also relates to methods of making the mouth dissolving pharmaceutical or nutraceutical composition in various dosage forms such as pellets, granules or tablets.
The term mouth dissolving composition as used in the specification is intended to mean a composition, which disintegrates to form a non-gritty solution or slurry immediately upon contact with water or saliva.
BACKGROUND OF THE INVENTION
Oral administration of medicaments and nutraceuticals is the most commonly used and preferred route, especially by pediatric and geriatric patients as they are easy to be taken orally and problems like choking which may occur while swallowing non-mouth dissolving solid dosage forms such as tablets or capsules do not occur with such compositions. Mouth dissolving compositions are also preferred to liquid dosage as the latter is prone to problems like spillage or inaccuracies in dosages when taken from time to time, lesser stability as compared to solid dosage forms or more storage space requirement.
Rapidly dissolving tablets are known to be prepared by adding a pharmaceutical ingredient to a particulate support matrix. The resulting mixture is compressed into tablets. The particulate matrix comprises polypeptide components, bulking agents and a volatilizing agent. This method is very expensive and complex in that additional steps in forming support matrix are required. Also, tablets formed by this method are very fragile and are to be coated thereby making the method costlier (US Patents Nos 5,635,210, 5,595,761, 5,807,576 and 5,587,180).
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US Patents Nos 4,305,502, 4,371516 and 5,738,875 describe a freeze dying process to prepare an amorphous and porous dosage form which dissolves rapidly. However, such formulations are very expensive and require sophisticated technologies. The tablets prepared by the method disclosed in these patents are difficult to handle and require special packaging.
Porous tablets are known to be prepared by mixing the tablet components with a liquid solvent or solid adjuvant that sublimes at temperatures, which do not adversely affect the properties of the tablet components. The resulting mixture is introduced into an inert cooling medium to solidify the solvent followed by pressing the mixture into tablets at temperatures below melting point of eutectic mixture of tablet component with solvent. The solvent is evaporated from the tablets by drying or lyophilization. The process is very complex and difficult to carry out as the high water content in the mixture makes compression into tablets difficult and cumbersome (US Patents Nos 5,762,961, 5,720,974, 4,134,943 and 3,885,026).
US Patent No 6,149,938 describes a process for making mouth soluble tablets of pharmaceutical active consisting of granulating a polyalcohol, an active ingredient, an edible acid and an aqueous solution of water soluble or water insoluble polymer in a fluidized bed followed by drying the granules in the fluidized bed. The tablets are effervescent and give unpleasant taste in mouth.
US Patent No 6,156,339 describes a process for the preparation of an oral solid rapidly disintegrating dosage form of a pharmaceutically active substance which has an unacceptable taste which process comprises forming a solution or a suspension in a solvent of a water soluble or water dispersible carrier, a filler and the pharmaceutically active substance with the unacceptable taste in association with a lipid; forming discrete units of the suspension or solution; and removing the solvent from the discrete units under conditions whereby unit dosages are formed comprising a network of carrier/filler carrying a dosage of the pharmaceutically active substance in association with the lipid. The process is very complex and requires sophisticated and expensive equipments. Also, the tablets require special type of packaging and
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need to be handled carefully during dispensing and actual administration since they are prone to breakage.
US 5,437,837 describes a method for the preparation of a pharmaceutical composition of porous particles as reconsitutable powder, powder filled in capsule or tablets. Stoichiometric amount of acid and base is mixed in a press to produce compact which is milled to form evenly distributed effervescent mixture and subsequently added to an active to form an active mixture. The above mixture is wet granulated and dried. During drying the acid and base react due to heat and water present in the granules thereby releasing gas to form the porous particles. The porous particles are milled to form a fine powder, which can be further compressed into tablets, or used as reconstitutable powder or filled in capsules as a quick dissolving powder. The compression pressure causes rearrangement of particles to form a less porous structure because of which dissolution time increases.
EP 0,494,972 describes solid dosage forms adapted for direct oral administration (mouth), which substantially completely disintegrates upon contact with water and / or saliva. The solid dosage forms are tablets comprising at least one water or saliva activated effervescent disintegration agent in an amount, which is effective to aid rapid disintegration of the tablets and also provide distinct sensation of effervescence upon disintegration of the tablets in the mouth. Tablets prepared by the above technique need to be handled carefully during dispensing and actual administration since they are prone to breakage. The effervescent tablets give unpleasant taste in mouth.
US 5464632 describes a rapidly disintegratable tablet for oral administration, the tablet comprising an active substance and a mixture of excipients, wherein said active substance is multiparticulate and in the form of coated microcrystals, coated microgranules or uncoated microgranules. The mixture of excipients is selected from the group consisting of at least one disintegrating agent and at least one swelling agent, which are responsible for the disintegration. The disintegrating agent is selected from the group consisting of carboxymethylcellulose and insoluble
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reticulated Polyvinylpyrrolidone and the swelling agent is selected from the group consisting of starch, modified starch and microcrystalline cellulose and direct compression sugar.
US Patent No 6,596,311 describes a fast disintegrating tablet comprising a drug in a multiparticulate form, substantially water insoluble components in amount of 50-99.5% by weight, one or more water insoluble inorganic excipients in amount of 2-40% by weight, one or more disintegrants in amount of 0.5-30% by weight, and one or more substantially water soluble excipients in amount of 4-16% by weight. The disintegrating agent is selected from the group consisting of a natural starch, directly compressible starch, modified starch, cross-linked polyvinylpyrrolidone and modified cellulose or combinations thereof.
US 20040258748 describes a process for preparing mouth dissolving dosage form which disintegrates quickly in the mouth. Active ingredient is blended with effervescent mixture comprising an acid source and a base to produce a tablet, which is subjected to moisture activation by exposing the tablet to controlled humidity or heat. The process is critical at the plant scale as slight moisture can imitate the reaction between acid and base, releasing cog gas, which acts as disintegrating agent. Besides this, the effervescent tablet gives a burning sensation in the mouth.
Freeze drying processes are generally used to prepare fast disintegrating dosage forms. Depending on the manufacturing process, the product obtained is characterized by a highly porous microstructure of the soluble supporting agent (i.e. mannitol, glycine, lactose or gelatins) in which the active is homogeneously dispersed. Therefore, the fast disintegrating tablets are generally very friable and require special packaging and are to be carefully handled. Freeze drying also increases the production cost because of the long duration of each freeze drying cycle (normally from 24 to 48 hours). The complexity of the industrial plants is another important factor, which prejudices the large scale use of this technology for the development of rapidly disintegrating tablets. Moreover, the thermal shocks, as a direct consequence of each freeze drying cycle, might physically modify the physico-chemical properties of the
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outer membrane of the microencapsulated particles.
OBJECTS OF INVENTION
An object of the invention is to provide a mouth dissolving pharmaceutical or nutraceutical composition, which dissolves rapidly in the mouth.
Another object of the invention is to provide a mouth dissolving pharmaceutical or nutraceutical composition, which has low friability values and does not require special type of packaging and careful handling.
Another object of the invention is to provide a mouth dissolving pharmaceutical or nutraceutical composition, which can be in various dosage forms.
Another object of the invention is to provide a method of making a mouth dissolving pharmaceutical or nutraceutical composition having the above properties, which method is simple and easy to carry out.
Another object of the invention is to provide a method of making a mouth dissolving pharmaceutical or nutraceutical composition having the above properties, which method is economical.
Another object of the invention is to provide a method of making a mouth dissolving pharmaceutical or nutraceutical composition having the above properties, which method is eco-friendly.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention there is provided mouth dissolving pharmaceutical or neutraceutical composition comprising 1 to 70% by weight of at least one pharmaceutical or neutraceutical active and 30 to 99% by weight of pharmaceutical^ acceptable excipients including at least one potassium salt of cross linked acrylic
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polymer as a super disintegrant in 1 to 30 % by weight of the pharmaceutical^ acceptable excipients; at least one pre-gelatinized starch or modified polysaccharide as softening agent in 5 to 50 % by weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of the pharmaceutically acceptable excipients.
The pharmaceutical or neutraceutical composition of the invention is in solid dosage forms such as pellets, granules or tablets.
The pharmaceutical active is, for example, selected from the group consisting of analgesics and anti-inflammatory agents such as aloxiprin, auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, rofecoxib, sulindac, tetrahydrocannabinol, tramadol or tromethamine; antihelminthics such as albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate or thiabendazole; anti-arrhythmic agents such as amiodarone HC1, disopyramide, flecainide acetate or quinidine sulfate; anti-asthma agents such as zileuton, zafirlukast, terbutaline sulfate, montelukast or albuterol; anti-bacterial agents such as alatrofloxacin, azithromycin, baclofen, benzathine penicillin, cinoxacin, ciprofloxacin HC1, clarithromycin, clofazimine, cloxacillin, demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone, grepafloxacin, imipenem, levofloxacin, lomefloxacin, moxifloxacin HC1, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim, trovafloxacin or vancomycin; anti-viral agents such as abacavir, amprenavir, delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir or stavudine; anti-coagulants such as cilostazol, clopidogrel, dicumarol, dipyridamole, nicoumalone, oprelvekin, phenindione,, ticlopidine or
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tirofiban; anti-depressants such as amoxapine, bupropion, citalopram, clomipramine, fluoxetine HCl, maprotiline HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl, trimipramine maleate or venlafaxine HCl; antidiabetics such as acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, miglitol, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide or troglitazone; anti-epileptics such as beclamide, carbamazepine, clonazepam, ethotoin, felbamate, fosphenytoin sodium, lamotrigine, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, primidone, sulthiame, tiagabine HCl, topiramate, valproic acid or vigabatrin; anti-fungal agents such as amphotericin, butenafine HCl, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine HCl, terconazole, tioconazole or undecenoic acid; anti-gout agents such as allopurinol, probenecid or sulphin-pyrazone; anti-hypertensive agents such as amlodipine, benidipine, benezepril, candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosin HCl, elanapril, eposartan, losartan mesylate, felodipine, , fenoldopam, fosenopril, guanabenz acetate, irbesartan, isradipine, lisinopril, minoxidil, nicardipine HCl, nifedipine, nimodipine, nisoldipine, phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan or valsartan; anti-malarials such as amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine or quinine sulfate; anti-migraine agents such as dihydroergotamine mesylate, ergotamine tartrate, frovatriptan, methysergide maleate, naratriptan HCl, pizotyline malate, rizatriptan benzoate, sumatriptan succinate or zolmitriptan; anti-muscarinic agents such as atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencyclimine HCl or tropicamide; antineoplastic agents and immunosuppressants such as aminoglutethimide, amsacrine, azathioprine, bicalutamide, bisantrene, busulfan, camptothecin, cytarabine, chlorambucil, cyclosporin, dacarbazine, ellipticine, estramustine, etoposide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, mofetil mycophenolate, nilutamide, paclitaxel, procarbazine HCl, sirolimus, tacrolimus, tamoxifen citrate, teniposide, testolactone, topotecan HCl
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or toremifene citrate; anti-protozoal agents such as atovaquone, benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furazolidone, metronidazole, nimorazole, nitrofurazone, ornidazole or tinidazole; antithyroid agents, such as carbimazole, paracalcitol or propylthiouracil; anti-tussives such as benzonatate; anxiolytics, sedatives, hypnotics and neuroleptics such as alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, chlorprothixene, clonazepam, clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, triflupromazine, fluphenthixol decanoate, fluphenazine decanoate, flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, mesoridazine, methaqualone, methylphenidate, midazolam, molindone, nitrazepam, olanzapine, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, pseudoephedrine, quetiapine, rispiridone, sertindole, sulpiride, temazepam, thioridazine, triazolam, Zolpidem or zopiclone; beta-blockers such as acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol or propranolol; cardiac inotropic agents such as amrinone, digitoxin, digoxin, enoximone, lanatoside C or medigoxin; corticosteroids such as beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, fluocortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone or triamcinolone; diuretics such as acetazolamide, amiloride, bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone or triamterene; anti-parkinsonian agents such as bromocriptine mesylate, lysuride maleate, pramipexole, ropinirole HCl or tolcapone; gastrointestinal agents such as bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, lansoprazole, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCl, rabeprazole sodium, ranitidine HCl or sulphasalazine; histamine H and H-receptor antagonists such as acrivastine, astemizole, chlorpheniramine, chlorpheniramine maleate, cinnarizine, cetrizine, clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlorpheniramine, dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclizine HCl, oxatomide or terfenadine; keratolytics such as acetretin, calcipotriene,
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calcifediol, calcitriol, cholecalciferol, ergocalciferol, etretinate, retinoids, targretin or tazarotene; lipid regulating agents such as atorvastatin, bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil, pravastatin, probucol or simvastatin; muscle relaxants such as dantrolene sodium or tizanidine HC1; nitrates and other anti-anginal agents such as amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate or pentaerythritol tetranitrate; nutritional agents such as calcitriol, carotenes, dihydrotachysterol, essential fatty acids, non-essential fatty acids, phytonadiol, vitamin A, vitamin B2, vitamin D, vitamin E or vitamin K; opioid analgesics such as codeine, codeine, dextropropoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone, morphine, nalbuphine or pentazocine; sex hormones such as clomiphene citrate, cortisone acetate, danazol, dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone, fluoxymesterone, medroxyprogesterone acetate, megestrol acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated estrogens, progesterone, rimexolone, stanozolol, stilbestrol, testosterone or tibolone; stimulants such as amphetamine, dexamphetamine, dexfenfluramine, fenfluramine or mazindol; gastrointestinal remedies and digestion-promoting agents such as loperamide, pectin, plantago ovata seeds, linseeds, mesalazine (5-aminosalicylic acid), olsalazine, cimetidine, ranitidine, famotidine, nizatidine, omeprazole, sucralfate, pantoprazole, metoclopramide, pancreatin, amylase, protease, lipase or sulphasalazine; laxatives such as dry extract of senna pods, frangula bark or extract, bisacodyl, sodium picosulphate or lactulose; analgesics and anti-rheumatics such as acetylsalicylic acid, paracetamol, ibuprofen, morphine, tramadol, acemetacin, propyphenazone, naproxen, diclofenac, ketoprofen, piroxicam, meloxicam or indomethacin; antiallergics such as dimetindene maleate, terfenadine, astemizole or ketotifen; antitussives and expectorants such as ambroxol, acetylcysteine, codeine or theophylline; beta-receptor blockers, calcium channel blockers and ACE inhibitors such as atenolol, metoprolol, pindolol, nifedipine, diltiazem, verapamil, captopril, lisinopril or enalapriI;coronary remedies such as isosorbide, isosorbide mononitrate or molsidomine; sedatives such as valerian extract, nitrazepam, temazepam, active ingredients such as aescin, high-dose amino acids, budesonide, furosemide or pentoxifylline; vitamins such as ascorbic acid, vitamin B.sub.l, B.sub.2, B.sub.6 and/or B.sub.12, folic acid or vitamin E;
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antibiotics such as ciprofloxacin, norfloxacin, ofloxacin, nalidixic acid, cinoxacin, pefloxacin, phenoxymethylpenicillin, amoxicillin and other penicillins with a penam structure, cephalosporins with a cephem structure such as cefaclor, cefadroxil, cefalexin, cefpodoxime, ceftibuten, cefuroxime and cefetamet, clavulanic acid in combination with amoxicillin, tetracycline, macrolide antibiotics such as erythromycin and its esters, spiramycin and josamycin, colistin and polymyxin B or nitrofurans such as nitrofurantoin, nitroimidazoles such as metronidazole; sulphonamides such as sulphadiazine or sulphasalazine and the like and pharmaceutically acceptable salts of such compounds such as olsalazine sodium, pantoprazole sodium, diclofenac sodium, morphine sulphate, codeine phosphate, metoprolol tartrate, diltiazem hydrochloride, verapamil hydrochloride, amitriptyline hydrochloride or thioridazine hydrochloride; mineral salts such as calcium lactate, calcium carbonate, calcium gluconate, magnesium carbonate, magnesium aspartate or zinc sulphate or trace elements; erectile dysfunction improvement agents; anti-osteoporosis agents; anti-obesity agents; cognition enhancers; anti-urinary incontinence agents or anti-benign prostate hypertrophy agents such as becaplermin, donepezil HC1, L-thryroxine, methoxsalen, verteporfin, physostigmine, pyridostigmine, raloxifene HC1, sibutramine HC1, sildenafil citrate, tacrine, tamsulosin HC1 or tolterodine.
The nutraceutical active is, for example, dietary or nutritional supplement also known as medical or functional or designer foods or phytochemicals and includes therapeutic foods, infant formulas, weight control foods or hypoallergic foods. The neutraceutical active is, for example, selected from the group consisting of herbs and botanicals such as capsicum, chamomile, cat's claw, echinacea, garlic, ginger, ginko, various ginseng, green tea, golden seal, kava kava, nettle, passion flower, saw palmetto, St. John's wort or valerian; mineral supplements such as calcium, copper, iodine, iron, magnesium, manganese, molybdenum, phosphorous, boron, selenium or zinc; weight loss agents such as chromium picolinate or phenylpropanolamine; benzoin, fructo-oligosaccharides, glucosamine, grapeseed extract, guarana, inulin, phosphotidylserine, phytosterols, phytochemicals, isoflavones, lecithin, lycopene, oligofructose, polyphenol or psyllium.
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The pharmaceutical or neutraceutical active can be of pleasant taste or non-bitter or can be of unpleasant taste or bitter and taste masked.
The bitter pharmaceutical or neutraceutical active is taste masked by techniques known in the art using taste masking agents selected from the group consisting of flavours, sweeteners and amino acids such as fenchone, borneol, isoborneol, stevia based sweetner extract and glycerine, anethol-B-cyclodextrin complex and saccharin, sodium phenolate, anethole, eucalyptol and methyl salicylate, sodium citrate dihydrate, sodium saccharin, sodium glutamate and vanilla essence, sodium bicarbonate, citric acid and lemon flavor, monosodium glycyrrhizinate, starch, lactose and mannitol or glycine alanine, lipids such as stearyl stearate, glycerol palmitostearate, carnauba wax and magnesium aluminium silicate, glyceryl monostearate, gelatin and mixture of partially hydrogenated soyabean oil, molten stearyl stearate, polyglycerine fatty acid esters, glycerine and chained triglycerides or homogenated suspensions of phospatidic acid or B-galactoglobulin; lecithin and lecithin like substances such as soyabean or phosphatidic acid, coating agents such as cellulose, shellac, L-hydroxypropyl cellulose, ethyl cellulose, methacrylic acid copolymer (Eudragit), Hydroxypropyl Methylcellulose, Polyvinylpyrrolidone, cellulose acetate, Microcrystalline Cellulose, cellulose acetate butyrate, calcium gluconate and sodium alginate, carrageenan, macrogol-400, gelatin, carbopol, corn starch or macrogol-6000; protein; gelatins; prolamines (Zein); zeolites; ion-exchange resins and complexing agents such as cyclodextrin, Hydroxypropyl 13- cyclodextrin, B-CD, Indion CRP 244, Indion CRP 254, Amberlite IRP 69, Indion 234; effervescent agents such as citric acid, fumaric acid, maleic acid, tartaric acid or sodium bicarbonate ; wax; benecoat BMI-60 phosphatidic acid or tannic acid.
The potassium salt of crosslinked acrylic polymer as super disintegrant is selected from Indion 414 (Ion Exchange India Ltd, Mumbai), Amberlite IRP-88 (Rohm & Haas (UK) Ltd., UK), Indion 234 (Ion Exchange India Ltd., India) or Indion 294 (Ion Exchange India Ltd., India). The preferred potassium salt of crosslinked acrylic polymer as super disintegrant is Indion 414, which has a swelling index of 800. As the
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ionic radius of K is high, the rate of water uptake by the composition is very high thereby resulting in fast disintegration thereof. The partially pre-gelatinized starch as softening agent is Starch 1500 (Colorcon Asia Pvt Ltd, India). The modified polysaccharide as softening agent is selected from Avicel RC 591 (micro-crystalline cellulose containing 11-13% sodium carboxymethylcellulose by FMC Biopolymer, Denmark), Avicel RC 581 (microcrystalline cellulose containing 11-13% sodiumcarboxy methylcellulose by FMC Biopolymer, Denmark), Avicel CL 611 (microcrystalline cellulose containing sodium carboxymethylcellulose by FMC Biopolymer, Denmark); preferably Avicel RC 591. The water soluble channelizing agent is selected from polysorbates, poloxamers, sodium lauryl sulfate or water soluble sugars such as mannitol, lactose, dextrose, sucrose, maltose, glucose, fructose, sorbitol, maltitol, or xylitol. The preferred channelizing agents are polysorbates or sodium lauryl sulfate or water soluble sugars such as dextrose, mannitol, lactose, xylitol or sucrose. The channelizing agents allow easy uptake of fluids into the composition and form channels that facilitate rapid softening and disintegration of the composition.
The other pharmaceutically acceptable excipients, which can be used in the composition of the invention, include one or more disintegrants, sweeteners, salivating agents, colouring agents, flavouring agents, preservatives or formulating agents.
The disintegrating agents are selected from clays, celluloses, sodium starch glycolate, starch, pregelatinised starch (Amigel, National 155), crosscarmellose sodium, microcrystalline cellulose (Avicel ), Polyvinylpyrrolidone cross linked, magnesium
aluminum silicate, alginates or sodium alginate. The disintegrants open up and disintegrate the composition upon contact with saliva.
The sweeteners render the composition palatable and are selected from sodium saccharin, aspartame, acesulfame potassium, monoammonium glycyrrhizinate (MAG), glycerine, polyols, lactitol, cyclamate or sucralose or combinations thereof.
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The salivation agents induce a sufficiently strong flow of saliva, which accelerates the action of channelizing agents and disintegrants. The salivating agents are selected from natural flavours or artificial flavours or weak or water-soluble organic acids such as citric acid.
The colours and flavours add aesthetic appeal and flavour to the composition. Flavour can be solid or liquid flavor and is selected from but not limited to Orange flavor, Raspberry flavor, Chocolate flavor, Strawberry flavor or Pineapple flavor.
Coloring agents that can be used include all F D and C and / or D and C dyes and / or lakes. Examples of coloring agents are Iron oxides, Carmoisine, Ponceau 4R, lake sunset yellow or tartrazine.
The preservatives prevent microbial growth during storage of the composition and are selected from parahydroxybenzoates or alkyl esters or salts thereof, sodium benzoate, benzoic acid, edetic acid, sorbic acid and salts, bronopol or the like. Preferably the preservatives are parahydroxybenzoates or alkyl esters thereof.
The formulating agents include diluents, binders, granulating agents, lubricating agents, tabletting agents or spheronising agents.
The diluents are selected from calcium phosphate, calcium sulphate dihydrate, granular calcium lactate trihydrate, glyceryl palmitostearate, microcrystalline cellulose, kaolin, magnesium carbonate, magnesium oxide, hydrolysed starches such as emdex or celutab, inositol, amylose, starches such as corn, wheat or potato, calcium carbonate, calcium triphosphate or sodium chloride. Preferably the diluents are microcrystalline cellulose, kaolin, calcium phosphate, magnesium carbonate, magnesium oxide.
The granulating agents are selected from cellulose and derivatives thereof, starch and its derivatives, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) pyrrolidone and derivatives thereof, or water. Preferably the granulating agents
14

are water, hydroxypropyl methylcellulose (HPMC), Polyvinylpyrrolidone or celluloses and derivatives thereof.
The lubricating agents are selected from calcium stearate, magnesium stearate, potassium stearate, sodium stearate, boric acid, hard paraffin, magnesium oxide, talc, stearic acid, colloidal silicon dioxide, polyethylene glycol 4000, corn starch, sodium lauryl sulphate, magnesium lauryl sulphate or D L - leucine. Preferably the lubricating agents are magnesium stearate, stearic acid or talc.
The tabletting agents are selected from calcium phosphate, magnesium carbonate, magnesium oxide, granular calcium lactate trihydrate, microcrystalline cellulose (Avicel® PH 101 and Avicel® PH 102), kaolin, hydrolysed starches such as Emdex or celutab, inositol, amylose, starches such as corn, wheat or potato, calcium carbonate. Preferably the tabletting agents are microcrystalline cellulose (Avicel® PH 101 and Avicel® PH 102), kaolin, calcium phosphate, magnesium carbonate, magnesium oxide..
The binders are selected from acacia, tragacanth, gelatin, starch, methyl cellulose, magnesium aluminium silicate, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, alginic acid, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, Polyvinylpyrrolidone, polymethacrylates, dextrin, zein , hydrogenated vegetable oil, hydroxy ethyl cellulose, guar gum, maltodextrin, sodium alginate, water or ammonium calcium alginate. Most preferred binder is HPMC or Polyvinylpyrrolidone eg. plasdone® K. 29/32 or water.
The spheronizing agents are selected from microcrystalline cellulose. Microcrystalline cellulose including all grades of Avicel® (FMC BioPolymer, Denmark) such as but not limited to Avicel® PH 101, Avicel® PH 102, Avicel® PH 103, Avicel® PH 105, Avicel® PH 112, Avicel® PH 113, Avicel® PH 200, Avicel® PH 301 and Avicel® PH 302.
According to the invention there is provided a method of making a mouth dissolving
15

pharmaceutical or neutraceutical composition as pellets, the method comprising
i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceutical
or neutraceutical active with 30 to 99 % w/w by weight of pharmaceutically
acceptable excipients including at least one potassium salt of cross linked
acrylic polymer as super disintegrant in 1 to 30 % by weight of the
pharmaceutically acceptable excipients, at least one pre-gelatinized starch or
modified polysaccharide as softening agent in 5 to 50 % by weight of
pharmaceutically acceptable excipients and at least one water soluble
channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable
excipients;
ii) dry mixing the mixture obtained by step (i) with at least one spheronization
agent;
iii a) mixing the mixture obtained by step (ii) with a binder solution;
iv a) extruding and spheronising the composition obtained by step (iii a) to
obtain pellets; and
v a) drying the pellets obtained by step (iv a) at 35 to 100°C.
According to the invention there is provided a method of making a mouth dissolving pharmaceutical or neutraceutical composition as granules, the method comprising
i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceutical
or neutraceutical active with 30 to 99% w/w by weight of pharmaceutically
acceptable excipients including at least one potassium salt of cross linked
acrylic polymer as super disintegrant in 1 to 30 % by weight of the
pharmaceutically acceptable excipients, at least one pre-gelatinized starch or
modified polysaccharide as softening agent in 5 to 50 % by weight of the
pharmaceutically acceptable excipients and at least one water soluble
channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable
excipients;
ii) dry mixing the mixture obtained in step (i) with at least one diluent;
iii b) granulating the mixture of step (ii) with a binder solution;
iv b) sieving the granules obtained by step (iii b);
v b) drying the granules of step (iv b) at 35 to 100° C; and
16

vi b) sieving the granules obtained by step (v b).
According to the invention there is provided a method of making a mouth dissolving pharmaceutical or neutraceutical composition as tablets, the method comprising
i) dry mixing at 25 to 45° C 1 to 70% by weight of at least one pharmaceutical
or neutraceutical active with 30 to 99% w/w by weight of pharmaceutically
acceptable excipients including at least one potassium salt of cross linked
acrylic polymer as super disintegrant in 1 to 30 % by weight of the
pharmaceutically acceptable excipients, at least one pre-gelatinized starch or
modified polysaccharide as softening agent in 5 to 50 % by weight of the
pharmaceutically acceptable excipients and at least one water soluble
channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable
excipients;
ii) dry mixing the mixture obtained by step (i) with at least one tabletting agent
and
iii c) compressing the mixture obtained by step (ii) into tablets.
Preferably, the dry mixing as per step (i) is carried out 25 to 35° C. Preferably, 10 to 60 % by weight of at least one pharmaceutical or neutraceutical active is dry mixed with 40 to 90 % w/w by weight of pharmaceutically acceptable excipients including at least one potassium salt of cross linked acrylic polymer as super disintegrant in 2 to 20 % by weight of the pharmaceutically acceptable excipients, at least one pre-gelatinized starch or modified polysaccharide as softening agent in 10 to 30 % by weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 5 to 70 % by weight of pharmaceutically acceptable excipients. The mixing of step (i) or step (ii) can be carried out in a blender. The mixing of step (iii a) can be carried out in a blender. The granulation step (iii b) is carried out in a granulator. The extrusion and spheronization of the composition as per step (iv a) can be carried out in extruder-spheronizer. The drying of the pellets or granules as per step (v a) or (v b) can be carried out on a fluid bed dryer or tray dryer, preferably at 40 to 60° C. The sieving of step (iv b) and (vi b) is carried out through meshes of 8 mesh and 40 mesh sieve respectively. The compression of the composition into tablets as
17

per step (iii c) can be carried out in a cadmach 8 station rotary machine.
A method of making a mouth dissolving pharmaceutical or neutraceutical composition as tablets where the method comprises granulating the mixture obtained by step (i) with a solution of a granulating agent or binder followed by mixing the granules with a tabletting agent and compressing the granules into tablets.
The granules or pellets prepared according to the invention can be used for fortification of liquids such as juices, milk, soy milk, etc and soft foods.
According to the invention, there is provided a mouth dissolving pharmaceutical or neutraceutical composition having very high dissolution or dispersion in the range of 5 to 65 seconds in water and/or upon contact with saliva and low friability in the range of 0.1 to 1%. The composition can be in different solid dosage forms such as pellets, granules or tablets. Due to low friability, the solid forms of the composition of the invention do not require special packaging or careful handling. The steps of the methods of the invention for formulating the composition of the invention into various solid dosage forms do not employ expensive equipments and machinery and are not complicated to carry out. The steps are very simple and easy to carry out. Water is used as the solvent. Therefore, the methods of the invention do not create any pollution and disposal problems and are eco-friendly. As the solid forms of the composition of the invention can be formulated into granules or pellets higher dosage of the actives can be incorporated into such dosage forms. The invention is also efficient and economical for the above reasons.
The following experimental examples are illustrative of the invention but not limitative of the scope thereof.
Example 1
Calcium citrate and vitamin D3 composition as granule
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[Example 1A]
20% w/w of calcium citrate and 0.0061% w/w of vitamin D3 were dry mixed with 3% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 1 % w/w of sodium saccharin, 1.5% w/w of orange flavor, 1 % w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% partially pregelatinized starch and 43.3% w/w dextrose in the blender. The resulting powder was granulated with 20% w/w of sucrose solution comprising 50% w/w sucrose in water in a granulator to obtain granules of calcium citrate and vitamin D3. The granules were sieved through 8# sieve and dried in a Fluidized bed drier at 40 °C. The granules were further sieved through 20# sieve and collected on a 80# sieve.
[Example 1 B]
Composition of calcium citrate and vitamin D3 as granules was prepared according to the Example 1 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of dextrose and partially pregelatinised starch.
Payability Test
Palatability of the dosages of Examples 1A and IB was tested on 25 volunteers using a scoring scale of 0-5 where 0 stood for high unpalatability and 5 stood for high palatability. The scores given by the volunteers were as follows: Granules of Example 1 A: 4-5 Granules of Example 1 B: 1-2
Dispersion test
5 gms of the granules of Example 1 A and Example 1 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 1-2 minutes respectively.
Example 2
Calcium citrate and vitamin D3 composition as tablets
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[Example 2 A]
60% w/w of calcium citrate and 0.0061% w/w of vitamin D3 were dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 0.8% w/w sodium lauryl sulfate, 1% w/w sodium saccharin and 1% w/w monoammonium glycyrrhizinate, 2.0% w/w of orange flavor, 2% w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 2% partially pregelatinized starch, 15% w/w Avicel® PH 102, 6.3% w/w Pearlitol, 3% w/w talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 2 B]
Composition of calcium citrate and vitamin D3 as tablets was prepared according to the Example 2 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of pearlitol and partially pregelatinised starch.
Palatability Test
Palatability of the tablets of Examples 2 A and 2 B was tested on 25 volunteers as in Example 1 and the scoring were as follows: Tablets of Example 2 A: 3-4 Tablets of Example 2 B: 1-2
Dispersion test
2 tablets of each of Example 2A and 2B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
Disintegration Test
Six tablets of each of Example 2A and 2B disintegrate in 1 minute and 3-4 minutes respectively.
Friability test
Friability was determined using 6 g of tablets of Example 2A and 2B in a Roche
20

friabilator for 4 min. at a speed of 25 rpm. The friability were as follows: Example 2 A : 0.36%
Example 2 B : 0.72%
Example 3 Calcium citrate and vitamin D3 composition as pellets
[Example 3 A]
60% w/w of calcium citrate and 0.0061% w/w of vitamin D3 were dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 5.99% dextrose, 0.8% w/w sodium lauryl sulfate, 1% w/w sodium saccharin and 1% w/w monoammonium glycyrrhizinate, 2.0% w/w of orange flavor, 2% w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 7% w/w Avicel® PH 101 and 10% w/w Avicel® RC 591 in suitable blender. The resulting mixture was granulated with water in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of calcium citrate and vitamin D3. The pellets were dried in a fluid bed dryer at 40 °C and fraction passing through 20# sieve and retained on a 40# sieve was collected.
[Example 3 B]
Composition of calcium citrate and vitamin D3 as pellets was prepared according to the Example 3 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of dextrose and Avicel® RC 591.
Palatability Test
Palatability of the pellets of Examples 3 A and 3 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Pellets of Example 3 A: 4-5
Pellets of Example 3 B: 1-2
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Dispersion test and swelling index
5 gms of the pellets of Example 3A and 3B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 3A and 3B in water and simulate saliva was 200-400% w/w and less than 100% w/w respectively.
Friability test
Friability of 6 g of pellets of Example 3A and 3B was tested as in Example 2 and friability was as follows : Example 3 A : 0.13% Example 3B : 0.23%
Example 4
Calcium citrate malate and vitamin D3 composition as granules.
[Example 4 A]
20% w/w of calcium citrate malate and 0.0061% w/w of vitamin D3 were dry mixed with 3% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 43.3% w/w dextrose, 1% w/w sodium saccharin, 1.5% w/w of orange flavor, 1% w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben, 10% partially pregelatinized starch in a in a blender at temperature in the range of 25 to 35° C. The resulting powder was granulated with 20 % w/w of sucrose solution comprising 50% w/w sucrose in water in a granulator to obtain granules of calcium citrate malate and vitamin D3. The granules were sieved through 8# sieve and dried in a fluidized bed drier at 40°C. The granules were further sieved through 20# sieve and collected on 80# sieve.
[Example 4 B]
Composition of calcium citrate malate and vitamin D3 as granules was prepared according to the Example 4 A using starch glycolate instead of Indion 414 and Magnesium carbonate instead of dextrose and partially pregelatinised starch.
22

Palatability Test
Palatability of the granules of Examples 4 A and 4 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Granules of Example 4 A: 4-5
Granules of Example 4 B: 1-2
Dispersion test
5 gms of the granules of Example 4 A and 4B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 1-2 minutes respectively.
Example 5
Calcium citrate malate and vitamin D3 composition as tablets
[Example 5 A]
60% w/w of calcium citrate malate and 0.0061% w/w of vitamin D3 were dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 6.3% w/w pearlitol and 0.8% w/w sodium lauryl sulfate, 1% w/w sodium saccharin and 1% w/w monoammonium glycyrrhizinate, 1.5% w/w of orange flavor, 1% w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 2% partially pregelatinized starch, 15% w/w Avicel® PH102, 3% w/w talc and 1% w/w magnesium stearate in blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 5 B]
Composition of calcium citrate malate and vitamin D3 as tablets was prepared according to the Example 5 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of Pearlitol and partially pregelatinised starch.
23

Payability Test
Palatability of the tablets of Examples 5 A and 5 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Tablets of Example 5 A: 3-4
Tablets of Example 5 B: 1-2
Dispersion test
2 tablets of each of Example 5 A and Example 5 B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
Disintegration Test
6 tablets of each of Example 5 A and 5B disintegrate in 1 minute and 3-4 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 5 A and 5B was tested as in Example 2 and the friability was as follows :
Example 5 A : 0.32%
Example 5 B : 0.33%
Example 6
Calcium citrate malate and vitamin D3 composition as pellets
[Example 6 A]
60% w/w of calcium citrate malate and 0.0061% w/w of vitamin D3 were dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 2.99% w/w dextrose and 0.8% w/w sodium lauryl sulfate, 1% w/w sodium saccharin and 1% w/w monoammonium glycyrrhizinate, 2.0% w/w of orange flavor, 2% w/w of lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH102 and 10% w/w Avicel® RC 591 in blender. The
24

resulting mixture was granulated with water in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of calcium citrate malate and vitamin D3. The pellets were dried on a fluid bed dryer at 40 °C and fraction passing through 20# sieve and collected on a 40# sieve was collected.
[Example 6 B]
Composition of calcium citrate malate and vitamin D3 as pellets was prepared according to the Example 6 A using sodium starch glycolate instead of Indion 414 and Magnesium carbonate instead of dextrose and Avicel® RC 591.
Payability Test
Palatability of the pellets of Examples 6 A and 6 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Pellets of Example 6 A: 4-5
Pellets of Example 6 B: 2-3
Dispersion test and swelling index
5 gms of the pellets of Example 6 A and 6 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 6 A and 6 B in water and simulate saliva was 200-400% w/w and less than 100% w/w.
Friability test
Friability of 6 g of pellets of Example 6A and 6B was tested as in Example 2 and the friability was as follows :
Example6A:0.1%
Example 6 B : 0.24%
Example 7 Ferrous fumarate composition as granules
25

[Example 7 A]
12.66% w/w of ferrous fumarate was dry mixed with 12% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 10% partially pregelatinized starch, 51.14 % w/w dextrose, 2% w/w aspartame, 5% w/w chocolate flavour, 2% w/w red iron oxide, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in blender at temperature in the range of 25 to 35° C. The resulting powder was granulated with 5 % w/w of sucrose solution comprising 50% w/w of sucrose in water in a granulator to obtain granules of ferrous fumarate. The granules were sieved through 8# sieve and dried in a fluid bed dryer at 40°C. The granules were further sieved through 20# sieve and collected on 80# sieve.
[Example 7 B]
Composition of ferrous fumarate as granules was prepared according to the Example 7 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 7 A and 7 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Granules of Example 7 A: 4-5
Granules of Example 7 B: 1-3
Dispersion test
5 gms of the granules of Example 7 A and 7 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 70-90 seconds respectively.
Example 8 Ferrous fumarate composition as tablets
[Example 8 A]
30.4% w/w of ferrous fumarate was dry mixed with 10% w/w Indion (Ion Exchange India Ltd, Mumbai). 0.4% w/w sodium lauryl sulfate and 20% w/w dextrose, 2 % w/w
26

aspartame, 5% w/w chocolate flavour, 2% w/w red iron oxide, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 3% partially pregelatinized starch, 15% w/w Avicel® PHI01. The dry mix was granulated with aqueous binding solution comprising of 3% Polyvinylpyrrolidone K29/32 and 5% HPMC of total weight in a granulator. The granules were passed through 8# sieve and then dried in fluidized bed drier at 40°C. The dried granules were passed through 20 # sieve. The granules were then mixed with 3% talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 8 B]
Composition of ferrous fumarate as tablets was prepared according to the Example 8 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
Payability Test
Palatability of the tablets of Examples 8 A and 8 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Tablet of Example 8 A: 4-5
Tablet of Example 8 B: 1-3
Dispersion test
2 tablets of each of Example 8 A and 8 B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
Disintegration Test
6 tablets of each of Example 8 A disintegrate in 50 seconds and 3-4 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 8 A and 8B was tested as in Example 2 and the
27

friability was as follows : Example 8 A : 0.63 % Example 8 B : 0.68 %
Example 9 Ferrous fumarate composition as pellets
[Example 9 A]
30.4% w/w of ferrous fumarate was dry mixed with 10% w/w Indion (Ion Exchange India Ltd, Mumbai). 0.4% w/w sodium lauryl sulfate and 17% dextrose, 2% w/w aspartame, 5% w/w chocolate flavour, 2% w/w red iron oxide, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 15% w/w Avicel® RC 591 in blender. The resulting mixture was granulated with aqueous solution of 3% w/w Polyvinylpyrrolidone K29/32 and 5% w/w HPMC in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of ferrous fumarate. The pellets were dried in a fluid bed dryer at 40 °C and fraction passing through 20# sieve and retained on a 40# sieve was collected.
[Example 9 B]
Composition of ferrous fumarate as pellets was prepared according to the Example 9 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and Avicel® RC 591.
Palatability Test
Palatability of the pellets of Examples 9 A and 9 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Pellets of Example 9 A: 4-5
Pellets of Example 9 B: 1-3
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Dispersion test and swelling index
5 gms of the pellets of Example 9 A and 9 B dispersed in 100 ml of water in 60 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 9 A and 9 B in water and simulate saliva was 200-450 % w/w and less than 120 % w/w respectively.
Friability test
Friability of 6 g of pellets of Example 9 A and 9 B was tested and the friability was as
follows :
Example 9 A : 0.21%
Example 9 B : 0.25%
Example 10 Carbonyl iron composition as granules
[Example 10A]
7.5% w/w of carbonyl iron was dry mixed with 12% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 2% w/w aspartame, 5% w/w chocolate flavour, 2% w/w lake red iron oxide, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% partially pregelatinized starch, 56.3% w/w dextrose. The resulting powder was granulated with 5% w/w of sucrose solution comprising 50% w/w dextrose in water in a granulator to obtain granules of carbonyl iron. The granules were sieved through a 8# sieve and dried in a fluid bed dryer at 40°C. The granules were further sieved through a 20# sieve and collected on a 80# sieve.
[Example 10B]
Composition of carbonyl iron as granules was prepared according to the Example 10 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
29

Palatability Test
Palatability of the granules of Examples 10 A and 10 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Granules of Example 10 A: 3-4
Granules of Example 10 B: 1-2
Dispersion test
5 gms of the granules of Example 10 A and 10 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 80-90 seconds respectively.
Example 11 Carbonyl iron composition as tablets
[Example 11 A]
7.5% w/w of carbonyl iron was dry mixed with 12% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 0.4% w/w sodium lauryl sulfate, 38.9% w/w mannitol, 2% w/w aspartame, 5% w/w chocolate flavour, 2% w/w lake brown, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% partially pregelatinized starch, 10% w/w Avicel® PHI01. The mixture was granulated with aqueous solution of 3% w/w Polyvinylpyrrolidone and 5 % w/w hydroxypropyl methyl cellulose in a granulator. The granules were passed through 8# sieve and then dried in fluidized bed dryer at 40°C. The dried granules were passed through 20# sieve. The granules were then mixed with 3% w/w talc and 1% w/w magnesium stearate in blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 11 B]
Composition of carbonyl iron as tablets was prepared according to the Example 11 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol and partially pregelatinised starch.
30

Palatability Test
Palatability of the tablets of Examples 11 A and 11 B was tested on 25 volunteers as in Example 1 scoring were as follows:
Tablets of Example 11 A: 3-4
Tablets of Example 11 B: 1-2
Dispersion test
2 tablets of each of Example 11 A and 11 B dispersed in 100 ml of water in 60-90 seconds and 4-5 minutes respectively.
Disintegration Test
6 tablets of each of Example 11 A and 11 B disintegrate in 1 minute and 3-4 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 11 A and 11 B was tested as in Example 2 and the friability was as follows :
Example 11 A : 0.45 %
Example 11 B : 0.23 %
Example 12 Carbonyl iron composition as pellets
[Example 12 A]
7.5% w/w of carbonyl iron was dry mixed with 12% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 0.4% w/w sodium lauryl sulfate and 37.9% w/w dextrose, 2% w/w aspartame, 5% w/w chocolate flavour, 2% w/w lake red iron oxide, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 15% w/w Avicel® RC 591 in blender. The resulting mixture was granulated with aqueous solution of 3% w/w Polyvinylpyrrolidone K29/32 and 5% w/w HPMC in a granulator to obtain granules. The resulting granules
31

were extruded and spheronised to obtain spherical pellets of carbonyl iron. The pellets were dried in fluid bed dryer at 40°C and sieved through a 20# sieve and collected on a 40# sieve.
[Example 12 B]
Composition of carbonyl iron as spherical pellets was prepared according to the Example 12 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and Avicel® RC 591.
Payability Test
Palatability of the pellets of Examples 12 A and 12 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Pellets of Example 12 A: 3-4
Pellets of Example 12 B: 1-2
Dispersion test and swelling index
5 gms of the pellets of Example 12 A and 12 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
The swelling index of the pellets of each of Example 12 A and 12 B in water and simulated saliva was 200-500% w/w and less than 150% w/w respectively.
Friability test
Friability of 6 g of pellets of Example 12 A and 12 B was tested as in Example 2 and the friability was as follows :
Example 12 A : 0.29 %
Example 12 B : 0.24%
Example 13 Chlorpheniramine maleate composition as granules
[Example 13 A]
7.5% w/w of chlorpheniramine maleate was dry mixed with 10 % w/w Indion 414
32

(Ion Exchange India Ltd, Mumbai). 60.7% w/w mannitol, 0.4% w/w sodium lauryl sulfate and 0.2% w/w Polysorbate 80, 2% w/w aspartame, 2% w/w pineapple flavour, 2% w/w lake tartrazine, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w partially pregelatinised starch. The resulting powder was granulated with 5 % w/w of sucrose solution comprising 50% w/w sucrose in water in a granulator to obtain granules of chlorpheniramine maleate. The granules were sieved through a 8# sieve and dried in fluid bed dryer at 40°C. The granules were further sieved through a 20# sieve and collected on 80# sieve.
[Example 13 B]
Composition of chlorpheniramine maleate as granules was prepared according to the Example 13 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 13 A and 13 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Granules of Example 13 A: 3-4
Granules of Example 13 B: 1-2
Dispersion test
5 gms of the granules of Example 13 A and 13 B dispersed in 25 ml of each of water and simulated saliva in 5-15 seconds and 50-60 seconds respectively.
Example 14 Chlorpheniramine maleate composition as tablets
[Example 14 A]
7.5% w/w of chlorpheniramine maleate was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 40.7% w/w mannitol and 0.4% w/w sodium lauryl sulfate and 0.2% w/w Polysorbate 80, 2% w/w aspartame, 2% w/w pineapple flavour,
33

2% w/w lake tartrazine, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben, 6% w/w partially pregelatinised starch in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 20% w/w Avicel® PHI01. The resultant mixture was granulated using aqueous solution of 5% HPMC in a granulator. The granules were passed through 8# sieve and dried in fluidized bed dryer at 40°C. The dried granules were passed through 20#. The granules were then mixed with 3% w/w talc and 1% w/w magnesium stearate in blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 14 B]
Composition of chlorpheniramine maleate as tablet was prepared according to the Example 14 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol and partially pregelatinised starch.
Payability Test
Palatability of the tablets of Examples 14 A and 14 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Tablets of Example 14 A: 3-4
Tablets of Example 14 B: 1-2
Dispersion test
2 tablets of each of Example 14 A and 14 B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
Disintegration Test
6 tablets of each of Example 14 A and 14 B disintegrate in 1 minute and 3-4 minutes respectively.
34

Friability test
Friability of 6 g of tablets of Example 14 A and 14 B was tested as in Example 2 and the friability was as follows :
Example 14 A : 0.59 %
Example 14 B : 0.67 %
Example 15 Chlorpheniramine maleate composition as pellets
[Example 15 A]
7.5% w/w of chlorpheniramine maleate was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 43.7% w/w mannitol, 0.4% w/w sodium lauryl sulfate and 0.2% w/w Polysorbate 80, 2% w/w aspartame, 2% w/w pineapple flavour, 2% w/w lake tartrazine, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben, 2% w/w Pregelatinised starch in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 15% w/w Avicel® RC 591 in blender. The resulting mixture was granulated with aqueous solution of 5% w/w HPMC in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of chlorpheniramine maleate. The pellets were dried in fluid bed dryer at 40°C and sieved through a 20# sieve and collected on a 40# sieve.
[Example 15 B]
Composition of chlorpheniramine maleate as spherical pellets was prepared according to the Example 15 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of mannitol and Avicel® RC 591.
Palatability Test
Palatability of the pellets of Example 15 A and 15 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Pellets of Example 15 A: 3-4
Pellets of Example 15 B: 1-2
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Dispersion test and swelling index
5 gms of the pellets of Example 15 A and 15 B dispersed in 100 ml of water in 40 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 15 A and 15 B in water and simulated saliva was 200-600 % w/w and less than 300 % w/w respectively.
Friability test
Friability of 6 g of pellets of Example 15 A and Example 15 B was tested as in Example 2 and the friability was as follows :
Example 15 A: 0.29%
Example 15 B :0.12%
Example 16 Loratidine composition as granules
[Example 16 A]
10% w/w of loratidine was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 10% partially pregelatinized starch, 59.3% w/w xylitol, 2% w/w aspartame and 1.5% w/w sodium saccharin, 3% w/w orange flavour, 1% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The resulting powder was granulated with aqueous solution of 5% w/w of sucrose and 3% w/w Polyvinylpyrrolidone solution in a granulator to obtain granules of loratidine. The granules were sieved through a 8# sieve and dried in a fluid bed dryer at 40°C. The granules were further sieved through a 20# sieve and collected on a 80# sieve.
[Example 16 B]
Composition of loratidine as granules was prepared according to the Example 16 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of xylitol and partially pregelatinised starch.
36

Palatability Test
Palatability of the granules of Examples 16 A and 16 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Granules of Example 16 A: 4-5
Granules of Example 16 B: 2-3
Dispersion test
5 gms of the granules of Example 16 A and 16 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 60-70 seconds respectively.
Example 17 Loratidine composition as tablets
[Example 17 A]
10% w/w of loratidine was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 10% partially pregelatinized starch, 62.3% w/w of Pearlitol, 2% w/w aspartame and 1.5% w/w sodium saccharin, 3% w/w orange flavour, 1% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 1% colloidal silicon dioxide, 3% w/w talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 17 B]
Composition of loratidine as tablet was prepared according to the Example 17 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of Pearlitol and partially pregelatinised starch.
Palatability Test
Palatability of the tablets of Examples 17 A and 17 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Tablets of Example 17 A: 4-5
37

Tablets of Example 17 B: 2-3
Dispersion test
2 tablets of each of Example 17 A and 17 B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
Disintegration Test
6 tablets of each of Example 17 A and 17 B disintegrate in 1 minute and 3-4 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 17 A and Example 17 B was tested as in Example 2 and the friability was as follows :
Example 17 A: 0.42%
Example 17 B: 0.59%
Example 18 Loratidine composition as pellets
[Example 18 A]
10% w/w of loratidine was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 47.3% w/w xylitol, 2% w/w aspartame and 1.5% w/w sodium saccharin, 3% w/w orange flavour, 1% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 15% w/w Avicel® RC 591 in blender. The resulting mixture was granulated with aqueous solution of 5% w/w Polyvinylpyrrolidone in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of loratidine. The pellets were dried in fluid bed dryer at 40°C and sieved through a 20# sieve and collected on a 40# sieve.
38

[Example 18 B]
Composition of loratidine as spherical pellets was prepared according to the Example 18 A using sodium starch glycolate instead of Indion 414 and calcium phosphate, dibasic instead of xylitol and Avicel® RC 591.
Payability Test
Palatability of the pellets of Examples 18 A and 18 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Pellets of Example 18 A: 4-5
Pellets of Example 18 B: 2-3
Dispersion test and swelling index
5 gms of the pellets of Example 18 A and 18 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 18 A and 18 B in water and simulated saliva was 200-400% w/w and less than 100% w/w respectively.
Friability test
Friability of 6 g of tablets of Example 18 A and Example 18 B was tested as in Example 2 and the friability was as follows :
Example 18 A: 0.27%
Example 18 B: 0.30%
Example 19 Paracetamol composition as granules
[Example 19 A]
12.5% w/w of paracetamol taste masked using 12.5% w/w Crosslinked Polyvinylpyrrolidone was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 43.8% w/w dextrose, 2% w/w orange flavour, 2% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in
39

a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w partially pregelatinized starch. The resulting powder was granulated with aqueous solution of 5% sucrose and 5% HPMC in a granulator to obtain granules of paracetamol. The granules were sieved through a 8# sieve and dried in fluid bed dryer at 40°C. The granules were further sieved through a 40# sieve.
[Example 19 B]
Composition of paracetamol as granules was prepared according to the Example 19 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 19 A and 19 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Granules of Example 19 A: 4-5
Granules of Example 19 B: 2-3
Dispersion test
5 gms of the granules of Example 19 A and 19 B dispersed in 25 ml of each of water and simulated saliva in 5-20 seconds and 60-70 seconds respectively.
Example 20 Paracetamol composition as tablets
[Example 20 A]
25% w/w of paracetamol taste masked using 25% w/w Crosslinked Polyvinylpyrrolidone was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 4% partially pregelatinized starch, 31.8% w/w Pearlitol, 2% w/w aspartame and 2% w/w sodium sacharin, 2% w/w orange flavor, 1% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 2% w/w talc in a blender. The resulting composition was compressed into
40

tablets in a cadmach 8 station rotary machine.
[Example 20 B]
Composition of paracetamol as tablet was prepared according to the Example 20 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of pearlitol and partially pregelatinised starch.
Palatability Test
Palatability of the tablets of Examples 20 A and 20 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Tablets of Example 20 A: 4-5
Tablets of Example 20 B: 2-3
Dispersion test
2 tablets of each of Example 20 A and 20 B dispersed in 100 ml of water in 1-2 minutes and 5-6 minutes respectively.
Disintegration Test
6 tablets of each of Example 20 A and 20 B disintegrate in 1 minute and 3-4 minutes respectively.
Friability test
Friability of 6 g of tablets of Example 20 A and Example 20 B was tested as in Example 2 and the friability was as follows :
Example 20 A : 0.79 %
Example 20 B : 0.82 %
Example 21 Paracetamol composition as pellets
[Example 21 A]
12.5% w/w of paracetamol taste masked using 12.5% w/w Crosslinked
41

Polyvinylpyrrolidone was dry mixed with 5% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 38.8% w/w dextrose, 2% w/w aspartame and 2% w/w sodium saccharin, 2% w/w orange flavor and 3% w/w citric acid, 2% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 10% Avicel® RC 591 in a blender. The resulting mixture was granulated with water in a granulator to obtain granules. The resulting granules were extruded and spheronised in an extruder and spheronizer to obtain spherical pellets of paracetamol. The pellets were dried in fluid bed dryer at 40°C and sieved through a 20# sieve and collected on a 40# sieve.
[Example 21 B]
Composition of paracetamol as pellets was prepared according to the Example 21 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and Avicel® RC 591.
Payability Test
Palatability of the pellets of Examples 21 A and 21 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Pellets of Example 21 A: 4-5
Pellets of Example 21 B: 2-3
Dispersion test and swelling index
5 gms of pellets of Example 21 A and 21 B dispersed in 100 ml of water in 60 seconds and 4 minutes respectively.
The swelling index of the pellets of Example 21 A and 21 B was 200-400% w/w and less than 100% w/w respectively.
Friability test
Friability of 6 g of tablets of Example 21 A and Example 21 B was tested as in Example 2 and the friability was as follows :
Example 21 A: 0.18%
42

Example 21 B: 0.29%
Example 22 Ofloxacin composition as granules
[Example 22 A]
2.5% w/w of ofloxacin taste masked using 5% w/w ion exchange resin was dry mixed with 3% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 10% partially pregelatinized starch, 54.3% w/w dextrose, 1% w/w aspartame, 2% w/w orange flavour, 2% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The resulting powder was granulated with 20% w/w sucrose solution comprising 50% w/w of sucrose in water in a granulator to obtain granules of ofloxacin. The granules were sieved through a 8# sieve and dried in a fluid bed dryer at 40°C. The granules were further sieved through a 80# sieve.
[Example 22 B]
Composition of ofloxacin as granules was prepared according to the Example 22 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and partially pregelatinised starch.
Palatability Test
Palatability of the granules of Examples 22 A and 22 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Granules of Example 22 A: 4-5
Granules of Example 22 B: 2-3
Dispersion test
5 gms of the granules of Example 22 A and 22 B dispersed in 25 ml of each of water and simulated saliva in 5-10 seconds and 60-70 seconds respectively.
43

Example 23 Ofloxacin composition as tablets
[Example 23 A]
20% w/w of ofloxacin taste masked using 40% w/w ion exchange resin was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 2% partially pregelatinized starch, 18.8% w/w Pearlitol, 2% w/w aspartame, 2% w/w orange flavour, 2% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 3% w/w talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 23 B]
Composition of ofloxacin as tablet was prepared according to the Example 23 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of pearlitol and partially pregelatinised starch.
Payability Test
Palatability of the Tablets of Examples 23 A and 23 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Tablets of Example 23 A: 4-5
Tablets of Example 23 B: 2-3
Dispersion test
2 tablets of each of Example 23 A and 23 B dispersed in 100 ml of water in 60-70 seconds and 3-4 minutes respectively.
Disintegration Test
6 tablets of each of Example 23 A and 23 B disintegrate in 50-60 seconds and 2-3 minutes respectively.
44

Friability test
Friability of 6 g of tablets of Example 23 A and Example 23 B was tested as in Example 2 and the friability was as follows :
Example 23 A : 0.66 %
Example 23 B : 0.49 %
Example 24 Ofloxacin composition as pellets
[Example 24 A]
5% w/w of ofloxacin taste masked using 10% w/w ion exchange resin was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai). 41.8% w/w dextrose, 2% w/w aspartame, 2% w/w orange flavour, 2% w/w lake sunset yellow, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 12% w/w Avicel® RC 591 in a blender. The resulting mixture was granulated with aqueous 5% w/w HPMC solution in a granulator to obtain granules. The resulting granules were extruded and spheronised to obtain spherical pellets of ofloxacin. The pellets were dried in fluid bed dryer at 40°C and sieved through a 20# sieve and collected on a 40# sieve.
[Example 24 B]
Composition of ofloxacin as spherical pellets was prepared according to the Example 24 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of dextrose and Avicel® RC 591 partially pregelatinised starch.
Payability Test
Palatability of the pellets of Examples 24 A and 24 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Pellets of Example 24 A: 4-5
Pellets of Example 24 B: 2-3
45

Dispersion test and swelling index
5 gms of the pellets of Example 24 A and 24 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 24 A and 24 B was 200-400% w/w and less than 100% w/w respectively.
Friability test
Friability of 6 g of tablets of Example 24 A and Example 24 B was tested as in Example 2 and the friability was as follows :
Example 24 A: 0.13%
Example 24 B : 0.29 %
Example 25 Azithromycin composition as granules
[Example 25 A]
10% w/w of azithromycin taste masked using 30% w/w ion exchange resin was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd., Mumbai). 5% partially pregelatinized starch, 1% w/w sodium sachharin and 0.5% w/w monoammonium glycyrrhizinate, 2% w/w strawberry flavour, 2% w/w lake ponceau red, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 26.8 % w/w xylitol. The resulting powder was granulated with 12.5% w/w sucrose solution comprising 50% w/w of sucrose in water in a granulator to obtain granules of azithromycin. The granules were sieved through a 8# sieve and dried in fluid bed dryer at 40°C. The granules were further sieved through a 80# sieve.
[Example 25 B]
Composition of Azithromycin as granules was prepared according to the Example 25 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of xylitol and partially pregelatinised starch.
46

Palatability Test
Palatability of the granules of Examples 25 A and 25 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Granules of Example 25 A: 4-5
Granules of Example 25 B: 2-3
Dispersion test
5 gms of the granules of Example 25 A and 25 B dispersed in 25 ml of each of water and simulated saliva in 5-10 seconds and 50-60 seconds respectively.
Example 26 Azithromycin composition as tablets
[Example 26 A]
10% w/w of azithromycin taste masked using 30% w/w ion exchange resin was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd, Mumbai. 3% partially pregelatinized starch, 28.3% w/w Pearlitol, 1% w/w sodium sachharin and 0.5% w/w monoammonium glycyrrhizinate, 2% w/w strawberry flavour (salivating agent), 2% w/w lake ponceau red (colouring agent), 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben (preservative) in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 102, 2% w/w talc and 1% w/w magnesium stearate in a blender. The resulting composition was compressed into tablets in a cadmach 8 station rotary machine.
[Example 26 B]
Composition of Azithromycin as tablet was prepared according to the Example 26 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of pearlitol and partially pregelatinised starch.
Palatability Test
Palatability of the tablets of Examples 26 A and 26 B was tested on 25 volunteers as
47

in Example 1 and the scoring were as follows: Tablets of Example 26A: 4-5
Tablets of Example 26B: 2-3
Dispersion test
2 tablets of each of Example 26A and 26B dispersed in 100 ml of water in 1-2 minutes and 4-5 minutes respectively.
Disintegration Test
6 tablets of each of Example 26A and 26B disintegrate in 1 minute and 3-4 minutes respectively
Friability test
Friability of 6 g of tablets of Example 26 A and Example 26 B was tested as in Example 2 and the friability was as follows:
Example 26 A: 023o%
Example 26 B : 0.25%
Example 27 Azithromycin composition as pellets
[Example 27 A]
10% w/w of azithromycin taste masked using 30% w/w ion exchange resin was dry mixed with 10% w/w Indion 414 (Ion Exchange India Ltd., Mumbai). 17.3% w/w xylitol, 1% w/w sodium sachharin and 0.5% w/w monoammonium glycyrrhizinate, 2% w/w strawberry flavour, 2% w/w lake ponceau red, 0.18% w/w sodium methyl paraben and 0.02% w/w sodium propyl paraben (preservative) in a blender at temperature in the range of 25 to 35° C. The mixture was further dry mixed with 10% w/w Avicel® PH 101 and 12% w/w Avicel® RC 591 in a blender. The resulting mixture was granulated with aqueous 5% w/w HPMC solution in a granulator to obtain granules. The resulting granules were extruded and Spheronized to obtain spherical pellets of azithromycin. The pellets were dried in fluid bed dryer at 40°C
48

and sieved through a 20# sieve and collected on a 40# sieve.
[Example 27 B]
Composition of Azithromycin as spherical pellets was prepared according to the Example 27 A using sodium starch glycolate instead of Indion 414 and calcium phosphate dibasic instead of xylitol and Avicel® RC 591.
Payability Test
Palatability of the pellets of Examples 27 A and 27 B was tested on 25 volunteers as in Example 1 and the scoring were as follows:
Pellets of Example 27 A: 4-5
Pellets of Example 27 B: 2-3
Dispersion test and swelling index
5 gms of the pellets of Example 27 A and 27 B dispersed in 100 ml of water in 50 seconds and 3 minutes respectively.
The swelling index of the pellets of Example 27 A and 27 B was 200-400% w/w and less than 100% w/w respectively.
Friability test
Friability of 6 g of tablets of Example 27 A and Example 27 B was tested as in Example 2 and the friability was as follows :
Example 27 A : 0.25 %
Example 27 B : 0.29%
49

We claim :
1) Mouth dissolving pharmaceutical or neutraceutical composition comprising 1 to 70% by weight of at least one pharmaceutical or neutraceutical active and 30 to 99% by weight of pharmaceutical^ acceptable excipients including at least one potassium salt of cross linked acrylic polymer as super disintegrant in 1 to 30 % by weight of the pharmaceutically acceptable excipients, at least one partially pre-gelatinized starch or modified polysaccharide as a softening agent in 5 to 50 % by weight of the pharmaceutically acceptable excipients and at least one water soluble channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable excipients.
2) Mouth dissolving composition as claimed in claim 1, wherein the potassium salt of crosslinked acrylic polymer is Indion 414.
3) Mouth dissolving composition as claimed in claim 1, wherein the partially pre-gelatinized starch is Starch 1500.
4) Mouth dissolving composition as claimed in claim 1, wherein the modified polysaccharide is Avicel RC 591.
5) Mouth dissolving composition as claimed in claim 1, wherein the water soluble channelizing agent is selected from polysorbates or sodium lauryl sulfate or water soluble sugars such as dextrose, mannitol including xylitol or sucrose.
6) Mouth dissolving composition as claimed in claim 1, which comprises granules.
7) Mouth dissolving composition as claimed in claim 1, which comprises tablets.
8) Mouth dissolving composition as claimed in claim 1, which comprises pellets.
50

9) A method of making a mouth dissolving pharmaceutical or neutraceutical
composition as pellets, the method comprising
i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one
pharmaceutical or neutraceutical active with 30 to 99% w/w by weight of
pharmaceutically acceptable excipients including at least one potassium salt of
cross linked acrylic polymer as super disintegrant in 1 to 30 % by weight of
the pharmaceutically acceptable excipients, at least one partially pre-
gelatinized starch or modified polysaccharide as a softening agent in 5 to 50 %
by weight of the pharmaceutically acceptable excipients and at least one water
soluble channelizing agent in 2 to 90 % by weight of pharmaceutically
acceptable excipients;
ii) dry mixing the mixture obtained by step (i) with at least one spheronization
agent;
iii a) mixing the mixture obtained by step (ii) with a binder solution;
iv a) extruding and spheronising the composition obtained by step (iii a) to
obtain pellets; and
v a) drying the pellets obtained by step (iv a) at 35 to 100°C.
10) A method of making mouth dissolving composition as claimed in claim 9, wherein the potassium salt of crosslinked acrylic polymer is Indion 414.
11) A method of making mouth dissolving composition as claimed in claim 9, wherein the partially pre-gelatinized starch is Starch 1500.
12) A method of making mouth dissolving composition as claimed in claim 9, wherein the modified polysaccharide is Avicel RC 591.
13) A method of making mouth dissolving composition as claimed in claim 9, wherein the water soluble channelizing agent is selected from polysorbates or sodium lauryl sulfate or water soluble sugars such as dextrose, mannitol including xylitol or sucrose
51

14) A method of making a mouth dissolving pharmaceutical or neutraceutical
composition as granules, the method comprising
i) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one pharmaceutical
or neutraceutical active with 30 to 99% w/w by weight of pharmaceutically
acceptable excipients including at least one potassium salt of cross linked
acrylic polymer as super disintegrant in 1 to 30 % by weight of the
pharmaceutically acceptable excipients, at least one partially pre-gelatinized
starch or modified polysaccharide as a softening agent in 5 to 50 % by weight
of the pharmaceutically acceptable excipients and at least one water soluble
channelizing agent in 2 to 90 % by weight of pharmaceutically acceptable
excipients;
ii) dry mixing the mixture obtained in step (i) with at least one diluent;
iii b) mixing the mixture of step (ii) with a binder solution to form granules;
iv b) sieving the granules obtained by step (iii b);
v b) drying the granules of step (iv b) at 35 to 100° C; and
vi b) sieving the granules obtained by step (v b).
15) A method of making mouth dissolving composition as claimed in claim 14, wherein the potassium salt of crosslinked acrylic polymer is Indion 414.
16) A method of making mouth dissolving composition as claimed in claim 14, wherein the partially pre-gelatinized starch is Starch 1500.
17) A method of making mouth dissolving composition as claimed in claim 14, wherein the modified polysaccharide is Avicel RC 591.
18) A method of making mouth dissolving composition as claimed in claim 14, wherein the water soluble channelizing agent is selected from polysorbates or sodium lauryl sulfate or water soluble sugars such as dextrose, mannitol including pearlitol, xylitol or sucrose
52

19) A method of making a mouth dissolving pharmaceutical or neutraceutical
composition as tablets, the method comprising
i ) dry mixing at 25 to 45° C, 1 to 70% by weight of at least one
pharmaceutical or neutral active With 30 to 99% W/W by Weight of
pharmaceutically acceptable excipients including at least One potassium salt of cross linked acrylic polymer as super disintegrant in 1 to 30 % by weight of
the pharmaceutically acceptable excipients, at least one partially pre-
gelatinized starch or modified polysaccharide as a softening agent in 5 to 50 %
by weight of the pharmaceutically acceptable excipients and at least one water
soluble channelizing agent in 2 to 90 % by weight of pharmaceutically
acceptable excipients;
ii) dry mixing the mixture obtained by step (i) with at least one tabletting agent
and at least one lubricating agent; and
iii c) compressing the mixture obtained by step (ii) into tablets.
20) A method of making mouth dissolving composition as claimed in claim 19, wherein the potassium salt of crosslinked acrylic polymer is Indion 414.
21) A method of making mouth dissolving composition as claimed in claim 19, wherein the partially pre-gelatinized starch is Starch 1500.
22) A method of making mouth dissolving composition as claimed in claim 19, wherein the modified polysaccharide is Avicel RC 591.
23) A method of making mouth dissolving composition as claimed in claim 19, wherein the water soluble channelizing agent is selected from polysorbates or sodium lauryl sulfate or water soluble sugars such as dextrose, mannitol including xylitol or sucrose.
24) A method of making a mouth dissolving pharmaceutical or neutraceutical composition as tablets as claimed in claim 19, wherein the dry mixture obtained by step (i) is granulated with solution of a granulating agent or binder
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followed by mixing the granules with a tabletting agent and compressing the granules into tablets.
Dated this 15th day of December 2006
(Dr Shilpa Gharve)
of Khaitan & Co
Agent for the Applicants
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