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USOO844.017OB2

(12) United States Patent (10) Patent No.: US 8.440,170 B2 Stroppolo et al. (45) Date of Patent: May 14, 2013

(54) ORALLY DISINTEGRATING TABLETS WITH (51) Int. Cl. SPECKLED APPEARANCE 469/44 (2006.01) A614.9/00 (2006.01) (75) Inventors: Federico Stroppolo, Mezzovico (CH): (52) U.S. Cl. Shahbaz Ardalan, Mezzovico (CH) USPC ...... 424/10.2: 424/10.3 (73) Assignee: Alpex Pharma SA, Mezzovico (CH) (58) Field of Classification Search ...... 19. (*) Notice: Subject to any disclaimer, the term of this See application file for complete search history. patent is extended or adjusted under 35 (56) U.S.C. 154(b) by 43 days. Refeeees Citede U.S. PATENT DOCUMENTS (21) Appl. No.: 12/811,737 3,555,144. A * 1/1971 Pazar et al...... 424,103 1-1. 2003/0180357 A1* 9, 2003 Martino et al...... 424/465 (22) PCT Filed: Jan. 30, 2009 2004/0213855 A1 * 10, 2004 Pettersson et al...... 424/489 (86). PCT No.: PCT/EP2009/051055 * cited by examiner E. Jul. 6, 2010 Primary Examiner — Fereydoun G Sajjadi (2), (4) Date: ul. O, Assistant Examiner — Genevieve S Alley (87) PCT Pub. No.: WO2O09/098169 (74) Attorney, Agent, or Firm — Rothwell, Figg, Ernst & Manbeck, P.C. PCT Pub. Date: Aug. 13, 2009 (57) ABSTRACT (65)65 PriorO PublicationDO Dat Orally disintegrating tablets containing colored granules of a US 2010/0278754 A1 Nov. 4, 2010 water-soluble Sugar which give them a speckled appearance are described. The orally disintegrating tablets with speckled Related U.S. Application Data appearance are readily and easy identifiable by physicians, nurses and patients. (60) Provisional application No. 61/026,249, filed on Feb. 5, 2008. 9 Claims, No Drawings US 8,440,170 B2 1. 2 ORALLY DISINTEGRATING TABLETS WITH users. For example, blue spots on a white or yellow tablet SPECKLED APPEARANCE Surface are easily visible, making Such tablets more identifi able than white or monocolored tablets. CROSS REFERENCE TO RELATED Solid or semisolid forms with speckled appearance are APPLICATION very common among cosmetic and laundry products, such as tooth pastes or Soaps. This application is a 35 U.S.C. 371 National Phase Entry They are prepared by incorporating colored beads of a Application from PCT/EP2009/051055, filed Jan. 30, 2009, different material into the composition. which claims the benefit of U.S. Provisional 61/026,249 filed In case of ODT, the colored beads must be soluble and Feb. 5, 2008, the disclosures of which are incorporated herein 10 in their entirety by reference. dissolve as fast as the tablets to avoid an unpleasant grinding The present invention generally relates to the identification sensation when the tablet disintegrates in the oral cavity. of orally disintegrating tablets. More particularly, the inven Moreover, the colored beads must be stable, i.e. they must not tion relates to orally disintegrating tablets with speckled release the color during storage, and should give minimal appearance for their easy identification by physicians, nurses 15 coloration of the oral cavity after disintegration of the tablet. and patients. The present invention relates to orally disintegrating tab Solid pharmaceutical dosage forms for oral administration lets containing colored granules which give a speckled are usually in pill, tablet or capsule form. These dosage forms appearance to the tablets for their readily and easy identifica are available in a limited variety of shapes, size, and colors, tion by physicians, nurses and patients. and many of them are very similar to each other in their The orally disintegrating tablets of the invention contains outward appearance. colored granules of a water-soluble Sugar. Frequently, users confuse such dosage forms, particularly The present invention relates to orally disintegrating tab if they are elderly or have limited vision. The consequences of lets (ODT) with speckled appearance which make them taking the wrong can be life-threatening. For this readily identifiable by users. reason Health Authorities require that each dosage form and 25 The ODT with speckled appearance are prepared by mix strength must be clearly identified simply by individual visual ing Soluble colored granules to the pharmaceutically accept inspection. able carrier. Identification of tablets is usually made by using different The term “colored granules” as used herein after means shapes, sizes, or colors, or by color coating, printing or granules of a color different from the color of the tablet. embossing them. Very often a double identification is 30 required such as embossing and coloring, or coating and Colored granules are, for example, blue or yellow granules in printing, etc. a white tablet, blue or white granules in a yellow tablet, Also correct intake of drugs is important for their effective yellow or white granules in a blue tablet, dark bluegranules in CSS. a light blue tablet, blue granules and red granules in a white Conventional tablets are swallowed, usually with some 35 tablet, etc. water or other liquids, and the absorption of the active ingre The soluble colored granules are granular particles of a dient occurs in the gastro-intestinal tract. water-soluble Sugar Such as Sucrose or a polyalcohol. Specific Orally Disintegrating Tablets (ODT) dissolve in the oral examples of polyalcohols are Sorbitol, , Xylitol, fruc cavity by contact with saliva, do not require water for inges tose, etc. tion and could permit a buccal absorption of the active ingre 40 Preferably, the same polyalcohol already present in the dient. The advantageous properties of ODT overconventional pharmaceutically acceptable carrier of the ODT is used for tablets are making them always more and more popular for the preparation of the colored granules of the invention. drug administrations. Preferably, the ODT of the present invention contains col For their correct intake, it would be very helpful if ODT ored granules of mannitol. were more easily detectable and identifiable over conven 45 Even if water-soluble Sugars are excipients usually present tional tablets. in ODT, their use to prepare colored granules suitable for the In case of ODT physical identification methods are limited preparation of ODT with speckled appearance requires a because ODT tablets are characterized by a low hardness specific particle size. which allows their rapid dissolution when in contact with In fact, the particle size of the colored granules is critical. saliva (i.e. EU pharmacopoeia requires a disintegration time 50 Colored granules with too small particle size are not visible of not more than 3 minutes in water). and the resulting tablets have no speckled appearance. On the Coating is not usually used because it could delay Saliva other side, the use of colored granules with too large particle penetration in the tablets, so delaying their disintegration. size results in a tablet which appears uniformly colored and As a consequence, identification of ODT by printing is also therefore not readily identifiable over mono-colored tablets. unusual because this technique requires a Smooth and shining 55 The colored granules used in the ODT of the present inven tablet Surface. Such as a film- or a Sugar-coated tablet. tion have a particle size from about 10 um to about 1200 um, Embossing is possible but the dimension of characters is preferably from about 200 um to about 800 um, most prefer usually too small, due to the limited tablet surface, to be easily ably from about 300 um to about 500 um. read by elderly people or by people with a limited vision. The selection of the particle size of the colored granules of Colored ODT can be prepared but the limited number of 60 the ODT of the present invention depends on several factors. pharmaceutically acceptable colors make difficult to obtain Since the Sucrose or polyalcohol used for the colored granules an ODT easily identifiable over conventional colored tablets. is preferably one of the excipients already present in the ODT. One way to solve the problem would be to make ODT the particle size must be different from the particle size of the identifiable by using a particular colored pattern. already present excipient. ODT with speckled (spotted) appearance, i.e. with a bicol 65 The selection of the suitable particle size also depends on ored appearance characterized by the presence of spots of a the desired colored pattern. For example, the use of a little different color on their surface can be easily identified by quantity of large particles tends to produce an ODT with few US 8,440,170 B2 3 4 large colored spots on its Surface. Higher amount of Smaller roid; adrenocorticotropic hormones such as ACTH particles tends to produce less discrete colored spots on the cosintropin; deterrents such as calcium cianamide surface of the tablets. citrate, and disulfiram; aldose reductase inhibitors such as Then, the amount of colored granules suitable for each epalrestat, tolrestat, and Zopolrestat; aldosterone antagonists tablet, according to the present invention, can vary within a Such as canrenone, and spironolattone; anabolics Such as relatively large range depending on the particle size of the androisoxazole, androstenediol, methandriol, methenolon, granule. Preferably, the amount of colored granules ranges methyltrienolone, and nandrolone; narcotic analgesics Such between about 0.1% w/w and about 50% w/w, still more as alfentanil, buprenorphine, and its derivatives, fen preferably between about 1% w/w and about 30% w/w. tanil, meperidine, , and its derivatives, Preferably the colored granules useful for the ODT with 10 pentazocine, phenazocine, propiram, propoxiphene, and speckled appearance of the present invention are prepared by Sufentanil; non narcotic analgesics such as , granulation of the water-soluble Sugar with an aqueous Sus acetaminophen, acetylsalicylic acid, , alminopro pension or solution of the coloring agentina Suitable fluidbed fen, antypirine, , benoxoprofen, , buce granulator. tin, , carbiphene, chlortenoxazin, cholin Sali Any soluble or insoluble pharmaceutically acceptable col 15 cylate, clometacin, , chloropamide, , oring agent can be used. , , , , , Non limiting examples of Suitable coloring agents are ibufenac, salicylate, indomethacin, , FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum , , , , nifenaZone, lake, FD&C green no. 1 aluminum lake, FD&C green no. 3 , propyphenaZone, Sutrofen, , terofe aluminum lake, FD&C red no. 2 aluminum lake, FD&C red namate, , tramadol, and Viminol; androgens no. 3 aluminum lake, FD&C red no. 6 aluminum lake, FD&C Such as boldenone, cloxotestosterone, mestanolone, mester red no. 7 aluminum lake, FD&C red no. 21 aluminum lake, olone, methandrostenolone, norethandrolone, FD&C red no. 27 aluminum lake, FD&C red no. 28 alumi normethandrone, Oxandrolone, oxymesterone, numlake, FD&C red no.30 aluminum lake, FD&C red no.33 oxymetholone, prasterone, stanolone, stanozolol, and test aluminum lake, FD&C red no. 40 aluminum lake, FD&C 25 osterone; angiotensin II receptor antagonists, such as cande yellow no. 5 aluminum lake, FD&C yellow no. 6 aluminum Sartan, eprosartan, ibesartan, losartan, and Valsartan; anorexic lake, FD&C yellow no. 10 aluminum lake, ferric oxide yel agents such as a minorex, amphecloral, anphetamine, benz low, ferric oxide brown, ferric oxidered, and mixture thereof. phetamine, chlorphentermine, clobenzorex, clortermine, fen The colored granules are incorporated into the composition fluramine, norpseudoephedrine, pentorex, phendimetrazine, of the ODT by conventional blending procedures. The ODT 30 phenmetrazine, and phentermine; anthelmintic agents such as according to the present invention are then prepared by com arecoline, aspidin, aspidinol, becanthone, and hycantone; pression of the resulting mixture containing the colored gran antiallergic agents such as amlexanoX, astemizole, azelastine, ules. cromolyn, fempiprane, ibudilast, lodoxamide, nedocromil. Since the incorporation of the colored granules does not oXatomide, repirinast, tazanolast, hystamine, beclometha change the manufacturing process and the characteristics of 35 Sone, dexamethasone, flunisolide, fluticasone, and triamcino the ODT, the ODT with speckled appearance according to the lone; antialopecia agents such as cioteronel, and minoxidil; present invention may be of any shape known among conven antiamebic agents such as arsthinol, carbasone, chlorbeta tional ODT may be embossed on the surface with symbol(s), mide, chloroquine, chlorphenoxamide, emetine, fumag letter(s) and/or number(s), may be scored, etc. gilline, and iodoquinol; antiarrhythmic agents such as acebu The ODT with speckled appearance according to the 40 tol, adenosine, ajmaline, alprenolol, amiodarone, atenolol. present invention have the same disintegrating properties of bupranolol, carazolol, carteolol, cloranolol, indenolol, iprat ODT of reference (i.e. without colored granules). Moreover, ropium , lidocaine, pindolol, propafenone, propra a the coloring agent does not spread over the tablet and the nolol, quinidine, timolol, and Verapamil; antiarteriosclerotic colored pattern is stable over time. agents such as pyridinol ; antiarthritic/antirheu The ODT with speckled appearance of the present inven 45 matic agents such as actarit, auranofin, aurothioglucose, tion can be a placebo tablet or preferably contain one or more aurothioglicanide, azathioprine, chloroquine, gold sodium active ingredients. thiosulfate, hydroxchloroquine, and methotrexate; antias Non-limiting examples active ingredients which can be matic agents such as azelastine, cromolyn, ibudilast, keto present in the ODT according to the present invention are: tifen, montelukast, oxotomide, pranlukast, , abortifacients such as E, and ; 50 Zafirlukast, Zileuton, beclomethasone, budesonide, dexam ACE inhibitors such as benazepril, captopril, delapril, enala ethasone, flunisolide, and triamcinolone acetonide; antibac pril, imidapril, and ramipril, C.-adrenergic agonists such as terial agents such as amikacin, gentamicin, kanamycin, neo adrenolone, , ephedrine, epinephrine, fenoxazoline, micin, tobramycin, chloramphenicol, thiamphenicol, ibopamine, methoxamine, nafazoline phenylephrine, phenyl rifamide, rifampin, rifamycin, rifapentine, rifaximin, cefa propanolamine, pseudoephedrine, tetrahydrozoline, trama 55 clor, cefamandole cefazolin, cefitime, cefoxitin, amoxicillin, Zoline, tuaminoheptane, and tyramine Xylomethazoline; ampicillin, oxacillin, lindomycin, erytromycin, gramicidin, B-adrenergic agonists such as albuterol, bambuterol, clen teicoplanin, Vancomycin, chlortetracyclin, doxycyline, tet buterol, clorprenaline, dopexamine, ephedrine, epinephrine, racyclin, trimetoprim, nifuradene, nitrofurantoin, ciprofloxa ethylnorepinephrine, fenoterol, formoterol, isoproterenol, cin, ofloxacin, lomefloxacin, benzylsulfamide, chloramine-t, mabuterol, metaproterenol, methoxyphenamine, oxyfedrine, 60 mafenide, Sulfabenzamide, Sulfacetamide, Sulfadiazine, Sul reproterol, salmeterol, soterenol, terbutaline, tulobuterol, and fadoxine, Sulfaguanidine, Sulfalene, Sulfanilamide, Sulfany Xanoterol, C.-adrenergic blockers such as dapiprazole, fen lurea, Sulfatyazole, Sulfisoxazole, acedapsone, dapsone, Sola spiride, nicergoline, prazosin, and yohimbine; B-adrenergic Sulfone, ethinamide, furonazide, isoniazide, and blockers such as acebutolol, alprenolol, atenolol, befnolol. streptomicyn; anticholinergic agents such as atropine, fento betaxolol, bupranolol, carazolol, carteolol, celiprolol, inde 65 nium bromide, homatropine, hyoscyamine, ipratropium bro nolol, levobunolol, mepindolol, metipranolol, moprolol, pin mide, isopropramide iodide, , and tropicamide; dolol, practolol, propranolol, and timolol; adrenocortical Ste anticoagulant agents such as acecumarol, bromindione, clo US 8,440,170 B2 5 6 rindione, coumetarol, dicumarol, diphenadione, fluindione, Zole, pirenzepine, ranitidine, and Sucralfate; anxiolytic agents heparin, hirundin, phenindione, and warfarin; anticonvulsant Such as buspirone, , , , agents such as albutoin, aloxidone, aminoglutethimide, bec , , and ; bronchodilators lamide, carbamazepine, , ethadine, ethotoin, fel such as albuterol, bambuterol, calbiterol, clenbuterol, clor bamate, mephenytoin, , nimethazepam, prenaline, ephedrine, ephineprine, follmoterol, metaproter , paramethadione, phenacemide, , enol, Salmeterol, terbutaline, ipratroprium bromide, and teo and phenitoin; agents such as citalopram, philline and derivatives; calcium channel blockers such as fencaine, nefopam, iproclozide, isocarboxazid, nialamide, diltiazem, Verapamil, amlodipine, lacidipine, micardipine, rolyciprine, maprotiline, metralindole, amytriptiline, clomi nifedipine, and nomerizine; cardiotonic agents such as digi pramide, desipramide, dibenzepin, imipramide, trimipra 10 talin, digitoxin, digoxin, dopamine, uabain, and Scillaren: mide, and bupropion; antidiabetic agents such as buformin, choleretic agents such as cholic acid, cynerin, dehydrocholic phenformin, insulin, carbutamide, chlorpopamide, glipizide, acid, dehoxycolic acid, and taurocolic acid; cholinergic phenbutamide, tolaZamide, tolbutamide, and tolcyclamide; agents such as acetylcholine, benzepirinium bromide, carba antidiarreal agents such as acetorphan, , difenoxin, chol, neostigmine, and physostigmine; CNS stimolants such diphenoxylate, loperamide, and mebiquine; antidiuretic 15 as amphetamine, caffeine, fenozolone, and phentermine; agents such as desmopressin, felypressin, ornipressin, and diuretic agents such as bendroflumethiazide, benzylhytro vasopressin; antidotes Such as , cysteamine, chlorothiazide, chlorothiazide, indapamide, mersalil, can methionine, and folinic acid; antidy skinetic agents such as drenone, oleandrin, spironolattone, acetazolamide, butazola amantidine, clonidine, haloperidol, pimozide, and tetrabena mide, clopramide, furosemide, and isosorbide; dopamine Zine; antiemetics such as alizapride, aZaSentron, benzquina receptoragonists Such as bromocriptine, cabercoline, dopex mide, bromopride, buclizine, , cyclizine, amine, and fenoldopam; dopamine receptor antagonists Such domperidone, granisetron, meclizine, metoclopramide, as amisulpride, domperidone, metoclopamide, and Sulpiride; ondansentron, prochlorerazine, Scopolamine, Sulpiride, and enzymes Such as amylase, lysozyme, and papain; expetorants tropistron; antifungal agents such as butenafine, butocona Such as , , carbocysteine, guaiacol, and Zole, econazole, fenticonazole, miconazole, tolciclate, tolin 25 ; gastric and pancreatic secretion stimulants such date, fluconazole, buclosamide, and triacetin; antiglaucoma as carnitine, and ceruletide; gastric proton pump inhibitors agents such as acetoZolamide, betaxolol, and bupranolol; Such as lansoprazole, omeprazole, and pantoprazole; gastric antigout agents such as allopurinol, colchicine, probenecid, secretion inhibitors such as enterogastrone, octretide, and and Sulfipyrazone; anthistaminic agents such as acrivastine, telenzepine; gastroprokinetic agents such as cinitapride, brompheniramine, chlorpheniramine, dimethindene, phe 30 cisapride, fenotozine, and loxiglumide; glucocorticoids Such niramine, tolpropamine, clemastine, diphenidramine, medril as beclomethasone, bethometaSone, budesonide, chloropred amyne, cetirizine, chlorcyclizine, cinnarizine, hidroxyzine, nisone, clobetasone, cortisone, corticosterone, deflazacort, fenethazine, , loratadine, antazoline, astemi dexamethasone, fluazacort, flumethasone, flunisolide, fluoci Zole, azelastine, ebastine, feXofenadine, and terfenadine; nolone acetonide, fluorometholone, fluprednisolone, hydro antihyperlipoproteinemic agents such as cholestiramine, ben 35 cortisone, methylprednisolone, prednisolone, prednisone, Zofibrate, clofibrate, etofibrate, genfibrozil, atorvastatin, lov and triamcinolone; hemolytic agents such as phenilhydra astatin, niceritrol, thyroxine, carnitine, chondroitinSulfate, Zine; histamine H-receptor antagonists such as cimetidine, ornithine, and probucol, antihypertensive agents such as ebrotidine, famotidine, nizatidine, and ranitidine; laxative/ bufuralol, acebutolol, atenolol, carteolol, metoprolol. cathartic agents such as frangulin, phenolphtaleine, and pico moprolol, pindolol, propranolol, timolol, chlorthiazide, 40 Sulfate Sodium; antagonists such as ibudilast, cyclopenthiazide, hydroflumethazide, benazepril, captopril, montelukast, pranlukast, and Zafirlukast, lipotropic agents lisinopril, ramipril, amlodipine, felodipine, lacidipine, nicar Such as buserelin, goserelin, histrelin, leuprolide, nafarelin, dipine, nitrendipine, bethnide, budralazine, hydralazine; and triptorelin; mineralcorticoid agents such as aldosterone, pheniprazine, phentolamine, bunaZosin, praZosin, reserpine, deoxycorticosterone, and fludrocortisones; monoamine oxi furosemide, ajmaline, fenoldopam, , methildopa, 45 dase inhibitors such as iproniazid, moclobemide, phenox and minoxidil; antihypotensive agents such as dopamine, ypropazine, and selegeline; mucolitic agents such as acetyl etillefrin, norepinephrine, and synephrine; nonsteroidal anti , bromexine, carbocysteine, lysozime, , and inflammatory agents such as , flufenamic acid, ; muscle relaxants such as , , mecofilenamic acid, tolfenamic acid, aceclofenac, alclofenac, curare, , dandrolene, decamethonium bromide, bromfenac, sodium, etodolac, ibufenac, 50 , eperisone, flumetramide, , mephenax indomethacin, piraZolac, , , , olone, methaxolone, , nimethazepam, Succyi ketorolac, , fenoprofen, flurbiprofen, , nylcholine bromide, , and tubocurarine; narcotic ketoprofen, naproxen, feprazone, benorylate, , antagonists Such as amiphenazole, naloxone, and naltaxone; , and ; antimalaria agents such as chlo nootropic agents such as aceglutamide, besipiride, piracetam, roquine, chlorproduanil, cinchonide, cycloguanil, and quini 55 and Vinconate; oxytocic agents such as , deami dine; antimigraine agents such as dolasetron, ergocornine, nooxytocic, ergonovine, gemeprost, methylergonovine, oxy ergocriptyne, ergot, ergotamine, lomerizine, and Sumatrip tocin, and prostaglandin F2, progestogens tan; antiparkinson agents amantadine, bromocriptine, carbi Such as drospirenone, dydrogesterone, ethynodiol, fluroge dopa, and levodopa; agents alizapride, amil stone acetato, lynestrenol, medrogestone, medroxyprogester Sulpiride, Sulpiride, , haloperidol, 60 one, megestrol acetate, norgesterone, pentagestrone, and acetophenazine, chlorpromazine, fluiphenazine, and pera ; prolactin inhibitors such as bromocriptine, Zine; antipyretic agents such as acetaminophen, alclofenac, cabergoline, lisuride, metergoline, and quinagoline; prostag , benorilate, and indomethacin; antispasmodic agents landins and analogs such as , carboprost, , aminopromazine, fentonium bromide, rociverine, and tiro gemeprost, limaprost, , , and pros pramide; antitussives such as , codeine and 65 taglandin E, E, F, respiratory stimulants such as almitrine, derivatives, , and ; antiulcer bemegride, cropropamide, dimorpholamine, lobeline, and ative agents acetoXolone, cimetidine, famotidine, omepra pyridopylline; retroviral transcriptase inhibitors such as US 8,440,170 B2 7 8 delavirdine, didanosine, dideoxyadenosine, lamivudine, sta EXAMPLE 2 Vudine, and Zidovudine, / such as acecar bromal, butoctamide, diethylbromoactamide, , tri Example 2A metozine, , , , , , , , mephobarbital, narcobarbital, , phenobarbital, , Perlitol(R) 160C (447.5 g), sucralose (5.5 g), citric acid (40 , , , , g), Povidone CL (Kollidon(R) CL 30.00 g) and Povidone K , nitrazepam, piperidione, , 30 (Kollidon(R)30–6 g) were placed in a fluid bed granulator , , , , meth Strea 1. aqualone, and ; serotonin/noradrenaline 10 Separately a quantity of purified water (50 ml) was pre reuptake inhibitors such as duloxetine, and Venlafaxine; sero pared. This solution was sprayed on the granular. At the end of tonin reuptake agonists such as buspirone, eltoprazine, spraying, the granular was dried at 40° C. until a residual ergotamine, and Sumatriptan; serotonin receptor antagonists moisture of NMT 0.5%. Such as aZaSentron, dolasentron, granisentron, ondasentron, The resultant granular was mixed in a cube blender mix ritanserin, and tropisentron; serotonin uptake inhibitors such 15 with peppermint flavor (5 g), magnesium Stearate (6.00 g) and as fomexitine, , and paroxetine; vasodilators such the colored granular (60 g) prepared as described in the as cinnarizine, citicoline, fenoxedil, flunarizine, lomerizine, example 1. nicergoline, nimodipine, papaverine, Vincamine, amotriph The mixture was blended until homogeneity and com ene, efloxate, nitroglicerin, pentrinitrol, trapidil, bradykinin, pressed in round biconcave tablets weighing 600 mg each. inositol, nicergoline, pentifillyne, and tolazoline; vitamins Such as calcitriol, ergosterol, Vitamin A, B and related B Example 2B complex, D and D complex, E, K, ascorbic acid, 3-carotene, and pantothenic acid; minerals such as calcium salts, phos phorous salts, iodine salts, iron salts, magnesium salts, potas Perlitol(R) 160C (507.5 g), sucralose (5.5g), citric acid (40 sium salts, chloride salts, chromium salts, molybdenum salts, 25 g), Povidone CL (Kollidon(R) CL 30.00 g) and Povidone K silicon and its salts, manganese salts, Zinc salts, 30 (Kollidon(R)30–6 g) were placed in a fluid bed granulator salts, boron salts, nickel salts, tin Salts, and Vanadium salts. Strea 1. The ODT with speckled appearance of the present inven Separately a quantity of purified water (50 ml) was pre tion can be prepared by incorporation of the soluble colored pared. This solution was sprayed on the granular. At the end of granules into any conventional ODT preparable by compres 30 spraying, the granular was dried at 40° C. until a residual sion. Non-limiting examples of these conventional ODT are moisture of NMT 0.5%. those disclosed in U.S. Pat. No. 6,149,938 (Elan), U.S. Pat. The resultant granular was mixed in a cube blender mix No. 6,024,981 (Cima), U.S. Pat. No. 6,221,392 (Cima), U.S. with peppermint flavor (5 g) and magnesium Stearate (6.00 g). Pat. No. 5,215,756 (Janssen), U.S. Pat. No. 5,264.632 The mixture was blended until homogeneity and com (Prographarm) and U.S. Pat. No. 6,872.405 (Yamanouchi). 35 pressed in round biconcave tablets weighing 600 mg each. Preferably the ODT with speckled appearance of the The comparison between the physical characteristics of the present invention are prepared by using the method described tablets prepared according to example 2A and according to in U.S. Pat. No. 6,149,938. example 2B is reported in the following table 1. In a preferred practical embodiment, the manufacturing 40 process of the ODT with speckled appearance object of the TABLE 1 present invention is the following. Comparison between the physical characteristics The active ingredient and the excipients are granulated in a of the tablets of examples 2A and 2B suitable fluid bed granulator. The colored granules and Tablets of Tablets of optional further excipients are added to the external phase and 45 example 2A example 2B the resultant mixture is blended in a suitable mixer. The Appearance White tablets with White homogeneous blended mixture is then compressed in a tabletting machine blue speckles tablets with punches of the desired shape obtaining ODT with speck Diameter 14 mm 14 mm led appearance according to the present invention. Thickness 4.4 mm 4.4 mm 50 Friability NMT1% NMT1% The following examples better illustrate the present inven Disintegration time in vitro NMT 60 seconds NMT 60 seconds tion without limiting it. (USP basket apparatus for tablets disintegration) Disintegration time in vivo 45 seconds 45 seconds EXAMPLE1 (mean of 3 healthy volunteers) 55 Grinding sensation in the mouth Absent Absent during disintegration of tablets Preparation of Blue Granules Perlitol(R) 400 (500 g) was placed in a fluid bed granulator The above data clearly shows that the presence of colored Strea 1. granules confers a easy identifiable colored pattern to the A homogeneous Suspension of FD&C blue no. 1 (1 g) in 60 ODT and does not affect the other physical characteristics of purified water (50 ml) was prepared. the ODT, in particular the disintegration characteristics. Air at about 30° C. was blown in the fluid bed and the Suspension was sprayed on the granular. EXAMPLE 3 At the end of spraying, the granular was dried at 40° C. 65 until a residual moisture of not more than (NMT) 0.5%. Phentermine hydrochloride (37.5g), Perlitol(R) 160C (410 The obtained granular was intensively colored in blue. g), sucralose (5.5 g), citric acid (40 g), Povidone CL (Kolli US 8,440,170 B2 10 don(R) CL-30.00g) and Povidone K30 (Kollidon(R)30–6 g) lidon(R) CL-15.00 g) and Povidone K30 (Kollidon R. 30 3 were placed in a fluid bed granulator Strea 1. g) were placed in a fluid bed granulator Strea 1. Separately a quantity of purified water (50 ml) was pre Separately a solution of purified water (25 ml) containing pared. This solution was sprayed on the granular. At the end of spraying, the granular was dried at 40° C. until a residual FD&C yellow lake no. 5 (0.6 g) was prepared. This solution moisture of NMT 0.5%. was sprayed on the granular. At the end of spraying, the The resultant granular was mixed in a cube blender mix granular was dried at 40°C. until a residual moisture of NMT with peppermint flavor (5 g), magnesium Stearate (6.00 g) and O.5%. the colored granular (60 g) prepared as described in the The resultant yellow granular was mixed in a cube blender example 1. mix with peppermint flavor (2.5 g), magnesium Stearate (3.00 The mixture was blended until homogeneity and com 10 g) and the colored granular (60g) prepared as described in the pressed in round biconcave tablets weighing 600 mg each and example 1. containing 37.5 mg of phentermine hydrochloride. The mixture was blended until homogeneity and com The physical characteristics of the resulting ODT are pressed in round tablets weighing 300 mg each and contain reported in the following table 2. 15 ing 15 mg of phentermine hydrochloride. The physical characteristics of the resulting ODT are TABLE 2 reported in the following table 4. Appearance White scored tablets with blue speckles and embossed with AX2 TABLE 4 Diameter 14 mm Thickness 4.4 mm Appearance Yellow tablets with blue Friability NMT1% speckles, embossed with AX4 Disintegration time in vitro NMT 60 seconds Diameter 10 mm (USP basket apparatus for Thickness 3.4 mm tablets disintegration) Friability NMT1% Disintegration time in vivo 45 seconds Disintegration time in vitro NMT 60 seconds (mean of 3 healthy volunteers) 25 (USP basket apparatus for Grinding sensation in the mouth Absent tablets disintegration) during disintegration of tablets Disintegration time in vivo 30 seconds (mean of 3 healthy volunteers) Grinding sensation in the mouth Absent during disintegration of tablets EXAMPLE 4 30 Phentermine hydrochloride (30 g), Perlitol(R) 160C (356.3 g), sucralose (5.5 g), citric acid (40 g), Povidone CL (Kolli EXAMPLE 6 don(R) CL-30.00g) and Povidone K30 (Kollidon(R)30–6 g) were placed in a fluid bed granulator Strea 1. 35 (15 g), Perlitol(R) 160C (432.5 g), sucralose Separately a solution of purified water (50 ml) containing (5.5 g), citric acid (40 g), Povidone CL (Kollidon(R) FD&C yellow lake no. 5 (1.2 g) was prepared. This solution CL 30.00 g) and Povidone K30 (Kollidon R. 30–6 g) were was sprayed on the granular. At the end of spraying, the placed in a fluid bed granulator Strea 1. granular was dried at 40°C. until a residual moisture of NMT O.5%. 40 Separately a quantity of purified water (50 ml) was pre The resultant yellow granular was mixed in a cube blender pared. This solution was sprayed on the granular. At the end of mix with peppermint flavor (5 g), magnesium Stearate (6.00 spraying, the granular was dried at 40° C. until a residual g) and Perlitol R 400 DC (120 g). moisture of NMT 0.5%. The mixture was blended until homogeneity and com The resultant granular was mixed in a cube blender mix pressed in round biconcave tablets weighing 600 mg each and 45 with Strawberry flavor (5 g), magnesium Stearate (6.00 g) and containing 30 mg of phentermine hydrochloride. the colored granular (60 g) prepared as described in the The physical characteristics of the resulting ODT are example 1. reported in the following table 3. The mixture was blended until homogeneity and com pressed in round biconcave tablets weighing 600 mg each and TABLE 3 50 containing 15 mg of meloxicam. Appearance Yellow tablets with white The physical characteristics of the resulting ODT are speckles and embossed with AX3 reported in the following table 5. Diameter 14 mm Thickness 4.4 mm Friability NMT1% 55 TABLE 5 Disintegration time in vitro NMT 60 seconds (USP basket apparatus for Appearance White tablets with blue speckles tablets disintegration) Diameter 14 mm Disintegration time in vivo 45 seconds Thickness 4.4 mm Friability NMT 190 (mean of 3 healthy volunteers) Meloxicam content 15 mg Grinding sensation in the mouth Absent 60 during disintegration of tablets Disintegration time in vitro NMT 60 seconds (USP basket apparatus for tablets disintegration) Disintegration time in vivo 40 seconds EXAMPLE 5 (mean of 3 healthy volunteers) Grinding sensation in the mouth Absent 65 during disintegration of tablets Phentermine hydrochloride (15g), Perlitol(R) 160C (178.15 g), sucralose (2.75 g), citric acid (20g), Povidone CL (Kol US 8,440,170 B2 11 The invention claimed is: 1. An orally disintegrating tablets with speckled appear ance comprising (a) speckles comprising colored granules of a water-soluble Sugar, and (b) a pharmaceutically acceptable carrier. 5 2. The orally disintegrating tablets according to claim 1 wherein the water-soluble Sugar is selected from the group consisting of Sucrose and polyalcohols. 3. The orally disintegrating tablets according to claim 2 wherein the water-soluble Sugar is selected from the group consisting of sucrose, Sorbitol, mannitol, xylitol, and fruc tOSe. 4. The orally disintegrating tablets according to claim 3 wherein the water-soluble Sugar is mannitol. 5. The orally disintegrating tablets according to claim 1 wherein the colored granules have a particle size from about 15 10 um to about 1200 um. 6. The orally disintegrating tablets according to claim 5 wherein the colored granules have a particle size from about 200 um to about 800 um. 7. The orally disintegrating tablets according to claim 6 wherein the colored granules have a particle size from about 300 um to about 500 um. 8. The orally disintegrating tablets according to claim 1 wherein the colored granules are present in an amount from about 0.1% w/w to about 50% w/w per tablet. 9. The orally disintegrating tablets according to claim 1 25 wherein the colored granules are present in an amount from about 1% w/w to about 30% w/w. k k k k k