FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)
"PROCESS FOR THE PREPARATION OF SALIVA-RAPIDLY-ERODIBLE
TABLET"
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAl-400059, MAHARASHTRA, INDIA

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.



2002

PROCESS FOR THE PREPARATION OF SALIVA-RAPIDLY-ERODIBLE
TABLET
The present invention relates to a process for the preparation of a saliva-rapidly-erodible tablet.
BACKGROUND OF THE INVENTION
Most pharmaceutical dosage forms for oral administration, such as tablets and capsules, are formulated to be chewed or swallowed. Elderly people and children sometimes have difficulty swallowing or chewing such dosage forms. This problem is even more serious in bedridden patients. Such difficulties may also arise for active working people who have no access to water. These problems can be resolved by rapidly disintegrating or dissolving dosage forms which dissolve or disintegrate rapidly in the mouth without chewing or the need for water within a short time frame. Because of their ease of administration, such compositions are particularly useful for the specific needs of pediatrics, geriatrics, and patients with dysphagia. Thus rapidly disintegrating or dissolving dosage form combines the advantages of both liquid and conventional tablet formulations, while also offering advantages over both the traditional dosage forms. They offer the convenience of a tablet formulation, while also allowing ease of swallowing provided by a liquid formulation and allow the luxury of much more accurate dosing than the oral liquids.
United States Patent No. 4,642,903, 5,188,825, 5,631,023, and 5,738,875 (R. P. Scherer Corporation) use lyophilization (freeze drying) process to make an amorphous, porous structure which dissolves rapidly. The process involves freeze-drying an aqueous suspension of the drug and excipients, which is then dispensed into blister packs and the water is removed by a freeze-drying step. These kind of dosage forms are costly to manufacture and difficult to package because of the tablet sensitivity to moisture and temperature. Also they are difficult to transport and handle due to the insufficient hardness of the tablets. Further, the process is not suitable for a drug that has low water solubility and a relatively high dose.
2

United States Patent No. 6,284,272 (Chiesi Farmaceutici) claims effervescent fast dissolving tablets comprising levodopa methyl ester and carbidopa, acidic component selected from fumaric acid, maleic acid or their salts, alkaline component which is sodium glycine carbonate and other excipients. The use of effervescent mixtures of acids and carbonates makes the tablet bulky as well as sensitive to humidity and temperature. The present invention avoids the use of effervescent mixtures.
United States Patent No. 5,587,172, 5,622,719, 5,851,553, 5,869,098 and 5,871,781 (Fuisz Technologies Ltd.) disclose quick dissolve/quick disperse units comprising Shearform matrix prepared by flash-flow processing of a feedstock which contains a carrier material. Shearform® is a cotton candy-like substance of mixed polysaccharides converted to amorphous fibers. The dosage form prepared by these techniques does not erode with water but melts in the mouth. This kind of technology requires specialized and precision-engineered equipment.
United States Patent No. 5,139,790 (Zetachron Inc.) discloses a buccal dosage form which disperses rapidly in the buccal cavity at body temperature. The dosage form comprises a low molecular weight and a medium to high molecular weight polyethylene glycol (PEG), a long chain carboxylic acid, colloidal silica and polyethylene oxide. When the dosage form is kept in the mouth, the PEG matrix is rapidly warmed to its melting point whereupon it melts and disintegrates within the buccal cavity. But these kind of low-melting dosage forms are sensitive to humidity and temperature and may be softened or deformed during shipping and storage. Moreover these dosage forms require individual blister packing which can be expensive.
United States Patent No. 5,466,464 (Yamanouchi Pharmaceutical Co., Ltd), 5,298,261 (Oregon Freeze Dry, Inc.), United States Patent No. 6,083,531 (Novartis Consumer Health S.A.) PCT Application No. 0247607 (Ranbaxy Laboratories Ltd.) describe fast dissolving or fast disintegrating molded tablets wherein the suspension or solution of the active ingredient with other excipients is dispensed into molds and dried by storage at
3

room temperature or even by freeze-drying. The process for making of such formulations is time consuming and slow.
United States Patent No. 5,576,014 (Yamanouchi Pharmaceutical Co., Ltd) discloses buccally quick dissolving tablets having a combination of a low moldability saccharide and a high moldability saccharide. This patent teaches that disintegration and dissolution of conventional compressed tablets in the buccal cavity is generally not quick or sufficient. The inventors of this patent used a saccharide of low moldability which imparted fast dissolution but insufficient hardness to the tablet when used alone and a saccharide of high moldability which imparted excellent moldability but inferior dissolution to the tablet when used alone, in combination to obtain tablets of adequate hardness and quick dissolution. These tablets are quick dissolving because of the dissolution of the saccharides in mouth and the excipients used in these tablets are soluble in water. Thus these tablets do not disintegrate or erode rapidly through a surface erosion process but dissolve in the mouth. The tablets of the '014 invention are not suitable for drugs that are not readily soluble in water and have a relatively high dose.
United States Patent No. 5,085,869 (Gist-Brocades N. V.) discloses tablets having microcrystalline cellulose filler and 0-0.5% binder. The patent recommends the avoidance of binder or low concentration (0-0.5% w/w) of binder for achieving rapid disintegration. However, binders function in a tablet formulation to produce tablets having the desired hardness, friability such that they maintain physical integrity during the process of manufacturing, packaging, handling and transport.
Hence there exists a need for saliva-rapidly-erodible tablets that can be made by simple, cost-effective conventional processes such as wet granulation, dry granulation or direct granulation.
OBJECT OF THE INVENTION
It is the object of the present invention to provide a process for the preparation of saliva-rapidly-erodible tablet, comprising mixing a drug, a binder and water dispersible excipient and converting the mixture to saliva-rapidly-erodible tablet by a conventional
4

wet granulation, dry granulation or direct compression process, wherein said saliva-rapidly-erodible tablet is devoid of effervescent agents or low melting compounds, wherein the erosion of the tablet in the mouth is characterized by rapid uptake of fluid by the tablet whereby the tablet rapidly erodes until complete erosion of the tablet occurs in less than three minutes, wherein the water dispersible excipient comprises a disintegrant, a wicking agent, and optionally a filler, and further wherein the process excludes a freeze-drying step and the melt-granulation process. It is further object of the present invention to provide a process for the preparation of the aforesaid saliva-rapidly-erodible tablets suitable for drugs that are not readily soluble in water and have relatively high dose. It is further the object of the invention to provide a process for the preparation of such a saliva-rapidly-erodible tablet comprising levodopa and carbidopa for the treatment of parkinsonism. It is another further object of the invention to provide a process for the preparation of saliva-rapidly-erodible tablets that have a good mouth feel and taste.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a process for the preparation of saliva-rapidly-erodible tablet that uses conventional excipients used in making tablets by conventional processes such as wet granulation, dry granulation or direct granulation wherein optimally effective quantities of binders are used. Accordingly the present invention provides a process for the preparation of saliva-rapidly-erodible tablet, comprising mixing a drug, a binder and water dispersible excipient and converting the mixture to saliva-rapidly-erodible tablet by a conventional wet granulation, dry granulation or direct compression process, wherein said saliva-rapidly-erodible tablet is devoid of effervescent agents or low melting compounds, wherein the erosion of the tablet in the mouth is characterized by rapid uptake of fluid by the tablet whereby the tablet rapidly erodes until complete erosion of the tablet occurs in less than three minutes, wherein the water dispersible excipient comprises a disintegrant, a wicking agent, and optionally a filler, and further wherein the process excludes a freeze-drying step and the melt-granulation process.
The term "devoid of effervescent agents or low melting compounds" as used herein means that the saliva-rapidly-erodible tablet of the present invention contains
5

effervescent agents or low melting compounds in amounts not more than about 5% w/w. Preferably the effervescent agents or low melting compounds may be present in amounts not more than about 3% w/w. It is most preferred that the formulation is devoid of such effervescent agents or low melting compounds. The term low melting compound as used herein refers to any pharmaceutically acceptable excipient that would soften in the mouth by partial or complete fusion.
Drugs that may be used in the present invention include drugs that require rapid delivery into the systemic circulation or drugs that are absorbable through the oral mucosa or drugs that are meant to be administered to children, the elderly and bedridden patients who otherwise have difficulty in swallowing oral tablets. The drug may be used in an amount suitable for therapy in humans. Examples of drugs that can be incorporated in the present invention are given below.
Adrenocorticosteroids such as dexamethasone acetate; methylprednisolone.
Agents to prevent alcohol abuse such as acamprosate; betahistine; disulfiram; naltrexone;
nalmefine; ondansetron; sodium oxybate.
Amino acids such as alanine; aspartic acid; cysteine; histidine; isoleucine; leucine; lysine; methionine; phenylalanine; proline; serine; threonine; tryptophan; tyrosine; valine. Active ingredients for ammonium detoxification such as arginine; arginine glutamate; arginine hydrochloride; glutamic acid.
Analgesics such as aceclofenac; acemetacin; acetaminophen; ademetionine; alefacept; alemtuzumab; alicaforsen; aminobenzoate; amiprilose; amlexanox; ampiroxicam; amtolmetin guacil; anakinra; antipyrine; aspirin; azelastine; basalazide; bromfenac; carbamazepine; celecoxib; cilomilast; cladribine; codeine; codeine phosphate; codeine sulfate; deligoparin sodium; denileukin diftitox; diflunisal; dihydrocodeine; dexketoprofen trometamol; diacerein; diclofenac potassium; etodolac; etoricoxib; fenoprofen; fenoprofen calcium; fenretinide; fenspiride; fepradinol; flobufen; flurbiprofen; hydromorphone; ibuprofen; iloprost; indomethacin farnesil; infliximab; interferon beta-la; levorphanol; lonazolac; lornoxicam; loteprednol etabonate; lumiracoxib; magnesium salicylate; malotilate; meloxicam; meperidine; methadone; mizoribine; morphine sulfate; mofezolac; mycophenolate mofetil; nabumetone;
6

nalmefene; naproxen; nimesulide; oxaprozin; oxycodone; oxycodone hydrochloride;
oxycodone terephthalate; oxymorphone; parecoxib; pentazocine; pentosan poiysulfate
sodium; pentoxifylline; pexelizumab; phenazopyridine; pimecrolinus; piroxicam;
pranoprofen; proglumetacin; propoxyphene; propoxyphene napsylate; rofecoxib;
roflumilast; tacrolimus; tenoxicam; tramadol; trimetrexate; tropesin; valdecoxib;
verteporfin; zaltoprofen; zileuton.
Androgens such as methyltestosterone; oxandrolone; oxymetholone; prasterone;
stanozolol; testosterone; testosterone cypionate; testosterone enanthate; testosterone
ketolaurate; testosterone phenylacetate; testosterone propionate.
Appetite suppressants (anorectics) such as mazindol; orlistat; phendimetrazine; phentermine; sibutramine.
Anthelmintics such as albendazole; albendazole oxide; cambendazole; carbantel; diethylcarbamazine; fenbendazole; flubendazole; flurantel; furodazole; ivermectin; levamisol; mebendazole; oxibendazole; piperazine adipate; piperazine calcium edetate; pyrantel pamoate; pyrantel tartrate; rafoxanide; thiabendazole.
Alpha I antagonists such as alfuzosin; bunazosin; dapiprazole; doxazosin; idazoxan;
indoramine; metazosin; mirtazapine; nefazodone; phentolamine; prazosin; reboxetine;
setiptiline; sildosin; tamsulosin; terazosin; urapidil; yohimbine.
ACE inhibitors such as alacepril; benazepril; benazeprilat; captopril; cilazapril;
cilazaprilat; delapril; enalapril; fosinopril; fosinoprilat; imidapril; imidaprilat; lisinopril;
moexipril; omapatrilat; perindopril; quinapril; quinaprilat; ramipril; spirapril; spiraprilat;
temocapril; temocaprilat; trandolapril; trandolaprilat; zofenopril; zofenoprilat.
Antiasthamatics (leukotriene antagonists) such as amalubant; cromolyn; montelukast;
pranlukast; zafirlukast.
Antiasthamatics (5 lipoxygenase inhibitor) such as linazolast; tepoxalin; ziteuton. Antihistamines such as acitazanolast; acrivastine; amlexanox; azatadine; bepotastine; brompheniramine maleate; cetirizine; chlorpheniramine maleate; chlorpheniramine polistirex; clemastine; cyproheptadine; desloratadine; diphenhydramine; doxylamine succinate; efletirizine; emedastine; ebastine; epinastine; fexofenadine; levocabastine; levocetirizine; loratadine; mizolastine; olopatadine; orphenadrine citrate; pheniramine maleate; pyrilamine maleate; rupatadine; tecastemizole; terfenadine; triprolidine.
7

Antiandrogens such as bicalutamide; nilutamide; osaterone.
Antianemics such as clotrimazole; darbepoetin alfa; epoetin alfa; epoetin beta; epoetin epsilon; epoetin gamma; epoetin omega; ferrous sulfate; folic acid; glutathione monoisopropyl ester; iron protein succinylate; leucovorin calcium; lenograstim. Antianginals (nitrates) such as isosorbide mononitrate; isosorbide dinitrate; nitroglycerine.
Anxiolytics such as abecarnil; aprepitant; buspirone; clobazam; dermaciclane; etizolam; gepirone; midazolam; ondansetron; pagoclone; siltopride; tandospirone citrate; tofisopam.
Antiarthritics (tyrosine kinase inhibitors) such as leflunomide; teriflunomide. Anticonvulsants such as benzobarbital carbamazepine; clobazam; clonazepam; divalproex sodium; ethosuximide; felbamate; flunarizine; fosphenytoin sodium; gabapentin; lamotrigine; levetiracetam; losigamon; mephobarbital; methsuximide; midazolam; oxcarbazepine; phenobarbital; phenytoin; phenytoin sodium; pregabalin; primidone; remacemide; tiagabine; topiramate; valproate sodium; valproic acid; vigabatrin; zonisamide.
Antidepressants such as adrafinil; amitriptyline; amoxapine; aprepitant; bupropion; buspirone hydrochloride; citalopram; clomipramine; desipramine; doxepin; duloxetine; escitalopram; flumazenil; fluoxetine; fluvoxamine; gepirone; imipramine; maprotiline; milnacipran; minaprine; mirtazapine; moclobemide; nefazodone; nortriptyline; paroxetine; phenelzine sulfate; pirlindole; pivagabine; reboxetine; sertraline; setiptiline; tianeptine; trazodone; trimipramine; trimipramine maleate; venlafaxine. Antidiabetics such as acarbose; acetohexamide; buformin; carbutamide; chlorpropamide; ciglitazone; darglitazone; englitazone; glipizide; glyburide (glibenclamide); glimepiride; gliclazide; glibornuride; gliquidone; glisoxepid; glyhexamide; emiglitate; metformin; miglitol; phenbutamide; phenformin; pioglitazone; repaglinide; rosiglitazone; tolazamide; tolbutamide; tolcyclamide; troglitazone; voglibose.
Aldose reductase inhibitors such as pioglitazone; rosiglitazone.
Antidiuretics such as argipressin tannate; desmopressin acetate; lypressin; tolterodine.
Antialopecia agents like finasteride.
Antiemetics such as azasetron; chlorpromazine; clebopride; dolasetron mesilate;
8

domperidone; dronabinol; granisetron; indisetron; lerisetron; levosulpride; meclizine;
metoclopramide; ondansetron; palonosetron; promethazine; ramosetron; scopalamine;
triflupromazine; tropisetron.
Antiestrogens (non-steroidal) such as raloxifen; tamoxifen citrate; toremifene citrate. Antihypertensives such as amlodipine; amlodipine besylate; aranidipine; azelnidipine; barnidipine; bendroflumethiazide; benidipine; candesartan cilexetil; carvedilol; chlorthiazide sodium; cilnidipine; clonidine; diltiazem malate; efonidipine; enalapril maleate; enalaprilat; eprosartan mesilate; felodipine; fosinopril sodium; gallopamil; guanabenz acetate; guanfacine; hydralazine; hydroflumethiazide; indapamide; irbesartan; isradipine; lacidipine; lercanidipine; lisinopril; lofexidine; losartan; mecamylamine; manidipine; methyclothiazide; methyldopa; metolazone; metoprolol tartarate; metoprolol succinate; metyrosine; minoxidil; nifedipine; nilvadipine; nisoldipine; nitrendipine; phenoxybenzamine; pranidipine; ramipril; rauwolfia serpentina; reserpine; riodipine; semotiadil; valsartan; verapamil.
Antiinflammatory agents such as aceclofenac; acemannan; acemetacin; adaimumab; ademetionine; alefacept; alpha amylase; amelometasone; ampiroxicam; amtolmetin guacil; balsalazide disodium; bromfenac; budesonide; celecoxib; clobetasone butyrate; dexamethazone dipropionate; dexketoprofen trometamol; diclofenac; diclofenac potassium; etodolac; fenspiride; flurbiprofen axetil; halopredone; ibuprofen; indomethacin; ketoprofen; licofelone; lonazolac; lornoxicam; loteprednol; malotilate; meclofenamate; meloxicam; methylprednisolone; mesalamine; misoprostol; mofezolac; nabumetone; nimesulide; olsalazine sodium; oxaprozin; pentosan polysulfate sodium; pexelizumab; piroxicam proglumetacin; rimexolone; salsalate; sulindac; rofecoxib; tenoxicam; tilmacoxib; tolmetin; tropesin; zaltoprofen.
Antimigraine agents such as almotriptan; azatadine; bromocriptine; dotarizine; eletriptan;
ergotamine; frovatriptan; metoclopramide-naproxen combination; naratriptan;
nimodipine; rizatriptan; sumatriptan; zolmitriptan.
Active ingredients for sea sickness and vomiting such as buclizine; cyclizine lactate; naboctate.
Antiparkinson agents such as apomorphine; benztropine mesilate; budipine; cabergoline; entacapon; etilevodopa; glatiramer acetate; idazoxan; iometopane; leteprinim; levodopa;
9

levodopa-carbidopa combination; melevodopa; pergolide mesylate; pramipexole;
procaine; rasagiline; ramacemide; riluzole; ropinirole; selegiline; sinnabidol; talipexole;
tolcapone.
Antiperistaltic agents such as difenoxin; diphenoxylate; loperamide.
Antitussives such as acetylcysteine; ambroxol; benzonatate; codeine; dextromethorphan;
erdosteine; fudostrine; hydrocodone; hydrocodone polistirex; stepronin; telmesteine.
Antiulcer agents such as camostat; cimetidine; clarithromycin; dosmalfate; ebrotidine;
ecabet; egualen; famotidine; gastrin 17 immunogen; irsogladine; lafutidine;
metronidazole-amoxicillin combination;; misoprostol; niperotidine; nizatidine;
omoprostil; pibutidine; polaprezinc; ranitidine; ranitidine bismuth citrate; ranitidine
nitrate; rebamipide; roxatidine; sucralfate.
Active ingredients for treating osteoporosis such as alendronic acid; alfacalcidol;
bazedoxifen; clodronic acid; doxercalciferol; elcatonin; falecalcitriol; ibandronic acid;
incadronic acid; ipriflavone; lasofoxifene; menatetrenone; minodronic acid; neridronic
acid; pamidronic acid; raloxifene; ranelic acid; risedronic acid; secalciferol; simvastatin;
somatropin; tariparatide; tiludronic acid; trafermin; zoledronic acid.
Antiarrhythmics such as amiodarone; disopyramide; dofetilide; flecainide; mexiletine;
procainamide; propafenone; quinidine; quinidine sulfate; tocainide.
Bronchodilators such as bambuterol; cilomilast; colforsin dapropate; dyphylline;
fenspiride; levosalbutamol; metaproterenol; salbutamol; salmeterol; salmeterol xinafoate;
theophylline; terbutaline; theophylline ethylenediamine; tiotropium bromide; tulobuterol.
Beta-blockers such as acebutolol; albuterol; amosulalob; arotinolol; atenolol; betaxolol;
bevantolol; bisoprolol; bopindolol; carteolol; carvedilol; celiprolol; esmolol;
hydroxycarteolol; hydroxytertatolol; labetalol; landiolol; levobetaxolol; levobunolol;
metoprolol; nadolol; nebivolol; penbutolol; propranolol; sotalol; tertatolol; tilisolol;
timolol.
Carbonic anhydrase inhibitors such as acetazolamide; dichlorphenamide; dorzolamide;
methazolamide.
Calcium regulators such as alfacalcidol; calcifediol; calcitriol; dihydrotachysterol;
doxercalciferol.
Cardiotonics such as digoxin.
10

Cerebrotonics such as cevimeline; donepezil; rivastigmine.
Cholinergic agents such as bethanechol chloride; neostigmine bromide; pyridostigmine
bromide.
Cholinesterase inhibitors such as acetohydroxamic acid.
Cytostatics such as altretamine; busulfan; capecitabine; chlorambucil; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin; erbulozole; esorubicin; estramustine;
etoposide; exemestane; hydroxyurea; letrozole; lomustine; megestrol acetate; melphalan;
mercaptopurine; methotrexate; methotrexate sodium; procarbazine; testolactone;
thioguanine.
Diuretics such as acetothiazide; alilusem; amiloride; azosemide; bumetanide; cicletanine;
chlorothiazide; chlorthalidone; ethacrynic acid; furosemide; hydrochlorothiazide;
polythiazide; spironolactone; torsemide; triamterene.
Enzyme inhibitors such as perindopril.
Estrogens such as estradiol cypionate; estradiol enanthate; estradiol undecylate; estradiol
valerate; estropipate; ethinyl estradiol; mestranol.
Fibrinolytics such as alteplase; amediplase; anistreplase; dermatan sulfate; monteplase;
nasaruplase; nateplase; pamiteplase; prourokinase; reteplase; silteplase; tenecteplase,
tisokinase.
Fungistatics such as fluconazole; flucytosine; griseofulvin; itraconazole; nystatin;
terbinafine; terconazole.
Glucocorticosteroids such as betamethasone; cortisone acetate; fludrocortisone;
hydrocortisone; hydrocortisone acetate; prednisolone; prednisolone sodium phosphate;
prednisone; triamcinolone; triamcinolone acetonide; triamcinolone diacetate;
triamcinolone hexacetonide.
Hemostatics such as aminocaproic acid.
Hormones such as medroxyprogesterone; norgestrel; norethynodrel; estradiol; megestrol;
norethindrone; levonorgestrel; ethyndiol; ethinyl estradiol; mestranol; estrone;
clomiphene; tamoxifen.
HMG-CoA reductase inhibitors such as atorvastatin; fluvasatin (Lescol); lovastatin
(Mevacor); pravastatin (Pravachol); simvastatin (Zocor).
Immunosuppressants such as azathioprine; cyclosporine.
11

Lipid-lowering agents such as acipimox; atorvastatin; avasimibe; cerivastatin;
ciprofibrate; colesevelam; colestilan; colestipol; fenofibrate; fluvastatin sodium;
gemfibrozil; lovastatin; niacin; orlistat; pitavastatin; policosanol; pravastatin; probucol;
rosuvastatin; simvastatin.
Active ingredients for treating impotence such as alprostadil; apomorphine; ascorbyl
gamolenate; midodrine; phentolamine; prazosin; sertraline; sildenafil; yohimbin.
Microbicides such as aztreonam; chlorhexidine gluconate; imidurea; lycetamine;
nibroxane; pirazmonam sodium; propionic acid; pyrithione sodium; sanguinarium
chloride; tigemonam dicholine.
Motility-increasing active ingredients such as cinitapride; cisapride (Propulsid);
clebopride; itopride; metoclopramide (Reglan); hyoscyamine; mosapride; prucalopride;
tegaserod.
Mucolytics such as acetylcysteine; ambroxol; erdosteine; erythromycin salnacedin;
fudosteine; neltenexine; ozagrel; stepronin; telmesteine; tiopronin.
Neuroleptics such as amisulpride; aripiprazole; blonanserin; bromperidol;
chlorpromazine; chlorpromazine hydrochloride; clozapine; fluphenazine decanoate;
fluspiperone; fluspirilene; flutroline; haloperidol; isofloxythepin; levosulpiride;
mesoridazine; molindone; mosapramine; nemonapride; olanzapine; perospirone;
perphenazine; pimozide; pramipexole; prochlorperazine; prochlorperazine maleate;
quetiapine; rimonabant; risperidone; sertindole; terguride; thioridazine; thioridazine
hydrochloride; thiothixene; trifluoperazine; triflupromazine; ziprasidone; zotepine.
Agent for treating Paget's disease such as etidronate; risedronate; tiludronate.
Progestins such as desogestrel; ethynodiol diacetate; norgestimate; norgestrel.
Psoriasis active ingredients such as acitretin; methoxsalen.
Muscle relaxants such as baclofen; carisoprodol; chlorzoxazone; cyclobenzaprine;
dantrolene; flavoxate; lanperisone; metaxalone; tizanidine.
Renin antagonists such as aliskiren; ditekiren; terlakiren; zankiren.
Sedatives such as propiomazine.
Hypnotics/sedatives: alprazolam; butabarbital; butabarbital sodium; butalbital; chloral
hydrate; chlordiazepoxide; diazepam; dichloralphenazone; flurazepam; estazolam;
meprobamate; pentobarbital; triazolam; zaleplon; Zolpidem tartrate.
12

Stimulants such as adrafinil; amphetamine sulfate; caffeine; dextroamphetamine; dextroamphetamine sulfate; flumazenil; methamphetamine hydrochloride; methylphenidate; modafinil; pemoline.
Antithrombotic such as abciximab; acadesine; alprostadil; alteplase; anagrelide; ancrod; anistreplase; antithrombin HI; ardeparin sodium; argatroban; bemiparin sodium; beraprost; bivalirudin; camonagrel; certoparin sodium; cilostazol; clopidogrel bisulfate; cloricromen; dalteparin sodium; domitroban; danaparoid sodium; deligoparin sodium; dermatan sulfate; desirudin; domitroban; enoxaparin sodium; epoprostenol; eptifibatide; ethyl eicosapentaenoate; fondaparinux sodium; iloprost; indobufen; lamifiban; lanoteplase; lepirudin; levosimendan; lexipafant; linsidomine; melagatran; monteplase; nadroparin calcium; nafamostat; nasaruplase; nateplase; ozagrel; pamicogrel; pamiteplase; parnaparin sodium; pimobendan; prourokinase; reteplase; reviparin sodium; roxifiban; sarpogrelate; saruplase; silteplase; tenecteplase; tezosentan; thrombomodulin; ticlopidine hydrochloride; tifacogin; tinzaparin sodium; tirofiban; tisokinase; triflusal; ximelagatran.
Tranquilizers such as bromazepam; buspirone; chlordiazepoxide; hydroxyzine; hydroxyzine pamoate; ketazolam; lorazepam; loxapine; loxapine succinate; oxazepam; temazepam.
Uricosuric agents such as probenecid.
Vasoconstrictors such as phenylephrine; phenylpropanolamine.
Vasodilators such as alprostadil; diltiazem; dipyridamole; felodipine; inositol niacinate; isoxsuprine; nicardipine; nicorandil; nifedipine; nimodipine; nisoldipine; pentoxifylline; pindolol.
Virustatic agents such as abacavir; acyclovir; amantadine hydrochloride; didanosine;
efavirenz; famciclovir; ganciclovir; indinavir sulfate; lamivudine; nelfinavir mesylate;
oseltamivir phosphate; rimantadine hydrochloride; saquinavir mesylate; stavudine;
valacyclovir hydrochloride; zalcitabine; zidovudine.
Xanthine oxidase inhibitors such as allopurinol; oxypurinol.
In a preferred embodiment, antiparkinsonism drugs are used, preferably comprising a mixture of (-)-L-alpha-amino-beta-(3,4-dihydroxybenzene) propanoic acid (levodopa)
13

and (-)-L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxybenzene) propanoic acid
(carbidopa). The (-)-L-alpha-amino-beta-(3,4-dihydroxybenzene) propanoic acid and (-)-
L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxybenzene) propanoic acid are
preferably used in a (3-12): 1 mass to mass ratio in the present invention. The term "(-)-
L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxybenzene) propanoic acid"
encompasses both the anhydrous carbidopa and its monohydrate.
The saliva-rapidly-erodible tablets of the present invention are prepared by well-tested, commercially successful conventional processes and yet provide the desired properties required in tablets meant for ready disintegration in the mouth. They can be made by using conventionally processed excipients that are well known to those skilled in the art. However this should not be understood to limit the scope of the invention because special excipients processed to be suitable for rapidly disintegrating or rapidly dissolving tablets and that are well known in the art may also be used. For example, one may use spray-dried or freeze-dried excipients. The present invention however now discloses art that makes it possible to make saliva-rapidly-erodible tablets even with conventional excipients, conventional processes and without the use of effervescent agents or low-melting compounds, and particularly for drugs that are not readily soluble in water and have a high dose. A particular advantage of the present invention is its usefulness in providing saliva-rapidly-erodible tablets with excellent desirable properties such as mouth feel, rapid disintegration and taste even for drugs that are not readily soluble in water/saliva and also have a high dose.
In embodiments of the present invention wherein the saliva-rapidly-erodible tablets comprise drugs that are not readily soluble in water and have a high dose, the amount of drug used more preferably comprises from about 40% to about 70% by weight of the composition.
The saliva-rapidly-erodible tablets of the present invention use binders to obtain optimum hardness and friability. Examples of binders that may be used in the present invention include starch, gelatin, sugars such as sucrose, glucose, dextrose, molasses, lactose, and
14

the like, dextrin, maltodextrin, natural and synthetic gums like acacia, alginic acid, sodium alginate, guar gum, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, veegum, arabogalactan and the like and mixtures thereof. The preferred binder used in the present invention is polyvinylpyrrolidone. The polyvinylpyrrolidone is preferably used in an amount ranging from about 0.1% w/w to about 10% w/w. It is more preferred that the polyvinylpyrrolidone be used in an amount ranging from about 0.5% w/w to about 5% w/w.
Water dispersible excipients used in the saliva-rapidly-erodible tablets of the present invention include all pharmaceutically acceptable water insoluble excipients as well as pharmaceutically acceptable water-soluble excipients, which disperse in water to form solutions, suspensions, films or colloids. The water dispersible excipients used in the present invention include a disintegrant, a wicking agent, a filler and the like and mixtures thereof. The water dispersible excipient is used in the present invention in an amount ranging from about 0.1% w/w to about 99% w/w. It is used more preferably in an amount ranging from about 20% w/w to about 99% w/w.
Disintegrants are pharmaceutically acceptable excipients that have been traditionally used to cause compressed tablets to disintegrate in the gastric fluids in the stomach. Examples of disintegrants that may be used in the present invention include starches, clays, Veegum HV, methylcellulose, agar, bentonite, cellulose and wood products, cation exchange resins, alginic acid, sodium alginate, guar gum, citrus pulp, methylcellulose, carboxymethylcellulose, microcrystalline cellulose, colloidal silicon dioxide, polacrilin potassium, super disintegrants like croscarmellose, crospovidone and sodium starch glycolate and the like and mixtures thereof. The preferred disintegrant in the present invention comprises a mixture of a conventional disintegrant with a superdisintegrant. It is also preferred that the superdisintegrant is incorporated intragranularly as well as extragranularly. The preferred conventional disintegrant used in the present invention is starch and the preferred superdisintegrant used is croscarmellose sodium. It is preferred
15

that the starch is used in an amount ranging from about 0.1% w/w to about 20% w/w and the croscarmellose sodium is used intragranularly in an amount ranging from about 0.5% w/w to about 10% w/w intragranularly and from about 0.5% w/w to about 10% w/w extragranularly. More preferably, the starch is used in an amount ranging from about 1% w/w to about 15% w/w and the croscarmellose sodium is used intragranularly in an amount ranging from about 1% w/w to about 6% w/w and extragranularly in an amount ranging from about 1% w/w to about 6%~w/w.
The wicking agents used in the present invention are characterized by having the ability to promote water uptake by the tablet. The term wicking as used herein particularly includes any substance that has the ability for water uptake. The water uptake may be by virtue of capillary action or by adsorption or absorption of water or by any other mechanism. Examples of wicking agents that may be used in the present invention include colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, alumina, niacinamide, sodium lauryl sulfate, m-pyrol, bentonite, magnesium aluminum silicate, vinylpyrrolidone polymers such as povidone, or crosslinked polyvinylpyrrolidone such as crospovidone; cellulose and cellulose derivatives such as microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl cellulose, carboxyalkyl celluloses or crosslinked carboxyalkylcelluloses and their alkali salts; sodium starch glycolate, starch and starch derivatives, ion-exchange resins and the like and mixtures thereof. The preferred wicking agent used in the present invention is a combination of microcrystalline cellulose and colloidal silicon dioxide. Preferably the microcrystalline cellulose is used in an amount ranging from about 0.1% w/w to about 20% w/w and the colloidal silicon dioxide is used in an amount ranging from about 0.1% w/w to about 20% w/v. More preferably the microcrystalline cellulose is used in an amount ranging from about 1% w/w to about 6% w/w and the colloidal silicon dioxide is used in an amount ranging from about 3% w/w to about 10% w/v.
A filler may be used to provide improved compaction properties to the composition used to form the saliva-rapidly-erodible tablets of the present invention. Examples of fillers that may be used include corn starch, glucose, lactose, various natural gums, ethyl
16

cellulose, methylcellulose, carboxymethylcellulose, microcrystalline cellulose, calcium phosphate, calcium carbonate, calcium sulfate, kaolin, sodium chloride, powdered cellulose, sucrose, mannitol, starch and the like and mixtures thereof. The preferred filler used in the present invention is lactose. The lactose is used in the invention in amounts ranging from 1% w/w to about 90% w/w. It is used more preferably in an amount ranging from about 6% w/w to about 28% w/w.
The present invention may also include various other pharmaceutically acceptable excipients, for example lubricants such as talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, polyethylene glycol and the like and mixtures thereof; sweetening agents such as aspartame, lactose, dextrose, fructose, honey, maltodextrin, maltose, mannitol, molasses, sorbitol, sucrose and the like and mixtures thereof; flavoring agents and other such excipients.
The present invention may be prepared by the conventional process of wet granulation, dry granulation or direct compression. In wet granulation, the drug along with the various excipients is mixed, granulated, the damp mass screened and dried. The dried mass may be screened, lubricated and compressed. Dry granulation involves mixing the drug with excipient, slugging, dry screening, lubrication and compression. Direct compression involves compressing tablets directly from the powdered material of the drug and the excipients.
The invention is further illustrated by the following examples, which are by no means intended to limit the scope of the invention but are given by way of illustration.
17

EXAMPLE 1 The preferred embodiments of the present invention is given in TABLE 1 below.
TABLE 1

S.No. Ingredients Amount, mg (Percent (w/w))
Stage-A:
1. (-)-L-alpha-amino-beta-(3,4-dihydroxybenzene) propanoic acid (levodopa) 250.00 mg (51.31%)
2. (-)-L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxybenzene) propanoic acid (carbidopa) 25.00 mg
(5.13%)
3. Lactose 82.40 mg (16.91%)
4. Microcrystalline cellulose 15.00 mg (3.08%)
5. Starch 22.00 mg
(4.52%)
6. Colloidal silicon dioxide (Aerosil-200) 25.00 mg
(5.13%)
7. Croscarmellose sodium 14.50 mg (2.98%)
8. Polyvinylpyrrolidone- K 30 9.70 mg (1.99%)
Stage-B:
1. Purified water* quantity sufficient
Stage-C:
1. Croscarmellose sodium 14.50 mg (2.98%)
2. Talcum 9.70 mg (1.99%)
3. Magnesium stearate 4.85 mg (1.0%)
4. Aspartame 9.70 mg (1.99%)
5. Flavour: Trusil Peppermint flavour 4.85 mg (1.0%)
* Used in the process only. Does not appear in the final product.
18

The levodopa, carbidopa, lactose, microcrystalline cellulose, starch, colloidal silicon dioxide, croscarmellose sodium and polyvinylpyrrolidone K-30 were sifted through 60 mesh. The powder mixture was mixed in a rapid mixer granulator for 10 minutes. The blend was granulated using purified water and the wet mass passed through 10 mm s.s. screen using clit mill. The granules were dried in fluid bed drier at 60°C till the loss on drying was between 1-2% w/w. The dried granules were milled through 1.75mm s.s screen using clit mill. Talcum, magnesium stearate, aspartame, croscarmellose sodium and trusil peppermint flavour were sifted through 60 mesh. This lubricant mixture was added to the dried granules and mixed well. The mixture was then compressed into tablets.
The physical parameters of the tablets were tested and the results are given in TABLE 2.
TABLE 2

S.No. Parameter Result
1 Description White colored, circular, flat, uncoated tablets with break line on one side and plain on the other side.
2 Average weight 485mg
3 Diameter 12mm
4 Thickness 3.6 ± 0.2mm
5 Hardness 2-4 Kg/cm2
6 Friability 0.4%
7 Disintegration time 2 min. 40 sec.
19

We claim:
1. A process for the preparation of saliva-rapidly-erodible tablet, comprising mixing a drug, a binder and water dispersible excipient and converting the mixture to saliva-rapidly-erodible tablet by a conventional wet granulation, dry granulation or direct compression process, wherein said saliva-rapidly-erodible tablet is devoid of effervescent agents or low melting compounds, wherein the erosion of the tablet in the mouth is characterized by rapid uptake of fluid by the tablet whereby the tablet rapidly erodes until complete erosion of the tablet occurs in less than three minutes, wherein the water dispersible excipient comprises a disintegrant, a wicking agent, and optionally a filler, and further wherein the process excludes a freeze-drying step and the melt-granulation process.
2. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 1 wherein, the drug used is not readily soluble in water and has a high dose.
3. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 2 wherein, the drug is used an amount ranging from about 40% to about 70% by weight of the tablet.
4. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 1 wherein, the binder is used in optimum effective amounts such that the tablets have the desired hardness and friability characteristics.
5. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 4 wherein, the binder used is polyvinylpyrrolidone.
6. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 5 wherein, the polyvinylpyrrolidone is used in an amount ranging from about 0.5% w/w to about 5% w/w.
7. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 1 wherein, the water dispersible excipient is used in an amount ranging from about 20% w/w to about 99% w/w.
8. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 1 wherein, the disintegrant comprises a mixture of a conventional disintegrant and a superdisintegrant.
20

9. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 8
wherein, the tablets are made by a granulation process whereby the superdisintegrant is
incorporated intragranularly as well as extragranularly.
10. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 8 wherein, the conventional disintegrant used is starch and the superdisintegrant used is croscarmellose sodium.
11. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 10 wherein, the starch is used in an amount ranging from about 1% w/w to about 15% w/w.
12. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 10 wherein, the croscarmellose sodium is used intragranularly in an amount ranging from about 1% w/w to about 6% w/w and extragranularly in an amount ranging from about 1% w/w to about 6% w/w.
13. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 1 wherein, the wicking agent used is a combination of microcrystalline cellulose and colloidal silicon dioxide.
14. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 13 wherein, the microcrystalline cellulose is used in an amount ranging from about 1% w/w to about 6% w/w and the colloidal silicon dioxide is used in an amount ranging from about 3% w/w to about 10% w/v.
15. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 1 wherein, the filler used is lactose.
16. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 15 wherein, the lactose is used in an amount ranging from about 6% w/w to about 28% w/w.
17. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 1 wherein, the binder used is polyvinylpyrrolidone used in an amount ranging from about 0.5% w/w to about 5% w/w; the disintegrant used comprises a mixture of a conventional disintegrant with a superdisintegrant, where the conventional disintegrant is starch used in an amount ranging from about 1% w/w to about 15% w/w and the superdisintegrant is croscarmellose sodium used intragranularly in an amount ranging from about 1% w/w to about 6% w/w and extragranularly in an amount ranging from about 1% w/w to about 6% w/w; the wicking agent used is a combination of microcrystalline cellulose and colloidal
21

silicon dioxide, where the microcrystalline cellulose is used in an amount ranging from about 1% w/w to about 6% w/w and the colloidal silicon dioxide is used in an amount ranging from about 3% w/w to about 10% w/v; and the filler used is lactose in an amount ranging from about 6% w/w to about 28% w/w.
18. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 1 wherein, the drug used is a combination of (-)-L-alpha-amino-beta-(3,4-dihydroxybenzene) propanoic acid and (-)-L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxybenzene) propanoic acid.
19. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 18 wherein, the binder used is polyvinylpyrrolidone.
20. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 19 wherein, the polyvinylpyrrolidone is used in an amount ranging from about 0.5% w/w to about 5% w/w.
21. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 18 wherein, the disintegrant comprises a mixture of a conventional disintegrant with a superdisintegrant.
22. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 21 wherein, the conventional disintegrant used is starch and the superdisintegrant used is croscarmellose sodium.
23. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 22 wherein, the starch is used in an amount ranging from about 1% w/w to about 15% w/w.
24. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 22 wherein, the croscarmellose sodium is used intragranularly in an amount ranging from about 1% w/w to about 6% w/w and extragranularly in an amount ranging from about 1% w/w to about 6% w/w.
25. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 18 wherein, the wicking agent used is a combination of microcrystalline cellulose and colloidal silicon dioxide.
26. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 25 wherein, the microcrystalline cellulose is used in an amount ranging from about 1% w/w
22

to about 6% w/w and the colloidal silicon dioxide is used in an amount ranging from about 3% w/w to about 10% w/v.
27. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 18 wherein, the filler used is lactose.
28. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 27 wherein, the lactose is used in an amount ranging from about 6% w/w to about 28% w/w.
29. A process for the preparation of saliva-rapidly-erodible tablet as claimed in claim 18 wherein, the binder used is polyvinylpyrrolidone used in an amount ranging from about 0.5% w/w to about 5% w/w; the disintegrant used comprises a mixture of a conventional disintegrant with a superdisintegrant, where the conventional disintegrant is starch used in an amount ranging from about 1% w/w to about 15% w/w and the superdisintegrant is croscarmellose sodium used intragranularly in an amount ranging from about 1% w/w to about 6% w/w and extragranularly in an amount ranging from about 1% w/w to about 6% w/w; the wicking agent used is a combination of microcrystalline cellulose and colloidal silicon dioxide, where the microcrystalline cellulose is used in an amount ranging from about 1% w/w to about 6% w/w and the colloidal silicon dioxide is used in an amount ranging from about 3% w/w to about 10% w/v; and the filler used is lactose in an amount ranging from about 6% w/w to about 28% w/w.
30. A process as claimed in claim 1 above, substantially as herein described and
illustrated by the examples herein.
Dated this 2nd day of August, 2002.
DILIP SHANGHVI
CHAIRMAN AND MANAGING DIRECTOR, SUN PHARMACEUTICAL INDUSTRIES LTD.
23