US 2010O278754A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0278754 A1 Stroppolo et al. (43) Pub. Date: Nov. 4, 2010

(54) ORALLY DISINTEGRATING TABLETS WITH (86). PCT No.: PCT/EP09/S1055 SPECKLED APPEARANCE S371 (c)(1), 2), (4) Date: Jul. 6, 2010 (75) Inventors: Federico Stroppolo, Mezzovico (2), (4) (CH); Shahbaz Ardalan Related U.S. Application Data Mezzovico (CH) (60) Provisional application No. 61/026,249, filed on Feb. 5, 2008. Correspondence Address: Publication Classification ROTHWELL, FIGG, ERNST & MANBECK, PC. 51) int. C 1425 KSTREET, N.W., SUITE 800 (51) Eikyu (2006.01) WASHINGTON, DC 20005 (US) A69/20 (2006.01) (52) U.S. Cl...... 424/10.2: 424/10.3 (73) Assignee: ALPEX PHARMASA, MEZZOVICO (CH) (57) ABSTRACT Orally disintegrating tablets containing colored granules of a (21) Appl. No.: 12/811,737 water-soluble Sugar which give them a speckled appearance y x- - - 9 are described. The orally disintegrating tablets with speckled appearance are readily and easy identifiable by physicians, (22) PCT Filed: Jan. 30, 2009 nurses and patients. US 2010/0278754 A1 Nov. 4, 2010

ORALLY DISINTEGRATING TABLETS WITH Surface are easily visible, making Such tablets more identifi SPECKLED APPEARANCE able than white or monocolored tablets. 0016 Solid or semisolid forms with speckled appearance are very common among cosmetic and laundry products, such 0001. The present invention generally relates to the iden as tooth pastes or soaps. tification of orally disintegrating tablets. More particularly, 0017. They are prepared by incorporating colored beads of the invention relates to orally disintegrating tablets with a different material into the composition. speckled appearance for their easy identification by physi 0018. In case of ODT, the colored beads must be soluble cians, nurses and patients. and dissolve as fast as the tablets to avoid an unpleasant 0002 Solid pharmaceutical dosage forms for oral admin grinding sensation when the tablet disintegrates in the oral istration are usually in pill, tablet or capsule form. These cavity. Moreover, the colored beads must be stable, i.e. they dosage forms are available in a limited variety of shapes, size, must not release the color during storage, and should give and colors, and many of them are very similar to each other in minimal coloration of the oral cavity after disintegration of their outward appearance. the tablet. 0003 Frequently, users confuse such dosage forms, par 0019. The present invention relates to orally disintegrating ticularly if they are elderly or have limited vision. The con tablets containing colored granules which give a speckled sequences of taking the wrong medication can be life-threat appearance to the tablets for their readily and easy identifica ening. For this reason Health Authorities require that each dosage form and strength must be clearly identified simply by tion by physicians, nurses and patients. individual visual inspection. 0020. The orally disintegrating tablets of the invention 0004 Identification of tablets is usually made by using contains colored granules of a water-soluble Sugar. different shapes, sizes, or colors, or by color coating, printing 0021. The present invention relates to orally disintegrating or embossing them. Very often a double identification is tablets (ODT) with speckled appearance which make them required such as embossing and coloring, or coating and readily identifiable by users. printing, etc. 0022. The ODT with speckled appearance are prepared by 0005 Also correct intake of drugs is important for their mixing Soluble colored granules to the pharmaceutically effectiveness. acceptable carrier. 0006 Conventional tablets are swallowed, usually with 0023 The term “colored granules” as used herein after some water or other liquids, and the absorption of the active means granules of a color different from the color of the ingredient occurs in the gastro-intestinal tract. tablet. Colored granules are, for example, blue or yellow 0007 Orally Disintegrating Tablets (ODT) dissolve in the granules in a white tablet, blue or white granules in a yellow oral cavity by contact with saliva, do not require water for tablet, yellow or white granules in a blue tablet, dark blue ingestion and could permit a buccal absorption of the active granules in a light blue tablet, blue granules and red granules ingredient. The advantageous properties of ODT over con in a white tablet, etc. ventional tablets are making them always more and more 0024. The soluble colored granules are granular particles popular for drug administrations. of a water-soluble Sugar Such as Sucrose or a polyalcohol. 0008 For their correct intake, it would be very helpful if Specific examples of polyalcohols are Sorbitol, mannitol, ODT were more easily detectable and identifiable over con Xylitol, fructose, etc. ventional tablets. 0025 Preferably, the same polyalcohol already present in 0009. In case of ODT physical identification methods are the pharmaceutically acceptable carrier of the ODT is used limited because ODT tablets are characterized by a low hard for the preparation of the colored granules of the invention. ness which allows their rapid dissolution when in contact with (0026. Preferably, the ODT of the present invention con saliva (i.e. EU pharmacopoeia requires a disintegration time tains colored granules of mannitol. of not more than 3 minutes in water). 0027 Even if water-soluble sugars are excipients usually 0010 Coating is not usually used because it could delay present in ODT, their use to prepare colored granules suitable saliva penetration in the tablets, so delaying their disintegra for the preparation of ODT with speckled appearance tion. requires a specific particle size. 0011. As a consequence, identification of ODT by printing 0028. In fact, the particle size of the colored granules is is also unusual because this technique requires a smooth and critical. Colored granules with too small particle size are not shining tablet Surface. Such as a film- or a Sugar-coated tablet. visible and the resulting tablets have no speckled appearance. 0012 Embossing is possible but the dimension of charac On the other side, the use of colored granules with too large ters is usually too small, due to the limited tablet surface, to be particle size results in a tablet which appears uniformly col easily read by elderly people or by people with a limited ored and therefore not readily identifiable over mono-colored vision. tablets. 0013 Colored ODT can be prepared but the limited num 0029. The colored granules used in the ODT of the present ber of pharmaceutically acceptable colors make difficult to invention have a particle size from about 10um to about 1200 obtain an ODT easily identifiable over conventional colored um, preferably from about 200 um to about 800 um, most tablets. preferably from about 300 um to about 500 um. 0014. One way to solve the problem would be to make 0030. The selection of the particle size of the colored ODT identifiable by using a particular colored pattern. granules of the ODT of the present invention depends on 00.15 ODT with speckled (spotted) appearance, i.e. with a several factors. Since the sucrose or polyalcohol used for the bicolored appearance characterized by the presence of spots colored granules is preferably one of the excipients already of a different color on their surface can be easily identified by present in the ODT, the particle size must be different from users. For example, blue spots on a white or yellow tablet the particle size of the already present excipient. US 2010/0278754 A1 Nov. 4, 2010

0031. The selection of the suitable particle size also fedrine, reproterol, salmeterol, soterenol, terbutaline, depends on the desired colored pattern. For example, the use tulobuterol, and Xanoterol, C-adrenergic blockers such as of a little quantity of large particles tends to produce an ODT dapiprazole, fenspiride, nicergoline, prazosin, and yohim with few large colored spots on its surface. Higher amount of bine; B-adrenergic blockers such as acebutolol, alprenolol. Smaller particles tends to produce less discrete colored spots atenolol, befnolol, betaxolol, bupranolol, carazolol, carteolol, on the surface of the tablets. celiprolol, indenolol, levobunolol, mepindolol, metipranolol. 0032. Then, the amount of colored granules suitable for moprolol, pindolol, practolol, propranolol, and timolol; each tablet, according to the present invention, can vary adrenocortical steroid; adrenocorticotropic hormones such as within a relatively large range depending on the particle size ACTH cosintropin; alcohol deterrents such as calcium ciana of the granule. Preferably, the amount of colored granules mide citrate, and disulfiram; aldose reductase inhibitors such ranges between about 0.1% w/w and about 50% w/w, still as epalrestat, tolrestat, and Zopolrestat; aldosterone antago more preferably between about 1% w/w and about 30% w/w. nists such as canrenone, and spironolattone; anabolics Such as 0033 Preferably the colored granules useful for the ODT androisoxazole, androstenediol, methandriol, methenolon, with speckled appearance of the present invention are pre methyltrienolone, and nandrolone; narcotic analgesics Such pared by granulation of the water-soluble Sugar with an aque as alfentanil, buprenorphine, codeine and its derivatives, fen ous Suspension or solution of the coloring agent in a Suitable tanil, meperidine, methadone, morphine and its derivatives, fluid bed granulator. pentazocine, phenazocine, propiram, propoxiphene, and 0034. Any soluble or insoluble pharmaceutically accept Sufentanil; non narcotic analgesics such as aceclofenac, able coloring agent can be used. acetaminophen, acetylsalicylic acid, alclofenac, alminopro 0035. Non limiting examples of suitable coloring agents fen, antypirine, benorilate, benoxoprofen, bromfenac, buce are FD&C blue no. 1 aluminum lake, FD&C blue no. 2 tin, carbamazepine, carbiphene, chlortenoxazin, cholin Sali aluminum lake, FD&C green no. 1 aluminum lake, FD&C cylate, clometacin, clonixin, chloropamide, diflunisal, green no. 3 aluminum lake, FD&C red no. 2 aluminum lake, etodolac, felbinac, fenoprofen, flufenamic acid, flurbiprofen, FD&C red no. 3 aluminum lake, FD&C red no. 6 aluminum ibufenac, imidazole salicylate, indomethacin, indoprofen, lake, FD&C red no. 7 aluminum lake, FD&C red no. 21 ketoprofen, ketorolac, mofeZolac, naproxen, nifenaZone, aluminum lake, FD&C red no. 27 aluminum lake, FD&C red phenacetin, propyphenaZone, Sutrofen, tenoxicam, terofe no. 28 aluminum lake, FD&C red no. 30 aluminum lake, namate, tolfenamic acid, tramadol, and Viminol; androgens FD&C red no. 33 aluminum lake, FD&C red no. 40 alumi Such as boldenone, cloxotestosterone, mestanolone, mester numlake, FD&C yellow no. 5 aluminum lake, FD&C yellow olone, methandrostenolone, norethandrolone, no. 6 aluminum lake, FD&C yellow no. 10 aluminum lake, normethandrone, Oxandrolone, oxymesterone, ferric oxide yellow, ferric oxide brown, ferric oxide red, and oxymetholone, prasterone, stanolone, stanozolol, and test mixture thereof. osterone; angiotensin II receptor antagonists, such as cande 0036. The colored granules are incorporated into the com Sartan, eprosartan, ibesartan, losartan, and Valsartan; anorexic position of the ODT by conventional blending procedures. agents such as a minorex, amphecloral, anphetamine, benz The ODT according to the present invention are then prepared phetamine, chlorphentermine, clobenzorex, clortermine, fen by compression of the resulting mixture containing the col fluramine, norpseudoephedrine, pentorex, phendimetrazine, ored granules. phenmetrazine, and phentermine; anthelmintic agents such as 0037 Since the incorporation of the colored granules does arecoline, aspidin, aspidinol, becanthone, and hycantone; not change the manufacturing process and the characteristics antiallergic agents such as amlexanoX, astemizole, azelastine, of the ODT, the ODT with speckled appearance according to cromolyn, fempiprane, ibudilast, lodoxamide, nedocromil. the present invention may be of any shape known among oXatomide, repirinast, tazanolast, hystamine, beclometha conventional ODT may be embossed on the surface with Sone, dexamethasone, flunisolide, fluticasone, and triamcino symbol(s), letter(s) and/or number(s), may be scored, etc. lone; antialopecia agents such as cioteronel, and minoxidil; 0038. The ODT with speckled appearance according to antiamebic agents such as arsthinol, carbasone, chlorbeta the present invention have the same disintegrating properties mide, chloroquine, chlorphenoxamide, emetine, fumag of ODT of reference (i.e. without colored granules). More gilline, and iodoquinol; antiarrhythmic agents such as acebu over, a the coloring agent does not spread over the tablet and tol, adenosine, ajmaline, alprenolol, amiodarone, atenolol. the colored pattern is stable over time. bupranolol, carazolol, carteolol, cloranolol, indenolol, iprat 0039. The ODT with speckled appearance of the present ropium bromide, lidocaine, pindolol, propafenone, propra invention can be a placebo tablet or preferably contain one or nolol, quinidine, timolol, and Verapamil; antiarteriosclerotic more active ingredients. agents such as pyridinol carbamate; antiarthritic/antirheu 0040. Non-limiting examples active ingredients which matic agents such as actarit, auranofin, aurothioglucose, can be present in the ODT according to the present invention aurothioglicanide, azathioprine, chloroquine, gold sodium are: abortifacients such as prostaglandin E, and mifepris thiosulfate, hydroxchloroquine, and methotrexate; antias tone; ACE inhibitors such as benazepril, captopril, delapril, matic agents such as azelastine, cromolyn, ibudilast, keto enalapril, imidapril, and ramipril, C.-adrenergic agonists Such tifen, montelukast, oxotomide, pranlukast, seratrodast, as adrenolone, clonidine, ephedrine, epinephrine, fenoxazo Zafirlukast, Zileuton, beclomethasone, budesonide, dexam line, ibopamine, methoxamine, nafazoline phenylephrine, ethasone, flunisolide, and triamcinolone acetonide; antibac phenyl-propanolamine, pseudoephedrine, tetrahydrozoline, terial agents such as amikacin, gentamicin, kanamycin, neo tramaZoline, tuaminoheptane, and tyramine Xylomethazo micin, tobramycin, chloramphenicol, thiamphenicol, line; B-adrenergic agonists such as albuterol, bambuterol, rifamide, rifampin, rifamycin, rifapentine, rifaximin, cefa clenbuterol, clorprenaline, dopexamine, ephedrine, epineph clor, cefamandole cefazolin, cefitime, cefoxitin, amoxicillin, rine, ethylnorepinephrine, fenoterol, formoterol, isoproter ampicillin, oxacillin, lindomycin, erytromycin, gramicidin, enol, mabuterol, metaproterenol, methoxyphenamine, oxy teicoplanin, Vancomycin, chlortetracyclin, doxycyline, tet US 2010/0278754 A1 Nov. 4, 2010 racyclin, trimetoprim, nifuradene, nitrofurantoin, ciprofloxa roquine, chlorproduanil, cinchonide, cycloguanil, and quini cin, ofloxacin, lomefloxacin, benzylsulfamide, chloramine-t, dine; antimigraine agents such as dolasetron, ergocornine, mafenide, Sulfabenzamide, Sulfacetamide, Sulfadiazine, Sul ergocriptyne, ergot, ergotamine, lomerizine, and Sumatrip fadoxine, Sulfaguanidine, Sulfalene, Sulfanilamide, Sulfany tan; antiparkinson agents amantadine, bromocriptine, carbi lurea, Sulfatyazole, Sulfisoxazole, acedapsone, dapsone, Sola dopa, and levodopa; antipsychotic agents alizapride, amil Sulfone, ethinamide, furonazide, isoniazide, and Sulpiride, Sulpiride, risperidone, haloperidol, streptomicyn; anticholinergic agents such as atropine, fento acetophenazine, chlorpromazine, fluiphenazine, and pera nium bromide, homatropine, hyoscyamine, ipratropium bro Zine; antipyretic agents such as acetaminophen, alclofenac, mide, isopropramide iodide, Scopolamine, and tropicamide; aspirin, benorilate, and indomethacin; antispasmodic agents anticoagulant agents such as acecumarol, bromindione, clo aminopromazine, fentonium bromide, rociverine, and tiro rindione, coumetarol, dicumarol, diphenadione, fluindione, pramide; antitussives such as cloperastine, codeine and heparin, hirundin, phenindione, and warfarin; anticonvulsant derivatives, dextromethorphan, and morclofone; antiulcer agents such as albutoin, aloxidone, aminoglutethimide, bec ative agents acetoXolone, cimetidine, famotidine, omepra lamide, carbamazepine, clonazepam, ethadine, ethotoin, fel Zole, pirenzepine, ranitidine, and Sucralfate; anxiolytic agents bamate, mephenytoin, narcobarbital, nimethazepam, Such as buspirone, alprazolam, bromazepam, camazepam, nitrazepam, paramethadione, phenacemide, phenobarbital, lorazepam, nordazepam, and meprobamate; bronchodilators and phenitoin; antidepressant agents such as citalopram, such as albuterol, bambuterol, calbiterol, clenbuterol, clor fencaine, nefopam, iproclozide, isocarboxazid, nialamide, prenaline, ephedrine, ephineprine, follmoterol, metaproter rolyciprine, maprotiline, metralindole, amytriptiline, clomi enol, Salmeterol, terbutaline, ipratroprium bromide, and teo pramide, desipramide, dibenzepin, imipramide, trimipra philline and derivatives; calcium channel blockers such as mide, and bupropion; antidiabetic agents such as buformin, diltiazem, Verapamil, amlodipine, lacidipine, micardipine, phenformin, insulin, carbutamide, chlorpopamide, glipizide, nifedipine, and nomerizine; cardiotonic agents such as digi phenbutamide, tolaZamide, tolbutamide, and tolcyclamide; talin, digitoxin, digoxin, dopamine, uabain, and Scillaren: antidiarreal agents such as acetorphan, catechin, difenoxin, choleretic agents such as cholic acid, cynerin, dehydrocholic diphenoxylate, loperamide, and mebiquine; antidiuretic acid, dehoxycolic acid, and taurocolic acid; cholinergic agents such as desmopressin, felypressin, ornipressin, and agents such as acetylcholine, benzepirinium bromide, carba vasopressin; antidotes Such as acetylcysteine, cysteamine, chol, neostigmine, and physostigmine; CNS stimolants such methionine, and folinic acid; antidy skinetic agents such as as amphetamine, caffeine, fenozolone, and phentermine; amantidine, clonidine, haloperidol, pimozide, and tetrabena diuretic agents such as bendroflumethiazide, benzylhytro Zine; antiemetics such as alizapride, aZaSentron, benzquina chlorothiazide, chlorothiazide, indapamide, mersalil, can mide, bromopride, buclizine, chlorpromazine, cyclizine, drenone, oleandrin, spironolattone, acetazolamide, butazola domperidone, granisetron, meclizine, metoclopramide, mide, clopramide, furosemide, and isosorbide; dopamine ondansentron, prochlorerazine, Scopolamine, Sulpiride, and receptoragonists Such as bromocriptine, cabercoline, dopex tropistron; antifungal agents such as butenafine, butocona amine, and fenoldopam; dopamine receptor antagonists Such Zole, econazole, fenticonazole, miconazole, tolciclate, tolin as amisulpride, domperidone, metoclopamide, and Sulpiride; date, fluconazole, buclosamide, and triacetin; antiglaucoma enzymes Such as amylase, lysozyme, and papain; expetorants agents such as acetoZolamide, betaxolol, and bupranolol; Such as ambroXol, bromhexine, carbocysteine, guaiacol, and antigout agents such as allopurinol, colchicine, probenecid, guaifenesin; gastric and pancreatic secretion stimulants such and Sulfipyrazone; anthistaminic agents such as acrivastine, as carnitine, and ceruletide; gastric proton pump inhibitors brompheniramine, chlorpheniramine, dimethindene, phe Such as lansoprazole, omeprazole, and pantoprazole; gastric niramine, tolpropamine, clemastine, diphenidramine, medril secretion inhibitors such as enterogastrone, octretide, and amyne, cetirizine, chlorcyclizine, cinnarizine, hidroxy Zine, telenzepine; gastroprokinetic agents such as cinitapride, fenethazine, promethazine, loratadine, antazoline, astemi cisapride, fenotozine, and loxiglumide; glucocorticoids Such Zole, azelastine, ebastine, feXofenadine, and terfenadine; as beclomethasone, bethometaSone, budesonide, chloropred antihyperlipoproteinemic agents such as cholestiramine, ben nisone, clobetaSone, cortisone, corticosterone, deflazacort, Zofibrate, clofibrate, etofibrate, genfibrozil, atorvastatin, lov dexamethasone, fluazacort, flumethasone, flunisolide, fluoci astatin, niceritrol, thyroxine, carnitine, chondroitinSulfate, nolone acetonide, fluorometholone, fluprednisolone, hydro ornithine, and probucol, antihypertensive agents such as cortisone, methylprednisolone, prednisolone, prednisone, bufuralol, acebutolol, atenolol, carteolol, metoprolol. and triamcinolone; hemolytic agents such as phenilhydra moprolol, pindolol, propranolol, timolol, chlorthiazide, Zine; histamine H-receptor antagonists such as cimetidine, cyclopenthiazide, hydroflumethazide, benazepril, captopril, ebrotidine, famotidine, nizatidine, and ranitidine; laxative/ lisinopril, ramipril, amlodipine, felodipine, lacidipine, nicar cathartic agents such as frangulin, phenolphtaleine, and pico dipine, nitrendipine, bethnide, budralazine, hydralazine; Sulfate Sodium; leukotriene antagonists such as ibudilast, pheniprazine, phentolamine, bunaZosin, praZosin, reserpine, montelukast, pranlukast, and Zafirlukast, lipotropic agents furosemide, ajmaline, fenoldopam, mebutamate, methildopa, Such as buserelin, goserelin, histrelin, leuprolide, nafarelin, and minoxidil; antihypotensive agents such as dopamine, and triptorelin; mineralcorticoid agents such as aldosterone, etillefrin, norepinephrine, and synephrine; nonsteroidal anti deoxycorticosterone, and fludrocortisones; monoamine oxi inflammatory agents such as etofenamate, flufenamic acid, dase inhibitors such as iproniazid, moclobemide, phenox mecofilenamic acid, tolfenamic acid, aceclofenac, alclofenac, ypropazine, and selegeline; mucolitic agents such as acetyl bromfenac, diclofenac sodium, etodolac, ibufenac, cysteine, bromexine, carbocysteine, lysozime, Sobrerol, and indomethacin, piraZolac, Sulindac, tolmetin, fenbufen, tyloxapol; muscle relaxants such as afloqualone, baclofen, ketorolac, alminoprofen, fenoprofen, flurbiprofen, ibuprofen, curare, cyclarbamate, dandrolene, decamethonium bromide, ketoprofen, naproxen, feprazone, benorylate, piroxicam, diazepam, eperisone, flumetramide, mephenesin, mephenax bendazac, and nimeSulide; antimalaria agents such as chlo olone, methaxolone, methocarbamol, nimethazepam, Succyi US 2010/0278754 A1 Nov. 4, 2010 nylcholine bromide, tetrazepam, and tubocurarine; narcotic with punches of the desired shape obtaining ODT with speck antagonists Such as amiphenazole, naloxone, and naltaxone; led appearance according to the present invention. nootropic agents such as aceglutamide, besipiride, piracetam, 0045. The following examples better illustrate the present and Vinconate; oxytocic agents such as carboprost, deami invention without limiting it. nooxytocic, ergonovine, gemeprost, methylergonovine, oxy tocin, prostaglandin E2 and prostaglandin F2, progestogens Such as drospirenone, dydrogesterone, ethynodiol, fluroge EXAMPLE 1. stone acetato, lynestrenol, medrogestone, medroxyprogester one, megestrol acetate, norgesterone, pentagestrone, and Preparation of Blue Granules progesterone; prolactin inhibitors such as bromocriptine, cabergoline, lisuride, metergoline, and quinagoline; prostag 0046 Perlitol R 400 (500 g) was placed in a fluid bed landins and analogs such as beraprost, carboprost, enprostil, granulator Strea 1. gemeprost, limaprost, misoprostol, prostacyclin, and pros 0047. A homogeneous suspension of FD&C blue no. 1 (1 taglandin E, E, F, respiratory stimulants such as almitrine, g) in purified water (50 ml) was prepared. bemegride, cropropamide, dimorpholamine, lobeline, and 0048 Air at about 30° C. was blown in the fluid bed and pyridopylline; retroviral transcriptase inhibitors such as the Suspension was sprayed on the granular. delavirdine, didanosine, dideoxyadenosine, lamivudine, sta 0049. At the end of spraying, the granular was dried at 40° Vudine, and Zidovudine, sedative/hypnotics such as acecar C. until a residual moisture of not more than (NMT) 0.5%. bromal, butoctamide, diethylbromoactamide, niaprazine, tri 0050. The obtained granular was intensively colored in metozine, Zolpidem, Zopiclone, allobarbital, amobarbital, blue. barbital, cyclopentobarbital, hexobarbital, mephobarbital, narcobarbital, pentobarbital, phenobarbital, tetrabarbital, estazolam, flunitrazepam, flurazepam, loprazolam, EXAMPLE 2 lormetazepam, nitrazepam, piperidione, acetophenone, clomethiazole, doxylamine, temazepam, triazolam, meth Example 2A aqualone, and glutethimide; serotonin/noradrenaline reuptake inhibitors such as duloxetine, and Venlafaxine; sero 0051 Perlitol(R) 160C (447.5 g), sucralose (5.5 g), citric tonin reuptake agonists such as buspirone, eltoprazine, acid (40 g), Povidone CL (Kollidon R CL 30.00 g) and ergotamine, and Sumatriptan; serotonin receptor antagonists Povidone K30 (Kollidon R. 30–6 g) were placed in a fluid Such as aZaSentron, dolasentron, granisentron, ondasentron, bed granulator Strea 1. ritanserin, and tropisentron; serotonin uptake inhibitors such 0.052 Separately a quantity of purified water (50 ml) was as fomexitine, fluoxetine, and paroxetine; vasodilators such prepared. This solution was sprayed on the granular. At the as cinnarizine, citicoline, fenoxedil, flunarizine, lomerizine, nicergoline, nimodipine, papaverine, Vincamine, amotriph end of spraying, the granular was dried at 40° C. until a ene, efloxate, nitroglicerin, pentrinitrol, trapidil, bradykinin, residual moisture of NMT 0.5%. inositol, nicergoline, pentifillyne, and tolazoline; vitamins 0053. The resultant granular was mixed in a cube blender Such as calcitriol, ergosterol, Vitamin A, B and related B mix with peppermint flavor (5 g), magnesium Stearate (6.00 complex, D and D complex, E, K, ascorbic acid, 3-carotene, g) and the colored granular (60g) prepared as described in the and pantothenic acid; minerals such as calcium salts, phos example 1. phorous salts, iodine salts, iron salts, magnesium salts, potas 0054 The mixture was blended until homogeneity and sium salts, chloride salts, chromium salts, molybdenum salts, compressed in round biconcave tablets weighing 600 mg silicon and its salts, manganese salts, Zinc salts, selenium each. salts, boron salts, nickel salts, tin Salts, and Vanadium salts. 0041. The ODT with speckled appearance of the present invention can be prepared by incorporation of the soluble Example 2B colored granules into any conventional ODT preparable by compression. Non-limiting examples of these conventional 0055 Perlitol(R) 160C (507.5 g), sucralose (5.5 g), citric ODT are those disclosed in U.S. Pat. No. 6,149,938 (Elan), acid (40 g), Povidone CL (Kollidon R CL 30.00 g) and U.S. Pat. No. 6,024,981 (Cima), U.S. Pat. No. 6,221,392 Povidone K30 (Kollidon R. 30—6 g) were placed in a fluid (Cima), U.S. Pat. No. 5,215,756 (Janssen), U.S. Pat. No. bed granulator Strea 1. 5,264.632 (Prographarm) and U.S. Pat. No. 6,872,405 (Ya 0056 Separately a quantity of purified water (50 ml) was manouchi). prepared. This solution was sprayed on the granular. At the 0042 Preferably the ODT with speckled appearance of the end of spraying, the granular was dried at 40° C. until a present invention are prepared by using the method described residual moisture of NMT 0.5%. in U.S. Pat. No. 6,149,938. 0057 The resultant granular was mixed in a cube blender 0043. In a preferred practical embodiment, the manufac mix with peppermint flavor (5 g) and magnesium Stearate turing process of the ODT with speckled appearance object of (6.00 g). the present invention is the following. 0058. The mixture was blended until homogeneity and 0044) The active ingredient and the excipients are granu compressed in round biconcave tablets weighing 600 mg lated in a suitable fluid bed granulator. The colored granules each. and optional further excipients are added to the external phase 0059. The comparison between the physical characteris and the resultant mixture is blended in a suitable mixer. The tics of the tablets prepared according to example 2A and blended mixture is then compressed in a tabletting machine according to example 2B is reported in the following table 1. US 2010/0278754 A1 Nov. 4, 2010

Solution was sprayed on the granular. At the end of spraying, TABLE 1. the granular was dried at 40°C. until a residual moisture of NMT 0.5%. Comparison between the physical characteristics 0068. The resultant yellow granular was mixed in a cube of the tablets of examples 2A and 2B blender mix with peppermint flavor(5g), magnesium Stearate Tablets of Tablets of (6.00 g) and Perlitol(R) 400 DC (120 g). example 2A example 2B 0069. The mixture was blended until homogeneity and Appearance White tablets with White homogeneous compressed in round biconcave tablets weighing 600mg each blue speckles tablets and containing 30 mg of phentermine hydrochloride. Diameter 14 mm 14 mm 0070 The physical characteristics of the resulting ODT Thickness 4.4 mm 4.4 mm Friability NMT1% NMT1% are reported in the following table 3. Disintegration time in vitro NMT 60 seconds NMT 60 seconds (USP basket apparatus for TABLE 3 tablets disintegration) Disintegration time in vivo 45 seconds 45 seconds Appearance Yellow tablets with white (mean of 3 healthy volunteers) speckles and embossed with AX3 Grinding sensation in the mouth Absent Absent Diameter 14 mm during disintegration of tablets Thickness 4.4 mm Friability NMT1% Disintegration time in vitro NMT 60 seconds 0060. The above data clearly shows that the presence of (USP basket apparatus for tablets disintegration) colored granules confers a easy identifiable colored pattern to Disintegration time in vivo 45 seconds the ODT and does not affect the other physical characteristics (mean of 3 healthy volunteers) of the ODT, in particular the disintegration characteristics. Grinding sensation in the mouth Absent during disintegration of tablets EXAMPLE 3 0061 Phentermine hydrochloride (37.5 g), Perlitol(R) 160C (410 g), sucralose (5.5 g), citric acid (40 g), Povidone EXAMPLE 5 CL (Kollidon RCL 30.00g) and Povidone K30 (Kollidon(R) 30–6 g) were placed in a fluid bed granulator Strea 1. (0071 Phentermine hydrochloride (15g), Perlitol(R) 160C 0062 Separately a quantity of purified water (50 ml) was (178.15g), sucralose (2.75 g), citric acid (20g), Povidone CL prepared. This solution was sprayed on the granular. At the (Kollidon(R) CL-15.00 g) and Povidone K 30 (Kollidon(R) end of spraying, the granular was dried at 40° C. until a 30 3 g) were placed in a fluid bed granulator Strea 1. residual moisture of NMT 0.5%. 0072 Separately a solution of purified water (25 ml) con 0063. The resultant granular was mixed in a cube blender taining FD&C yellow lake no. 5 (0.6 g) was prepared. This mix with peppermint flavor (5 g), magnesium Stearate (6.00 Solution was sprayed on the granular. At the end of spraying, g) and the colored granular (60g) prepared as described in the the granular was dried at 40°C. until a residual moisture of example 1. NMT 0.5%. 0064. The mixture was blended until homogeneity and 0073. The resultant yellow granular was mixed in a cube compressed in round biconcave tablets weighing 600mg each blender mix with peppermint flavor (2.5 g), magnesium Stear and containing 37.5 mg of phentermine hydrochloride. ate (3.00 g) and the colored granular (60 g) prepared as 0065. The physical characteristics of the resulting ODT described in the example 1. are reported in the following table 2. 0074 The mixture was blended until homogeneity and compressed in round tablets weighing 300 mg each and con TABLE 2 taining 15 mg of phentermine hydrochloride. (0075. The physical characteristics of the resulting ODT Appearance White scored tablets with blue speckles and embossed with AX2 are reported in the following table 4. Diameter 14 mm Thickness 4.4 mm TABLE 4 Friability NMT1% Disintegration time in vitro NMT 60 seconds Appearance Yellow tablets with blue (USP basket apparatus for speckles, embossed with AX4 tablets disintegration) Diameter 10 mm Disintegration time in vivo 45 seconds Thickness 3.4 mm (mean of 3 healthy volunteers) Friability NMT1% Grinding sensation in the mouth Absent Disintegration time in vitro NMT 60 seconds during disintegration of tablets (USP basket apparatus for tablets disintegration) Disintegration time in vivo 30 seconds (mean of 3 healthy volunteers) EXAMPLE 4 Grinding sensation in the mouth Absent during disintegration of tablets 0066 Phentermine hydrochloride (30 g), Perlitol(R) 160C (356.3 g), sucralose (5.5 g), citric acid (40 g), Povidone CL (Kollidon R CL 30.00 g) and Povidone K30 (Kollidon(R) EXAMPLE 6 30—6 g) were placed in a fluid bed granulator Strea 1. 0067 Separately a solution of purified water (50 ml) con (0076 Meloxicam (15g), Perlitol(R) 160C (432.5 g), sucral taining FD&C yellow lake no. 5 (1.2 g) was prepared. This ose (5.5 g), citric acid (40 g), Povidone CL (Kollidon(R) US 2010/0278754 A1 Nov. 4, 2010

CL 30.00 g) and Povidone K30 (Kollidon R. 30–6 g) were 2) Orally disintegrating tablets according to claim 1 placed in a fluid bed granulator Strea 1. wherein the water-soluble Sugar is selected from the group 0077 Separately a quantity of purified water (50 ml) was consisting of Sucrose and polyalcohols. prepared. This solution was sprayed on the granular. At the 3) Orally disintegrating tablets according to claim 2 end of spraying, the granular was dried at 40° C. until a wherein the water-soluble Sugar is selected from the group residual moisture of NMT 0.5%. consisting of Sucrose, Sorbitol, mannitol. Xylitol, and fruc 0078. The resultant granular was mixed in a cube blender tOSe. mix with Strawberry flavor (5 g), magnesium Stearate (6.00g) 4) Orally disintegrating tablets according to claim 3 and the colored granular (60g) prepared as described in the wherein the water-soluble Sugar is mannitol. example 1. 5) Orally disintegrating tablets according to claim 1 007.9 The mixture was blended until homogeneity and wherein the colored granules have a particle size from about compressed in round biconcave tablets weighing 600mg each 10 um to about 1200 um. and containing 15 mg of meloxicam. 6) Orally disintegrating tablets according to claim 5 0080. The physical characteristics of the resulting ODT wherein the colored granules have a particle size from about are reported in the following table 5. 200 um to about 800 um. 7) Orally disintegrating tablets according to claim 6 TABLE 5 wherein the colored granules have a particle size from about Appearance White tablets with blue speckles 300 um to about 500 um. Diameter 14 mm 8) Orally disintegrating tablets according to claim 1 Thickness 4.4 mm wherein the colored granules are present in an amount from Friability NMT1% about 0.1% w/w to about 50% w/w per tablet. Meloxicam content 15 mg 9) Orally disintegrating tablets according to claim 1 Disintegration time in vitro NMT 60 seconds (USP basket apparatus for wherein the colored granules are present in an amount from tablets disintegration) about 1% w/w to about 30% w/w. Disintegration time in vivo 40 seconds 10) A method for the identification of orally disintegrating (mean of 3 healthy volunteers) tablets comprising the use of an orally disintegrating tablet Grinding sensation in the mouth Absent with speckled appearance according to claim 1. during disintegration of tablets 11) A method according to claim 10 wherein the orally disintegrating tablet is scored and embossed with one or more 1) Orally disintegrating tablets with speckled appearance symbols, letters, numbers or combination thereof. comprising colored granules of a water-soluble Sugar in admixture with a pharmaceutically acceptable carrier. c c c c c