(12) Ulllted States Patent
`Stroppolo et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,440,170 B2
`May 14, 2013
`
`US008440l70B2
`
`(54) ORALLY DISINTEGRATING TABLETS WITH
`SPECKLED APPEARANCE
`
`(75)
`
`.
`Inventors: Federico Stroppolo, Mezzovico (CH);
`Shahbaz Ardalan, Mezzovico (CH)
`.
`.
`(73) Assignee: Alpex Pharma SA, Mezzovico (CH)
`( * ) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 43 days.
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 9/44
`A61K 49/00
`(52) U_s_ CL
`USPC ....................................... .. 424/10.2, 424/103
`(58) Field of Classification Search ............... .. 424/ 10.2,
`424/10.3
`See application file for Complete Search history’
`R f
`C. d
`e °r°“°°s
`"e
`U.S. PATENT DOCUMENTS
`
`56
`
`(
`
`)
`
`(21) App]. No.:
`.
`(22) PCT F11ed3
`
`12/811,737
`
`Jam 302 2009
`
`................ .. 424/10.3
`l/1971 Pazar et al.
`3,555,144 A *
`
`.. 424/465
`1.
`9/2003 M '
`2003/0180357 A1 *
`,,,,,,,,,, H 424/439
`2004/0213355 A1* 10/2004 peiigrggoit :t 31,
`
`(86) PCT No.:
`
`PCT/EP2009/051055
`
`* cited by examiner
`
`§371(°)(1)=
`(2), (4) Date:
`
`Jul. 6, 2010
`
`(87) PCT Pub. No.: WO2009/098169
`
`PCT Pub. Date: Aug. 13, 2009
`
`(65)
`
`Prior Publication Data
`
`US 2010/0278754 A1
`
`Nov. 4, 2010
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/026,249, filed on Feb.
`5, 2008.
`
`GS " d’
`d
`' —F
`E
`P’
`ajja 1
`erey oun
`rzmary xamzner
`Assistant Examiner — Genevieve S Alley
`(74) Attorney, Agent, or Firm —Rothwell, Figg, Ernst &
`Manbeck, P.C.
`
`(57)
`
`ABSTRACT
`
`Orally disintegrating tablets containing colored granules of a
`water-soluble sugar which give them a speckled appearance
`are described. The orally disintegrating tablets with speckled
`appearance are readily and easy identifiable by physicians,
`nurses and patients.
`
`9 Claims, No Drawings
`
`Bass and Spangenberg
`Bass and Spangenberg
`Exhibit 1001
`Exhibit 1001
`
`

`
`US 8,440,170 B2
`
`1
`ORALLY DISINTEGRATING TABLETS WITH
`SPECKLED APPEARANCE
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`
`This application is a 35 U.S.C. 371 National Phase Entry
`Application from PCT/EP2009/051055, filed Jan. 30, 2009,
`which claims the benefit of U.S. Provisional 61/026,249 filed
`Feb. 5, 2008, the disclosures ofwhich are incorporated herein
`in their entirety by reference.
`The present invention generally relates to the identification
`of orally disintegrating tablets. More particularly, the inven-
`tion relates to orally disintegrating tablets with speckled
`appearance for their easy identification by physicians, nurses
`and patients.
`Solid pharmaceutical dosage forms for oral administration
`are usually in pill, tablet or capsule form. These dosage forms
`are available in a limited variety of shapes, size, and colors,
`and many of them are very similar to each other in their
`outward appearance.
`Frequently, users confuse such dosage forms, particularly
`ifthey are elderly or have limited vision. The consequences of
`taking the wrong medication can be life-threatening. For this
`reason Health Authorities require that each dosage form and
`strength must be clearly identified simply by individual visual
`inspection.
`Identification of tablets is usually made by using different
`shapes, sizes, or colors, or by color coating, printing or
`embossing them. Very often a double identification is
`required such as embossing and coloring, or coating and
`printing, etc.
`Also correct intake of drugs is important for their effective-
`ness.
`
`Conventional tablets are swallowed, usually with some
`water or other liquids, and the absorption of the active ingre-
`dient occurs in the gastro-intestinal tract.
`Orally Disintegrating Tablets (ODT) dissolve in the oral
`cavity by contact with saliva, do not require water for inges-
`tion and could permit a buccal absorption of the active ingre-
`dient. The advantageous properties ofODT over conventional
`tablets are making them always more and more popular for
`drug administrations.
`For their correct intake, it would be very helpful if ODT
`were more easily detectable and identifiable over conven-
`tional tablets.
`
`In case of ODT physical identification methods are limited
`because ODT tablets are characterized by a low hardness
`which allows their rapid dissolution when in contact with
`saliva (i.e. EU pharmacopoeia requires a disintegration time
`of not more than 3 minutes in water).
`Coating is not usually used because it could delay saliva
`penetration in the tablets, so delaying their disintegration.
`As a consequence, identification of ODT by printing is also
`unusual because this technique requires a smooth and shining
`tablet surface, such as a film- or a sugar-coated tablet.
`Embossing is possible but the dimension of characters is
`usually too small, due to the limited tablet surface, to be easily
`read by elderly people or by people with a limited vision.
`Colored ODT can be prepared but the limited number of
`pharmaceutically acceptable colors make difficult to obtain
`an ODT easily identifiable over conventional colored tablets.
`One way to solve the problem would be to make ODT
`identifiable by using a particular colored pattern.
`ODT with speckled (spotted) appearance, i.e. with a bicol-
`ored appearance characterized by the presence of spots of a
`different color on their surface can be easily identified by
`
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`25
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`35
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`45
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`users. For example, blue spots on a white or yellow tablet
`surface are easily visible, making such tablets more identifi-
`able than white or monocolored tablets.
`
`Solid or semisolid forms with speckled appearance are
`very common among cosmetic and laundry products, such as
`tooth pastes or soaps.
`They are prepared by incorporating colored beads of a
`different material into the composition.
`In case of ODT, the colored beads must be soluble and
`dissolve as fast as the tablets to avoid an unpleasant grinding
`sensation when the tablet disintegrates in the oral cavity.
`Moreover, the colored beads must be stable, i.e. they must not
`release the color during storage, and should give minimal
`coloration of the oral cavity after disintegration of the tablet.
`The present invention relates to orally disintegrating tab-
`lets containing colored granules which give a speckled
`appearance to the tablets for their readily and easy identifica-
`tion by physicians, nurses and patients.
`The orally disintegrating tablets of the invention contains
`colored granules of a water-soluble sugar.
`The present invention relates to orally disintegrating tab-
`lets (ODT) with speckled appearance which make them
`readily identifiable by users.
`The ODT with speckled appearance are prepared by mix-
`ing soluble colored granules to the pharmaceutically accept-
`able carrier.
`
`The term “colored granules” as used herein after means
`granules of a color different from the color of the tablet.
`Colored granules are, for example, blue or yellow granules in
`a white tablet, blue or white granules in a yellow tablet,
`yellow or white granules in a blue tablet, dark blue granules in
`a light blue tablet, blue granules and red granules in a white
`tablet, etc.
`The soluble colored granules are granular particles of a
`water-soluble sugar such as sucrose or a polyalcohol. Specific
`examples ofpolyalcohols are sorbitol, marmitol, xylitol, fruc-
`tose, etc.
`Preferably, the same polyalcohol already present in the
`pharmaceutically acceptable carrier of the ODT is used for
`the preparation of the colored granules of the invention.
`Preferably, the ODT of the present invention contains col-
`ored granules of marmitol.
`Even if water-soluble sugars are excipients usually present
`in ODT, their use to prepare colored granules suitable for the
`preparation of ODT with speckled appearance requires a
`specific particle size.
`In fact, the particle size of the colored granules is critical.
`Colored granules with too small particle size are not visible
`and the resulting tablets have no speckled appearance. On the
`other side, the use of colored granules with too large particle
`size results in a tablet which appears uniformly colored and
`therefore not readily identifiable over mono-colored tablets.
`The colored granules used in the ODT ofthe present inven-
`tion have a particle size from about 10 pm to about 1200 um,
`preferably from about 200 pm to about 800 um, most prefer-
`ably from about 300 pm to about 500 pm.
`The selection of the particle size of the colored granules of
`the ODT of the present invention depends on several factors.
`Since the sucrose orpolyalcohol used for the colored granules
`is preferably one ofthe excipients already present in the ODT,
`the particle size must be different from the particle size of the
`already present excipient.
`The selection of the suitable particle size also depends on
`the desired colored pattern. For example, the use of a little
`quantity of large particles tends to produce an ODT with few
`
`

`
`US 8,440,170 B2
`
`3
`large colored spots on its surface. Higher amount of smaller
`particles tends to produce less discrete colored spots on the
`surface of the tablets.
`
`5
`
`Then, the amount of colored granules suitable for each
`tablet, according to the present invention, can vary within a
`relatively large range depending on the particle size of the
`granule. Preferably, the amount of colored granules ranges
`between about 0.1% w/w and about 50% w/w, still more
`preferably between about 1% w/w and about 30% w/w.
`Preferably the colored granules useful for the ODT with 10
`speckled appearance of the present invention are prepared by
`granulation of the water-soluble sugar with an aqueous sus-
`pension or solution ofthe coloring agent in a suitable fluidbed
`granulator.
`Any soluble or insoluble pharmaceutically acceptable col-
`oring agent can be used.
`Non limiting examples of suitable coloring agents are
`FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum
`lake, FD&C green no. 1 aluminum lake, FD&C green no. 3
`aluminum lake, FD&C red no. 2 aluminum lake, FD&C red 20
`no. 3 aluminum lake, FD&C red no. 6 aluminum lake, FD&C
`red no. 7 aluminum lake, FD&C red no. 21 aluminum lake,
`FD&C red no. 27 aluminum lake, FD&C red no. 28 alumi-
`num lake, FD&C red no. 30 aluminum lake, FD&C red no. 33
`aluminum lake, FD&C red no. 40 aluminum lake, FD&C 25
`yellow no. 5 aluminum lake, FD&C yellow no. 6 aluminum
`lake, FD&C yellow no. 10 aluminum lake, ferric oxide yel-
`low, ferric oxide brown, ferric oxide red, and mixture thereof.
`The colored granules are incorporated into the composition
`of the ODT by conventional blending procedures. The ODT 30
`according to the present invention are then prepared by com-
`pression of the resulting mixture containing the colored gran-
`ules.
`
`15
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`45
`
`4
`
`as ACTH
`such
`hormones
`adrenocorticotropic
`roid;
`cosintropin; alcohol deterrents such as calcium cianarnide
`citrate, and disulfiram; aldose reductase inhibitors such as
`epalrestat, tolrestat, and zopolrestat; aldosterone antagonists
`such as canrenone, and spironolattone; anabolics such as
`androisoxazole, androstenediol, methandriol, methenolon,
`methyltrienolone, and nandrolone; narcotic analgesics such
`as alfentanil, buprenorphine, codeine and its derivatives, fen-
`tanil, meperidine, methadone, morphine and its derivatives,
`pentazocine, phenazocine, propirarn, propoxiphene, and
`sufentanil; non narcotic analgesics such as aceclofenac,
`acetaminophen, acetylsalicylic acid, alclofenac, alminopro-
`fen, antypirine, benorilate, benoxoprofen, bromfenac, buce-
`tin, carbarnazepine, carbiphene, chlortenoxazin, cholin sali-
`cylate,
`clometacin,
`clonixin,
`chloropamide,
`diflunisal,
`etodolac, felbinac, fenoprofen, flufenamic acid, flurbiprofen,
`ibufenac,
`imidazole salicylate,
`indomethacin,
`indoprofen,
`ketoprofen, ketorolac, mofezolac, naproxen, nifenazone,
`phenacetin, propyphenazone, sutrofen,
`tenoxicam, terofe-
`narnate, tolfenamic acid, tramadol, and viminol; androgens
`such as boldenone, cloxotestosterone, mestanolone, mester-
`olone,
`methandrostenolone,
`norethandrolone,
`normethandrone,
`oxandrolone,
`oxymesterone,
`oxymetholone, prasterone, stanolone, stanozolol, and test-
`osterone; angiotensin II receptor antagonists, such as cande-
`sartan, eprosartan, ibesartan, losartan, and valsartan; anorexic
`agents such as a minorex, amphecloral, anphetarnine, benz-
`phetamine, chlorphentermine, clobenzorex, clortermine, fen-
`fluramine, norpseudoephedrine, pentorex, phendimetrazine,
`phenmetrazine, and phentermine; anthelmintic agents such as
`arecoline, aspidin, aspidinol, becanthone, and hycantone;
`antiallergic agents such as amlexanox, astemizole, azelastine,
`cromolyn, fempiprane, ibudilast, lodoxamide, nedocromil,
`oxatomide, repirinast,
`tazanolast, hystamine, beclometha-
`sone, dexarnethasone, flunisolide, fluticasone, and triamcino-
`lone; antialopecia agents such as cioteronel, and minoxidil;
`antiamebic agents such as arsthinol, carbasone, chlorbeta-
`mide, chloroquine, chlorphenoxamide, emetine,
`fumag-
`gilline, and iodoquinol; antiarrhythmic agents such as acebu-
`tol, adenosine, ajmaline, alprenolol, amiodarone, atenolol,
`bupranolol, carazolol, carteolol, cloranolol, indenolol, iprat-
`ropium bromide, lidocaine, pindolol, propafenone, propra-
`nolol, quinidine, timolol, and verapamil; antiarteriosclerotic
`agents such as pyridinol carbamate; antiarthritic/antirheu-
`matic agents such as actarit, auranofin, aurothioglucose,
`aurothioglicanide, azathioprine, chloroquine, gold sodium
`thiosulfate, hydroxchloroquine, and methotrexate; antias-
`matic agents such as azelastine, cromolyn, ibudilast, keto-
`tifen, montelukast, oxotomide, pranlukast,
`seratrodast,
`zafirlukast, zileuton, beclomethasone, budesonide, dexam-
`ethasone, flunisolide, and triamcinolone acetonide; antibac-
`terial agents such as amikacin, gentarnicin, kanamycin, neo-
`micin,
`tobramycin,
`chloramphenicol,
`thiamphenicol,
`rifamide, rifampin, rifamycin, rifapentine, rifaximin, cefa-
`clor, cefamandole cefazolin, cefitime, cefoxitin, amoxicillin,
`ampicillin, oxacillin, lindomycin, erytromycin, gramicidin,
`teicoplanin, vancomycin, chlortetracyclin, doxycylline, tet-
`racyclin, trimetoprim, nifuradene, nitrofurantoin, ciprofloxa-
`cin, ofloxacin, lomefloxacin, benzylsulfarnide, chlorarnine-t,
`mafenide, sulfabenzamide, sulfacetamide, sulfadiazine, sul-
`fadoxine, sulfaguanidine, sulfalene, sulfanilamide, sulfany-
`lurea, sulfatyazole, sulfisoxazole, acedapsone, dapsone, sola-
`sulfone,
`ethinamide,
`furonazide,
`isoniazide,
`and
`streptomicyn; anticholinergic agents such as atropine, fento-
`nium bromide, homatropine, hyoscyamine, ipratropium bro-
`mide, isoproprarnide iodide, scopolarnine, and tropicamide;
`anticoagulant agents such as acecumarol, bromindione, clo-
`
`Since the incorporation of the colored granules does not
`change the manufacturing process and the characteristics of 35
`the ODT, the ODT with speckled appearance according to the
`present invention may be of any shape known among conven-
`tional ODT, may be embossed on the surface with symbol(s),
`letter(s) and/or number(s), may be scored, etc.
`The ODT with speckled appearance according to the 40
`present invention have the same disintegrating properties of
`ODT of reference (i.e. without colored granules). Moreover,
`a the coloring agent does not spread over the tablet and the
`colored pattern is stable over time.
`The ODT with speckled appearance of the present inven-
`tion can be a placebo tablet or preferably contain one or more
`active ingredients.
`Non-limiting examples active ingredients which can be
`present in the ODT according to the present invention are:
`abortifacients such as prostaglandin E2, and mifepristone;
`ACE inhibitors such as benazepril, captopril, delapril, enala-
`pril, imidapril, and ramipril; ot-adrenergic agonists such as
`adrenolone, clonidine, ephedrine, epinephrine, fenoxazoline,
`ibopamine, methoxamine, nafazoline phenylephrine, phenyl-
`propanolamine, pseudoephedrine, tetrahydrozoline, trarna-
`zoline,
`tuarninoheptane, and tyramine xylomethazoline;
`[3-adrenergic agonists such as albuterol, bambuterol, clen-
`buterol, clorprenaline, dopexamine, ephedrine, epinephrine,
`ethylnorepinephrine,
`fenoterol,
`formoterol,
`isoproterenol,
`mabuterol, metaproterenol, methoxyphenamine, oxyfedrine,
`reproterol, salmeterol, soterenol, terbutaline, tulobuterol, and
`xanoterol; ot-adrenergic blockers such as dapiprazole, fen-
`spiride, nicergoline, prazosin, and yohimbine; [3-adrenergic
`blockers such as acebutolol, alprenolol, atenolol, befnolol,
`betaxolol, bupranolol, carazolol, carteolol, celiprolol, inde-
`nolol, levobunolol, mepindolol, metipranolol, moprolol, pin-
`dolol, practolol, propranolol, and timolol; adrenocortical ste-
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`US 8,440,170 B2
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`5
`rindione, coumetarol, dicumarol, diphenadione, fluindione,
`heparin, hirundin, phenindione, and warfarin; anticonvulsant
`agents such as albutoin, aloxidone, aminoglutethimide, bec-
`lamide, carbamazepine, clonazepam, ethadine, ethotoin, fel-
`bamate, mephenytoin,
`narcobarbital,
`nimethazepam,
`nitrazepam, paramethadione, phenacemide, phenobarbital,
`and phenitoin; antidepressant agents such as citalopram,
`fencaine, nefopam,
`iproclozide,
`isocarboxazid, nialamide,
`rolyciprine, maprotiline, metralindole, amytriptiline, clomi-
`pramide, desipramide, dibenzepin,
`imipramide,
`trimipra-
`mide, and bupropion; antidiabetic agents such as buformin,
`phenformin, insulin, carbutamide, chlorpopamide, glipizide,
`phenbutamide, tolazamide, tolbutamide, and tolcyclamide;
`antidiarreal agents such as acetorphan, catechin, difenoxin,
`diphenoxylate,
`loperamide, and mebiquine; antidiuretic
`agents such as desmopressin, felypressin, omipressin, and
`vasopressin; antidotes such as acetylcysteine, cysteamine,
`methionine, and folinic acid; antidyskinetic agents such as
`amantidine, clonidine, haloperidol, pimozide, and tetrabena-
`zine; antiemetics such as alizapride, azasentron, benzquina-
`mide, bromopride, buclizine, chlorpromazine, cyclizine,
`domperidone,
`granisetron, meclizine, metoclopramide,
`ondansentron, prochlorerazine, scopolamine, sulpiride, and
`tropistron; antifungal agents such as butenafine, butocona-
`zole, econazole, fenticonazole, miconazole, tolciclate, tolin-
`date, fluconazole, buclosamide, and triacetin; antiglaucoma
`agents such as acetozolamide, betaxolol, and bupranolol;
`antigout agents such as allopurinol, colchicine, probenecid,
`and sulfipyrazone; anthistaminic agents such as acrivastine,
`brompheniramine, chlorpheniramine, dimethindene, phe-
`niramine, tolpropamine, clemastine, diphenidramine, medril-
`amyne, cetirizine, chlorcyclizine, cinnarizine, hidroxyzine,
`fenethazine, promethazine,
`loratadine, antazoline, astemi-
`zole, azelastine, ebastine, fexofenadine, and terfenadine;
`antihyperlipoproteinemic agents such as cholestiramine, ben-
`zofibrate, clofibrate, etofibrate, genfibrozil, atorvastatin, lov-
`astatin, niceritrol, thyroxine, carnitine, chondroitinsulfate,
`ornithine, and probucol; antihypertensive agents such as
`bufuralol,
`acebutolol,
`atenolol,
`carteolol, metoprolol,
`moprolol, pindolol, propranolol,
`timolol, chlorthiazide,
`cyclopenthiazide, hydroflumethazide, benazepril, captopril,
`lisinopril, ramipril, amlodipine, felodipine, lacidipine, nicar-
`dipine, nitrendipine, bethnide, budralazine, hydralazine;
`pheniprazine, phentolamine, bunazosin, prazosin, reserpine,
`furosemide, ajmaline, fenoldopam, mebutamate, methildopa,
`and minoxidil; antihypotensive agents such as dopamine,
`etilefrin, norepinephrine, and synephrine; nonsteroidal anti-
`inflammatory agents such as etofenamate, flufenamic acid,
`mecoflenamic acid, tolfenamic acid, aceclofenac, alclofenac,
`bromfenac,
`diclofenac
`sodium,
`etodolac,
`ibufenac,
`indomethacin, pirazolac,
`sulindac,
`tolmetin,
`fenbufen,
`ketorolac, alminoprofen, fenoprofen, flurbiprofen, ibuprofen,
`ketoprofen, naproxen,
`feprazone, benorylate, piroxicam,
`bendazac, and nimesulide; antimalaria agents such as chlo-
`roquine, chlorproquanil, cinchonide, cycloguanil, and quini-
`dine; antimigraine agents such as dolasetron, ergocormne,
`ergocriptyne, ergot, ergotamine, lomerizine, and sumatrip-
`tan; antiparkinson agents amantadine, bromocriptine, carbi-
`dopa, and levodopa; antipsychotic agents alizapride, amil-
`sulpiride,
`sulpiride,
`risperidone,
`haloperidol,
`acetophenazine, chlorpromazine, fluphenazine, and pera-
`zine; antipyretic agents such as acetaminophen, alclofenac,
`aspirin, benorilate, and indomethacin; antispasmodic agents
`aminopromazine, fentonium bromide, rociverine, and tiro-
`pramide; antitussives such as cloperastine, codeine and
`derivatives, dextromethorphan, and morclofone; antiulcer-
`ative agents acetoxolone, cimetidine, famotidine, omepra-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`zole, pirenzepine, ranitidine, and sucralfate; anxiolytic agents
`such as buspirone, alprazolam, bromazepam, camazepam,
`lorazepam, nordazepam, and meprobamate; bronchodilators
`such as albuterol, bambuterol, calbiterol, clenbuterol, clor-
`prenaline, ephedrine, ephineprine, folmoterol, metaproter-
`enol, salmeterol, terbutaline, ipratroprium bromide, and teo-
`philline and derivatives; calcium channel blockers such as
`diltiazem, verapamil, amlodipine, lacidipine, micardipine,
`nifedipine, and nomerizine; cardiotonic agents such as digi-
`talin, digitoxin, digoxin, dopamine, uabain, and scillaren;
`choleretic agents such as cholic acid, cynerin, dehydrocholic
`acid, dehoxycolic acid, and taurocolic acid; cholinergic
`agents such as acetylcholine, benzepirinium bromide, carba-
`chol, neostigmine, and physostigmine; CNS stimolants such
`as amphetamine, caffeine, fenozolone, and phentermine;
`diuretic agents such as bendroflumethiazide, benzylhytro-
`chlorothiazide, chlorothiazide,
`indapamide, mersalil, can-
`drenone, oleandrin, spironolattone, acetazolamide, butazola-
`mide, clopramide, furosemide, and isosorbide; dopamine
`receptor agonists such as bromocriptine, cabercoline, dopex-
`amine, and fenoldopam; dopamine receptor antagonists such
`as amisulpride, domperidone, metoclopamide, and sulpiride;
`enzymes such as amylase, lysozyme, and papain; expetorants
`such as ambroxol, bromhexine, carbocysteine, guaiacol, and
`guaifenesin; gastric and pancreatic secretion stimulants such
`as carnitine, and ceruletide; gastric proton pump inhibitors
`such as lansoprazole, omeprazole, and pantoprazole; gastric
`secretion inhibitors such as enterogastrone, octretide, and
`telenzepine; gastroprokinetic agents such as cinitapride,
`cisapride, fenotozine, and loxiglumide; glucocorticoids such
`as beclomethasone, bethometasone, budesonide, chloropred-
`nisone, clobetasone, cortisone, corticosterone, deflazacort,
`dexamethasone, fluazacort, flumethasone, flunisolide, fluoci-
`nolone acetonide, fluorometholone, fluprednisolone, hydro-
`cortisone, methylprednisolone, prednisolone, prednisone,
`and triamcinolone; hemolytic agents such as phenilhydra-
`zine; histamine H2-receptor antagonists such as cimetidine,
`ebrotidine, famotidine, nizatidine, and ranitidine; laxative/
`cathartic agents such as frangulin, phenolphtaleine, and pico-
`sulfate sodium;
`leukotriene antagonists such as ibudilast,
`montelukast, pranlukast, and zafirlukast; lipotropic agents
`such as buserelin, goserelin, histrelin, leuprolide, nafarelin,
`and triptorelin; mineralcorticoid agents such as aldosterone,
`deoxycorticosterone, and fludrocortisones; monoamine oxi-
`dase inhibitors such as iproniazid, moclobemide, phenox-
`ypropazine, and selegeline; mucolitic agents such as acetyl-
`cysteine, bromexine, carbocysteine, lysozime, sobrerol, and
`tyloxapol; muscle relaxants such as afloqualone, baclofen,
`curare, cyclarbamate, dandrolene, decamethonium bromide,
`diazepam, eperisone, flumetramide, mephenesin, mephenax-
`olone, methaxolone, methocarbamol, nimethazepam, succyi-
`nylcholine bromide, tetrazepam, and tubocurarine; narcotic
`antagonists such as amiphenazole, naloxone, and naltaxone;
`nootropic agents such as aceglutamide, besipiride, piracetam,
`and vinconate; oxytocic agents such as carboprost, deami-
`nooxytocic, ergonovine, gemeprost, methylergonovine, oxy-
`tocin, prostaglandin E2, and prostaglandin F20; progestogens
`such as drospirenone, dydrogesterone, ethynodiol, fluroge-
`stone acetato, lynestrenol, medrogestone, medroxyprogester-
`one, megestrol acetate, norgesterone, pentagestrone, and
`progesterone; prolactin inhibitors such as bromocriptine,
`cabergoline, lisuride, metergoline, and quinagoline; prostag-
`landins and analogs such as beraprost, carboprost, enprostil,
`gemeprost, limaprost, misoprostol, prostacyclin, and pros-
`taglandin E1, E2, F2a; respiratory stimulants such as almitrine,
`bemegride, cropropamide, dimorpholamine,
`lobeline, and
`pyridopylline;
`retroviral
`transcriptase inhibitors such as
`
`

`
`US 8,440,170 B2
`
`7
`delavirdine, didanosine, dideoxyadenosine, lamivudine, sta-
`vudine, and zidovudine; sedative/hypnotics such as acecar-
`bromal, butoctamide, diethylbromoactamide, niaprazine, tri-
`metozine, zolpidem, zopiclone, allobarbital, amobarbital,
`barbital, cyclopentobarbital, hexobarbital, mephobarbital,
`narcobarbital, pentobarbital, phenobarbital,
`tetrabarbital,
`estazolam,
`flunitrazepam,
`flurazeparn,
`loprazolam,
`lormetazepam,
`nitrazepam,
`piperidione,
`acetophenone,
`clomethiazole, doxylamine,
`temazeparn,
`triazolam, meth-
`aqualone,
`and
`glutethimide;
`serotonin/noradrenaline
`reuptake inhibitors such as duloxetine, and venlafaxine; sero-
`tonin reuptake agomsts such as buspirone, eltoprazine,
`ergotamine, and sumatriptan; serotonin receptor antagonists
`such as azasentron, dolasentron, granisentron, ondasentron,
`ritanserin, and tropisentron; serotonin uptake inhibitors such
`as fomexitine, fluoxetine, and paroxetine; vasodilators such
`as cinnarizine, citicoline, fenoxedil, flunarizine, lomerizine,
`nicergoline, nimodipine, papaverine, vincarnine, amotriph-
`ene, efloxate, nitroglicerin, pentrinitrol, trapidil, bradykinin,
`inositol, nicergoline, pentifillyne, and tolazoline; vitamins
`such as calcitriol, ergosterol, vitamin A, B and related B
`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-
`sium salts, chloride salts, chromium salts, molybdenum salts,
`silicon and its salts, manganese salts, zinc salts, selenium
`salts, boron salts, nickel salts, tin salts, and vanadium salts.
`
`The ODT with speckled appearance of the present inven-
`tion can be prepared by incorporation of the soluble colored
`granules into any conventional ODT preparable by compres-
`sion. Non-limiting examples of these conventional ODT are
`those disclosed in U.S. Pat. No. 6,149,938 (Elan), U.S. Pat.
`No. 6,024,981 (Cima), U.S. Pat. No. 6,221,392 (Cima), U.S.
`Pat. No. 5,215,756 (Janssen), U.S. Pat. No. 5,264,632
`(Prographarm) and U.S. Pat. No. 6,872,405 (Yamanouchi).
`Preferably the ODT with speckled appearance of the
`present invention are prepared by using the method described
`in U.S. Pat. No. 6,149,938.
`
`In a preferred practical embodiment, the manufacturing
`process of the ODT with speckled appearance object of the
`present invention is the following.
`The active ingredient and the excipients are granulated in a
`suitable fluid bed granulator. The colored granules and
`optional further excipients are added to the external phase and
`the resultant mixture is blended in a suitable mixer. The
`
`blended mixture is then compressed in a tabletting machine
`with punches ofthe desired shape obtaining ODT with speck-
`led appearance according to the present invention.
`The following examples better illustrate the present inven-
`tion without limiting it.
`
`EXAMPLE 1
`
`Preparation of Blue Granules
`Perlitol® 400 (500 g) was placed in a fluid bed granulator
`Strea 1.
`
`A homogeneous suspension of FD&C blue no. 1 (1 g) in
`purified water (50 ml) was prepared.
`Air at about 30° C. was blown in the fluid bed and the
`
`suspension was sprayed on the granular.
`At the end of spraying, the granular was dried at 40° C.
`until a residual moisture of not more than (NMT) 0.5%.
`The obtained granular was intensively colored in blue.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`EXAMPLE 2
`
`Example 2A
`
`Perlitol® 160C (447.5 g), sucralose (5.5 g), citric acid (40
`g), Povidone CL (Kollidon® CL—30.00 g) and Povidone K
`30 (Kollidon® 30—6 g) were placed in a fluid bed granulator
`Strea 1.
`
`Separately a quantity of purified water (50 ml) was pre-
`pared. This solution was sprayed on the granular. At the end of
`spraying, the granular was dried at 40° C. until a residual
`moisture of NMT 0.5%.
`
`The resultant granular was mixed in a cube blender mix
`withpeppermint flavor (5 g), magnesium stearate (6.00 g) and
`the colored granular (60 g) prepared as described in the
`example 1.
`The mixture was blended until homogeneity and com-
`pressed in round biconcave tablets weighing 600 mg each.
`
`Example 2B
`
`Perlitol® 160C (507.5 g), sucralose (5.5 g), citric acid (40
`g), Povidone CL (Kollidon® CL—30.00 g) and Povidone K
`30 (Kollidon® 30—6 g) were placed in a fluid bed granulator
`Strea 1.
`
`Separately a quantity of purified water (50 ml) was pre-
`pared. This solution was sprayed on the granular. At the end of
`spraying, the granular was dried at 40° C. until a residual
`moisture of NMT 0.5%.
`
`The resultant granular was mixed in a cube blender mix
`withpeppermint flavor (5 g) and magnesium stearate (6.00 g).
`The mixture was blended until homogeneity and com-
`pressed in round biconcave tablets weighing 600 mg each.
`The comparison between the physical characteristics ofthe
`tablets prepared according to example 2A and according to
`example 2B is reported in the following table 1.
`
`TABLE 1
`
`Comparison between the physical characteristics
`ofthe tablets of examples 2A and 2B
`Tablets of
`Tablets of
`example 2A
`example 2B
`
`White tablets with White homogeneous
`blue speckles
`tablets
`14 mm
`14 mm
`4.4 mm
`4.4 mm
`NMT 1%
`NMT 1%
`NMT 60 seconds NMT 60 seconds
`
`Appearance
`Diameter
`Thickness
`Friability
`Disintegration time in vitro
`(USP basket apparatus for
`tablets disintegration)
`Disintegration time in vivo
`(mean of 3 healthy volunteers)
`Grinding sensation in the mouth Absent
`during disintegration of tablets
`
`45 seconds
`
`45 seconds
`
`Absent
`
`The above data clearly shows that the presence of colored
`granules confers a easy identifiable colored pattern to the
`ODT and does not affect the other physical characteristics of
`the ODT, in particular the disintegration characteristics.
`
`EXAMPLE 3
`
`Phentermine hydrochloride (37.5 g), Perlitol® 160C (410
`g), sucralose (5.5 g), citric acid (40 g), Povidone CL (Kolli-
`
`

`
`US 8,440,170 B2
`
`9
`don® CL—30.00 g) and Povidone K 30 (Kollidon® 30—6 g)
`were placed in a fluid bed granulator Strea 1.
`Separately a quantity of purified water (50 ml) was pre-
`pared. This solution was sprayed on the granular. At the end of
`spraying, the granular was dried at 40° C. until a residual
`moisture of NMT 0.5%.
`The resultant granular was mixed in a cube blender mix
`with peppermint flavor (5 g), magnesium stearate (6.00 g) and
`the colored granular (60 g) prepared as described in the
`example 1.
`The mixture was blended until homogeneity and com-
`pressed in round biconcave tablets weighing 600 mg each and
`containing 37.5 mg of phentermine hydrochloride.
`The physical characteristics of the resulting ODT are
`reported in the following table 2.
`
`Appearance
`Diameter
`Thickness
`Friability
`Disintegration time in Vitro
`(USP basket apparatus for
`tablets disintegration)
`Disintegration time in Vivo
`(mean of 3 healthy volunteers)
`Grinding sensation in the mouth
`during disintegration of tablets
`
`TABLE 2
`
`White scored tablets with blue
`speckles and embossed with AX2
`14 mm
`4.4 mm
`NMT 1%
`NMT 60 seconds
`
`45 seconds
`
`Absent
`
`EXAMPLE 4
`
`Phentermine hydrochloride (30 g), Perlitol® 160C (356.3
`g), sucralose (5.5 g), citric acid (40 g), Povidone CL (Kolli-
`don® CL—30.00 g) and Povidone K 30 (Kollidon® 30—6 g)
`were placed in a fluid bed granulator Strea 1.
`Separately a solution of purified water (50 ml) containing
`FD&C yellow lake no. 5 (1.2 g) was prepared. This solution
`was sprayed on the granular. At the end of spraying, the
`granular was dried at 40° C. until a residual moisture ofNMT
`0.5%.
`
`The resultant yellow granular was mixed in a cube blender
`mix with peppermint flavor (5 g), magnesium stearate (6.00
`g) and Perlitol® 400 DC (120 g).
`The mixture was blended until homogeneity and com-
`pressed in round biconcave tablets weighing 600 mg each and
`containing 30 mg of phentermine hydrochloride.
`The physical characteristics of the resulting ODT are
`reported in the following table 3.
`
`Appearance
`Diameter
`Thickness
`Friability
`Disintegration time in Vitro
`(USP basket apparatus for
`tablets disintegration)
`Disintegration time in Vivo
`(mean of 3 healthy volunteers)
`Grinding sensation in the mouth
`during disintegration of tablets
`
`TABLE 3
`
`Yellow tablets with white
`speckles and embossed with AX3
`14 mm
`4.4 mm
`NMT 1%
`NMT 60 seconds
`
`45 seconds
`
`Absent
`
`EXAMPLE 5
`
`Phentermine hydrochloride (15 g), Perlitol® 160C (178.15
`g), sucralose (2.75 g), citric