USOO890.06O2B2

(12) United States Patent (10) Patent No.: US 8,900,602 B2 Fujiwara et al. (45) Date of Patent: *Dec. 2, 2014

(54) DISINTEGRATING PARTICLE FOREIGN PATENT DOCUMENTS COMPOSITION AND ORALLY RAPIDLY DISINTEGRATING TABLET EP 1523974 4/2005 JP 10-120554 5, 1998 JP 11-310539 11, 1999 (75) Inventors: Keiichi Fujiwara, Ibaraki (JP); Tadashi JP 2000,86537 3, 2000 Fukami, Kamiichi-machi (JP); Haruka JP 2005-139168 6, 2005 Koizumi, Kamiichi-machi (JP) JP 2005-306770 11/2005 ...... 424/401 JP 2005, 306770 11, 2005 JP 2009-1141.13 5, 2009 (73) Assignee: Fuji Chemical Industry Co., Ltd., WO 2005/037254 4/2005 Toyama (JP) WO 2005.37319 4/2005 WO 2007 O29376 3, 2007 (*) Notice: Subject to any disclaimer, the term of this WO 2007/29379 3, 2007 patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS This patent is Subject to a terminal dis claimer. Translation of JP2005-306770 A. Inventors: Ishikawa, T. Published Nov. 4, 2005. Cited in IDS filed Feb. 10, 2012.* (21) Appl. No.: 13/389,874 International Preliminary Report on Patentability and Written Opin ion issued Mar. 13, 2012 in International Application No. PCT/ (22) PCT Filed: Aug. 11, 2010 JP2010/063602, of which the present application is the national Stage. (86). PCT No.: PCT/UP2O10/063602 International Search Report issued Oct. 5, 2010 in International (PCT) Application No. PCT/JP2010/063602, of which the present S371 (c)(1), application is the national stage. (2), (4) Date: Feb. 10, 2012 Supplementary European Search Report issued Dec. 12, 2012 in corresponding European Patent Application No. 10808229.8. (87) PCT Pub. No.: WO2011/019046 English abstract of JP 2005-139168, Jun. 2, 2005. PCT Pub. Date: Feb. 17, 2011 English abstract of JP 2000-086537, Mar. 28, 2000. English abstract of JP 2005-306770, Nov. 4, 2005. (65) Prior Publication Data English abstract of JP 10-120554, May 12, 1998. US 2012/O165413 A1 Jun. 28, 2012 English abstract of JP 2009-1141 13, May 28, 2009. English abstract of JP 11-310539, Nov. 9, 1999. (30) Foreign Application Priority Data * cited by examiner Aug. 11, 2009 (JP) ...... 2009-186648 (51) Int. Cl. Primary Examiner — Audrea Buckley A2.3L L/48 (2006.01) (74) Attorney, Agent, or Firm — Wenderoth, Lind & Ponack, A6 IK 47/26 (2006.01) LLP. A6 IK9/20 (2006.01) A 6LX3/5.375 (2006.01) A6 IK9/00 (2006.01) (57) ABSTRACT (52) U.S. Cl. Disclosed is an orally rapidly disintegrating tablet which has CPC ...... A61 K9/0056 (2013.01); A61 K9/2018 a good texture and taste in the oral cavity, Such a sufficient (2013.01); A61K3I/5375 (2013.01) hardness as not giving any worry of being chipped or dusted USPC ...... 424/400: 514/770; 514/769: 426/661 during production or transportation and good disintegrating (58) Field of Classification Search properties in the oral cavity. The orally rapidly disintegrating USPC ...... 424/400 tablet, which has a good texture and taste, an appropriate See application file for complete search history. hardness, and good disintegrating properties, can be pro duced by using a composition, which is prepared by dispers (56) References Cited ing, by spray-drying, an inorganic excipient and starch(es) in complex particles composed of mannitol and Xylitol, in an U.S. PATENT DOCUMENTS orally rapidly disintegrating tablet. 2005/0106240 A1* 5/2005 Tanaka et al...... 424/464 2007/0275058 A1 11, 2007 Tanaka et al. 2008/0206327 A1 8/2008 Stroppolo et al. 6 Claims, No Drawings US 8,900,602 B2 1. 2 DISINTEGRATING PARTICLE DISCLOSURE OF INVENTION COMPOSITION AND ORALLY RAPIDLY DISINTEGRATING TABLET Problems to be Solved by the Invention TECHNICAL FIELD 5 The present invention is directed to provide a disintegrating particle composition which is appropriate for an orally rap The present invention relates to a disintegrating particle idly disintegrating tablet which have an improved texture and composition which is prepared by dispersing mannitol. Xyli taste in the oral cavity, such a Sufficient hardness as not giving tol, inorganic excipient(s) and starch(es) in complex particles, any worry during production or transportation and good dis and an orally rapidly disintegrating tablet comprising the 10 integrating properties in the oral cavity, compared to orally disintegrating particle composition. rapidly disintegrating tablets in the conventional art, and an orally rapidly disintegrating tablet comprising the disinte BACKGROUND ART grating particle composition. Orally rapidly disintegrating tablets have been developed 15 as a form which is easy to be taken by patients, elderly people, Means of Solving the Problems children, etc. who have difficulty in Swallowing drugs, or is easy to be taken without water. The orally rapidly disintegrat According to extensive studies to achieve the above pur ing tablets should have Such a sufficient hardness as not being pose, the present inventors have found a disintegrating par chipped or dusted during production or transportation oftab ticle composition, which is prepared by homogeneously dis lets or opening, and in addition, it is required that a disinte persing inorganic excipient(s) and starch(es) in complex gration time in the oral cavity is within about 60 seconds and particles which are composed of mannitol and xylitol. The a texture and taste in the oral cavity has no problem. There are present inventors have also found an orally rapidly disinte more problems to be solved in the orally rapidly disintegrat grating tablet which has excellent disintegrating properties, ing tablets compared to normal tablets. Specifically, a disin 25 Such a sufficient hardness as not giving any worry during tegration time and hardness are contradictory factors, and in production or transportation and a Sufficient texture and taste general, disintegration times tend to be extended as molding in the oral cavity, which is prepared by mixing the disinte pressures are increased for the purpose of the increase of grating particle composition together with an active ingredi hardness, and hardness tends to be decreased as molding ent, disintegrant(s), and ingredient(s) such as lubricant, pressures are decreased for the purpose of the shortening of 30 excipient, binders which do not impair the effect of the disintegration times. present invention. An orally rapidly disintegrating composition which is pre Specifically, the present invention is the following (1) to pared by granulating an organic acid Such as tartaric acid, a (11). hydrogen carbonate salt of alkali metal Such as Sodium hydro (1) A disintegrating particle composition, which is prepared gen carbonate, a network maintenance agent such as corn 35 starch or potato starch, a color protection agent such as man by dispersing inorganic excipient(s) and starch(es) in com nitol or xylitol, followed by compressing to mold has been plex particles which are composed of mannitol and Xylitol, known (Patent Document 1). The composition becomes fizzy wherein by the reaction of an organic acid with a carbonate salt under (a) the sum of mannitol and xylitol is 70 to 90 parts by weight; moisture condition in the oral cavity, and a drying process is 40 (b) the inorganic excipient(s) are in the amount of 2 to 15 parts required to prepare the composition in addition to the com by weight; pression molding process. (c) the starch(es) are in the amount of 5 to 25 parts by weight, An orally rapidly disintegrating formulation which is pre and pared by dry-blending hydroxypropylstarch, spray-dried the total amount of the ingredients (a), (b) and (c) is 100 parts D-mannitol, a physiologically active ingredient and anhy 45 by weight; drous silicic acid, followed by compressing to mold has been (2) A disintegrating particle composition, which is prepared known (Patent Document 2). by homogeneously dispersing inorganic excipient(s) and An orally rapidly disintegrating tablet comprising a phar starch(es) in complex particles which are composed of man maceutical composition obtained by dispersing Sugar and an nitol and xylitol, wherein inorganic compound in water and spray-drying (Patent Docu 50 (a) the sum of mannitol and xylitol is 70 to 90 parts by weight; ment 3), and a composition for an orally rapidly disintegrat (b) the inorganic excipient(s) are in the amount of 2 to 15 parts ing tablet characterized by dispersing complex particles of by weight; Sugar, a disintegrant and an inorganic Substance in the pres (c) the starch(es) are in the amount of 5 to 25 parts by weight, ence of water (Patent Documents 4, 5, 6) have been known. and It has never been known that a disintegrating particle com 55 the total amount of the ingredients (a), (b) and (c) is 100 parts position which is prepared by dispersing inorganic by weight; excipient(s) and starch(es) in complex particles which are (3) The composition of (2), wherein composed of mannitol and Xylitol, and an orally rapidly dis (a) the sum of mannitol and xylitol is 75 to 85 parts by weight; integrating tablet comprising the composition have better (b) the inorganic excipient(s) are in the amount of 3 to 9 parts molding properties, hardness and disintegrating properties 60 by weight; and than those prepared by the conventional method. (c) the starch(es) are in the amount of 10 to 15 parts by weight; Patent document 1 JP-A-11-310539 (4) The composition of (3), wherein the ratio by weight of Patent document 2.JP-A-2005-306770 mannitol to xylitol is 99:1 to 90:10; Patent document 3 JP-A-2000-86537 (5) The composition of (3), wherein the ratio by weight of Patent document 4 WO 2005/37319 pamphlet 65 mannitol to xylitol is 99:1 to 95:5; Patent document 5 WO 2005/37254 pamphlet (6) The composition of any one of (1) to (5), wherein the Patent document 6 WO 2007/29376 pamphlet inorganic excipient(s) are at least one or more agents selected US 8,900,602 B2 3 4 from magnesium aluminometasilicate, magnesium alumino The average particle size of the disintegrating particle com silicate, anhydrous silicic acid, calcium silicate, calcium position of the present invention may be 1 to 400 um, prefer hydrogen phosphate, calcium carbonate or talc; ably 5 to 300 um, in view of preventing roughness in the oral (7) The composition of any one of (1) to (5), wherein the cavity and disintegrating properties. In view of the disinte starch(es) are at least one or more agents selected from potato grating properties in the oral cavity, fluidity during prepara starch, flour starch, Sticky rice starch, Sweet potato starch, tion of tablet and loading properties, the more spherical the tapioca starch, rice starch, cornstarch, waxy cornstarch or disintegrating particle composition of the present invention hydroxypropylstarch; is, the more preferable it is, and the degree of sphericity is 0.7 (8) A method for preparing the composition of any one of (1) or more, more preferably 0.8 or more. The degree of spheric to (7), comprising a step wherein a dispersion comprising the 10 ity is calculated by ratios of minor axis/major axis in SEM ingredients (a) to (c) is spray-dried; images or optical microscope. The average particle size of the (9) An orally rapidly disintegrating tablet, comprising 0.1 to disintegrating particle composition of the present invention 200 parts by weight of the active ingredient and 10 to 100 obtained above is measured by Laser Diffraction Particle Size parts by weight or less of a disintegrant per 100 parts by Analyzer HELOS & RODOS of SYMPATEC, Inc., for weight of the composition of any one of (1) to (7), 15 example. (10) The orally rapidly disintegrating tablet of (9), wherein In the present invention, the inorganic excipient refers to an the disintegrant is potato starch, flour starch, Sticky rice agent having high-specific Surface areas which is insoluble or starch, Sweet potato starch, tapioca Starch, rice starch, corn hardly soluble in water, and includes at least one or more starch, waxy cornstarch, hydroxypropylstarch or crospovi agents selected from magnesium aluminometasilicate, mag done, and nesium aluminosilicate, anhydrous silicic acid, calcium sili (11) The orally rapidly disintegrating tablet of any one of (9) cate, magnesium silicate, aluminum silicate, calcium hydro to (10), further comprising a lubricant, wherein the lubricant gen phosphate, anhydrous calcium hydrogen phosphate, an is externally added. agglomerated material of anhydrous calcium hydrogen phos phate, hydrotalcite, calcium phosphate, calcium carbonate, Effect of Invention 25 magnesium oxide, magnesium hydroxide, magnesium hydroxide-aluminium hydroxide co-precipitate, dried alumi The orally rapidly disintegrating tablet comprising the num hydroxide gel, magnesium carbonate, calcium carbonate orally rapidly disintegrating particle composition of the or talc. Preferable one is at least one or more agents selected present invention is characterized by having Such a sufficient from magnesium aluminometasilicate, magnesium alumino hardness as not giving any worry during production or trans 30 silicate, anhydrous silicic acid, calcium silicate, calcium portation and good disintegration times in the oral cavity and hydrogen phosphate, calcium carbonate or talc. being able to prepare in simple steps. The orally rapidly It is preferable that the inorganic excipient has high-spe disintegrating tablet may be also used in medicine or food cific Surface areas in view of water-conducting properties or which rapid disintegrating properties in the oral cavity are dispersibilities in complex particles, and BET-specific sur required. 35 face area is 20 to 500 m/g and a preferable BET-specific surface area is 50 to 300 m/g. It is considered that one having BEST MODE FOR CARRYING OUT THE high-specific Surface areas improves permeabilities of water INVENTION in granulated particles by water-conducting effects and dis rupts granulated particles immediately in contact with water The disintegrating particle composition of the present 40 due to its aggregated structure of a few micrometers or less of invention is a spherical particulate composition which is pre primary particles. When an inorganic excipient with high pared by dispersing inorganic excipient(s) and starch(es) in specific Surface areas is used to compress and mold into a complex particles which are composed of mannitol and Xyli tablet form in the production of the granulated particles of the tol, preferably the composition wherein the dispersing is present invention, the inorganic excipient reduces the water homogeneous dispersing. The “complex particles' composed 45 content of Sugar by adjusting concentrations of water in a of mannitol and xylitol refer to particles wherein xylitol is tablet. Binding forces at junction points of disintegrating Solid-dispersed in mannitol particles. The "dispersing incom particle compositions proceed to reduce under humid condi plex particles' is observed by SEM images (scanning electron tions after opening by the adjusting effect. When the inor micrograph), etc., preferably “homogeneously dispersing in ganic excipient is used, the granulation efficiency by spray complex particles'. The "homogeneously dispersing in com 50 may be improved and the yields of the disintegrating particle plex particles' refers to a state wherein each ingredient which composition of the present invention may be improved. is identifiable by SEM images, etc. is dispersed in smaller In the present invention, the starch(es) are preferably those particle sizes close to primary particles than apparent particle which are hardly soluble in water for the purpose of dispers sizes upon addition in complex particles. The apparent par ing in complex particles, and include at least one or more ticle sizes refer to average particle sizes measured by a dry 55 agents selected from potato starch, flour starch, Sticky rice particle size distribution analyzer. starch, Sweet potato starch, tapioca Starch, rice starch, corn Among Sugar, mannitol is easy to use, since it is stable as an starch, waxy cornstarch, pregelatinized Starch, hydroxypro excipient in that it is not hygroscopic, it is not colored by a pyl starch or sodium carboxymethyl starch. Preferable one is reaction Such as Maillard reaction and it is poorly reactive at least one or more agents selected from potato starch, flour with agents, but it is disadvantageous in that its molding 60 starch, Sticky rice starch, Sweet potato starch, tapioca starch, properties are bad. The disintegrating particle composition of rice starch, cornstarch, waxy cornstarch or hydroxypropyl the present invention has good molding properties and disin starch. tegrating properties as well as temporal stabilities by spray Mannitol and starch(es) with 0.1 to 500 um of the average drying or freeze-drying mannitol to granule or to prepare particle size, preferably 1 to 200 um of the average particle amorphous, or by Solid-dissolving or Solid-dispersing Xylitol 65 size, may be used for the purpose of preventing roughness in into mannitol to prepare a complex base. These factors are the oral cavity. The inorganic excipient(s) which are hardly described in JP-A-2005-139168. soluble in water may be used in the average particle size of 0.1 US 8,900,602 B2 5 6 to 60 um, preferably 0.1 to 20 m or less, for the purpose of other ingredients to be blended without impairing disintegrat the dispersion in the composition or the prevention of rough ing properties are blended, these agents are added to spray ness in the oral cavity. drying during the preparation of the dispersion. The blending amounts of each ingredient in the disintegrat The above aqueous solvent may be any solvent which do ing particle composition of the present invention is 70 to 90 not affect properties of the disintegrating particle composi parts by weight of the sum of mannitol and xylitol. 2 to 15 tion and may be acceptable for pharmaceuticals or foods, and parts by weight of the inorganic excipient(s) and 5 to 25 parts includes water, ethanol, acetone, for example. The dispersion by weight of starch(es) per 100 parts by weight of the total may be prepared according to the known method which amount of the ingredients (a) to (c), preferably 75 to 85 parts includes conventional stirring, colloid milling, high-pressure by weight of the sum of mannitol and xylitol, 3 to 9 parts by 10 homogenizing, ultrasonic irradiation, wet-type atomizing, for weight of the inorganic excipient(s) and 10 to 15 parts by example, and may be any methods which may highly disperse weight of starch(es), further preferably 75 to 80 parts by particles in an aqueous dispersion. The concentration of the weight of the sum of mannitol and xylitol, 4 to 8 parts by composition in the dispersion may be any concentration to the weight of the inorganic excipient(s) and 12 to 14 parts by extent that the dispersion can be spray-dried which may vary weight of starch(es). 15 depending on the Viscosity of the dispersion, specifically 5 to The complex particles of the present invention are com 50% by weight, preferably 10 to 45% by weight. posed of mannitol and xylitol, and the ratio by weight of Conditions of spray-drying are not limited, but a preferable mannitol and xylitol is 99:1 to 90:10, preferably 99:1 to 95:5, spray-drying machine is a disk or nozzle type spray-drying further preferably 99:1 to 97:3. machine. The temperature in the spray-drying is preferably The static specific Volume of the disintegrating particle about 120 to 220° C. at inlet temperature, and about 80 to 130° composition of the present invention is preferably 1.5 to 4.0 C. at outlet temperature. The concentration of solid materials ml/g, more preferably 1.5 to 3.5 ml/g, further preferably 1.5 to in the aqueous dispersion in the spray drying may be any 2.5 ml/g. Such a static specific Volume of the disintegrating concentrations which spray drying may be carried out. The particle composition can achieve Smoothness during formu particle size of the disintegrating particle composition may be lation due to ease of loading into mortar during molding 25 optionally controlled by concentrations of an aqueous solu tablet, and excellent tableting properties to provide homoge tion or aqueous dispersion, spray-drying methods, drying neous compression of tablet. The static specific Volume may conditions. be measured in accordance with conventional methods. The "orally rapidly disintegrating tablet' in the present The disintegrating particle composition of the present invention refers to a tablet which may rapidly disintegrate in invention may comprise the following active ingredient and 30 the oral cavity, for example within 60 seconds, preferably otheringredients to be blended without impairing disintegrat within 40 seconds, further preferably within 30 seconds. The ing properties, if needed, and the blending amount of each disintegration time in the oral cavity herein is time needed in ingredient is 0.01 to 200 parts by weight of the active ingre the following conditions of the orally rapidly disintegrating dient, 10 to 100 parts by weight of a disintegrant and 0.1 to tabletor Example methods. The disintegration time in the oral 100 parts by weight of other ingredients to be blended without 35 cavity differs between tablets depending on the size or figure impairing disintegrating properties per 100 parts by weight as of tablet, which is also included in the present invention. the Sum of mannitol. Xylitol, inorganic excipient(s) and In the present invention, the “texture' which does not gen starch(es), preferably 0.1 to 100 parts by weight of the active erate discomfort in the oral cavity refers to the feeling without ingredient, 10 to 50 parts by weight of a disintegrant and 0.1 causing mealy texture or muddy Smell which does not cause to 50 parts by weight of other ingredients to be blended 40 a feeling wherein blending materials just absorb water to without impairing disintegrating properties per 100 parts by swell and a tablet does not disintegrate, i.e. without fluffy weight as the sum of mannitol. Xylitol, inorganic excipient(s) feelings, and the “taste' which does not generate discomfort and starch(es). in the oral cavity refers to the feeling without tartness (i.e., The disintegrating particle composition of the present Sourness), bitter taste, hard taste derived from starting mate invention may be usually prepared by any methods wherein 45 rials. each ingredient may be dispersed such as spraying methods The orally rapidly disintegrating tablet of the present including spray drying, tumbling granulation, agitation invention may comprise an active ingredient, a disintegrant granulation, fluidized-bed granulation, freeze-drying meth and other ingredients to be blended without impairing disin ods. It is preferable that the composition is prepared by the tegrating properties, if needed. The blending ratio of each spraying method wherein the ingredients are easy to be dis 50 ingredient is 0.01 to 200 parts by weight of an active ingre persed and spherical particles are easy to prepare. The disin dient, 10 to 100 parts by weight of a disintegrant and 0.1 to tegrating particle composition of the present invention may 100 parts by weight of other ingredients to be blended without be prepared by the common spraying method in which man impairing disintegrating properties per 100 parts by weight of nitol. Xylitol, inorganic excipient(s) and starch(es) are dis the disintegrating particle composition, preferably 0.1 to 100 persed in an aqueous solvent and the dispersion is spray dried. 55 parts by weight of an active ingredient, 10 to 50 parts by More specifically, mannitol. Xylitol, inorganic excipient(s) weight of a disintegrant and 0.1 to 50 parts by weight of other and starch(es) are added to an aqueous solvent to prepare a ingredients to be blended without impairing disintegrating dispersion in the method, and a dosing order of the ingredi properties per 100 parts by weight of the total amount of ents is not specified. In order to completely dissolve the mannitol. Xylitol, inorganic excipient(s) and starch(es). ingredients, it is preferable that mannitol and Xylitol are pre 60 In the present invention, the disintegrant is, for example, liminarily dissolved or dispersed in an aqueous solvent, fol one or more agents selected from adipic acid, alginic acid, lowed by inorganic excipient(s), Starch(es) are homoge Sodium alginate, pregelatinized starch, erythritol, fructose, neously dispersed to prepare. After that, the dispersion may Sodium carboxymethyl starch, carmellose, carmellose cal be spray-dried to give the disintegrating particle composition cium, carmellose sodium, aqueous silicon dioxide, agar, Xyli of the present invention. When the active ingredient, an agent 65 tol, guar gum, calcium citrate, croScarmellose Sodium, controlling the influence of the active ingredient on the mold crospovidone, synthetic aluminum silicate, magnesium alu ing properties or disintegrating properties, and the following minosilicate, low-substituted hydroxypropylcellulose, crys US 8,900,602 B2 7 8 talline cellulose, crystalline cellulose carmellose Sodium, Antiepileptic agents include acetylpheneturide, gabapen Sticky rice starch, potato starch, flour starch, Sweet potato tin, carbamazepine, clonazepam, clobazam, Sultiame, Zonisa starch, tapioca Starch, rice starch, cornstarch, waxy corn mide, trimethadione, sodium Valproate, phenytoin, primi starch, cellulose acetate phthalate, dioctyl sodium sulfo Suc done. cinate. Sucrose fatty acid ester, magnesium hydroxide-alu Antipyretics, analgesics or antiphlogistics include actarit, minium hydroxide co-precipitate, calcium Stearate, polyoxyl , acetaminophen, , , Stearate, Sorbitan sesquioleate, gelatin, shellac, Sorbitol, Sor indomethacin, indomethacinfarnesyl , , bitan fatty acid ester, talc, Sodium hydrogen carbonate, mag epirizole, emorfaZone, tramadol hydrochloride, buprenor nesium carbonate, precipitated calcium carbonate, dextrin, phine hydrochloride, , , Sodium salicy 10 late, , sodium, , Sulpyrine Sodium dehydroacetate, cornstarch, tragacanth, trehalose, hydrate, , , tiaramide hydrochloride, lactose, maltose, saccharose, hydrotalcite, honey, palatinit, , , bucolome, pentazocin, mefenamic palatinose, potato starch, hydroxyethylmethylcellulose, acid, , mofeZolac, Sodium hydrate. hydroxypropyl starch, hydroxypropylcellulose, glucose, ben Antiparkinson agents include amantadine hydrochloride, tonite, partially pregelatinized starch, monosodium fumarate, selegiline hydrochloride, talipexole hydrochloride, pirohep polyethylene glycol, polyoxyethylene hardened castor oil, 15 tine hydrochloride, pramipexole hydrochloride hydrate, polyoxyethylene polyoxypropylene glycol, polysorbate, maZaticol hydrochloride, metixene hydrochloride, entaca polyvinyl acetal diethylamino acetate, polyvinylpyrrolidone, pone, cabergoline, trihexyphenidyl hydrochloride, droxi dopa, biperiden, bromocriptine mesilate, pergolide mesilate, maltitol, D-mannitol, anhydrous citric acid, anhydrous silicic levodopa. acid, magnesium aluminometasilicate, methylcellulose, Psychoneurotic agents include amitriptyline hydrochlo glycerin monostearate or sodium lauryl Sulfate, and any one ride, amoxan, aripiprazole, imipramine hydrochloride, eti of them may be used alone and two or more of them may be Zolam, sultopride hydrochloride, sertraline hydrochloride, mixed. Preferable one is crospovidone, hydroxypropyl trazodone hydrochloride, paroxetine hydrochloride hydrate, starch, Sticky rice starch, potato starch, flour starch, Sweet floropipamide hydrochloride, perospirone hydrochloride potato starch, tapioca Starch, rice starch, cornstarch or waxy 25 hydrate, mianserin hydrochloride, milnacipran hydrochlo cornstarch. ride, methylphenidate hydrochloride, mosapramine hydro In the present invention, the active ingredient refers to an chloride, moperone hydrochloride, lofepramine hydrochror active principle for medicament or a nutrient component in ide, oxypertine, olanzapine, carpipramine, clocapramine food. The active ingredient may be added alone, or in the hydrochloride hydrate, clotiazepam, clomipramine hydro 30 chloride chlorpromazine, spiperone, Sulpiride, Zotepine, sustained releasable form or the coated or granulated form of lithium carbonate, timiperone, haloperidol decanoate, nem the active ingredient so as to mask bitter taste. The coating onapride, nortriptyline hydrochloride, haloperidol, hydrox processing includes a method spray drying the active ingre yZine hydrochloride, hydroxy Zine pamoate, pimozide, que dient and agents such as an insoluble polymer, stomach tiapine fumarate, fluphenazine, prochlorperazine, soluble polymer, enteric polymer, a method mixing the active propericiazine, bromperidol, perphenazine, maprotiline ingredient with methylcellulose and mannitol. 35 hydrochloride, Setiptiline maleate, trifluoperazine maleate, The active ingredient includes central nervous system trimipramine maleate, fluvoxamine maleate, modafinil, ris agents, peripheral nervous system agents, agents affecting peridone, levomepromazine. sensory organs, agents affecting circulatory organs, agents Other central nervous system agents include tiapride affecting respiratory organs, agents affecting digestive hydrochloride, donepezil hydrochloride, taltirelin hydrate, organs, hormonal agents, agents affecting genitourinary 40 terguride, mazindol, riluzole. apparatus, medicaments affecting other organs, vitamin Regional anesthetics among the peripheral nervous system preparations, revitalizers, agents for blood or body fluid, agents include ethylaminobenzoate, bupivacaine hydrochlo other metabolized drugs, cellular stimulants, antineoplastic ride, ropivacaine hydrochloride hydrate, oxethazaine, agents, radioactive agents, anti-allergic agents, other medica procaine hydrochloride, mepivacaine hydrochloride, ments for tissue cellular functions, natural medicine, Chinese 45 lidocain. medicine, other natural medicine and medicine based on Chi Autonomic agents include ambenonium chloride, oxapium nese medicine prescription, antibiotic agents, chemothera iodide, distigmine bromide, propantheline bromide, mepen peutic agents, biological preparations, agents against para Zolate bromide. sitic animals, other medicine against pathogenic organism, Spasmolytic agents include afloqualone, eperisone hydro dispensing agents, diagnostic agents, agents for public health, 50 chloride, piperidolate hydrochloride, tizanidine hydrochlo extracorporeal diagnostic agents, other agents not mainly ride, timepidium bromide hydrate, tolperisone hydrochlo intended for treatment, alkaloidal narcotics (natural narcot ride, baclofen, papaverine hydrochloride, butylscopolamine ics), and non-alkaloidal narcotics (Drugs in Japan 2008, bromide, butropium bromide, flopropione, N-methylscopo Jihou, Inc.), but is not limited thereto. lamine methylsulfate. Hypnosedatives or anti-anxiety agents among the central Otological agents of the agents affecting sensory organs nervous system agents include alprazolam, estaZoram, 55 include amlexanox, lomefloxacin hydrochloride, ofloxacin, dexmedetomidine hydrochloride, rilmazafone hydrochlo chloramphenicol. Antimotionsickness agents include isopro ride, oxazolam, quazepam, tandospirone citrate, cloxazolam, terenol hydrochloride, diphenidol hydrochloride, betahistine cloraZepate dipotassium, chlordiazepoxide, diazepam, potas mesylate. sium bromide, calcium bromide, Sodium bromide, Zolpidem Cardiotonic agents among the agents affecting circulatory tartrate, secobarbital sodium, Zopiclone, tofisopam, triaz 60 organs include aminophylline hydrate, etillefrine hydrochlo olam, triclofos Sodium, nitrazepam, nimetazepam, passiflora ride, isoproterenolhydrochloride, choline theophylline, digi extract, barbital, haloxazolam, phenobarbital, prazepam, flu toxin, digoxin, denopamine, pimobendan, proxyphylline, diazepam, flutazolam, flutoprazepam, flunitrazepam, flu Vesnarinone, methyldigoxin, ubidecarenone. razepam hydrochloride, brotizolam, bromazepam, bromoV Antiarrhythmic agents include ajimarine, acebutolol alerylurea, pentobarbital, chloral hydrate, midazolam, 65 hydrochloride, atenolol, alprenolol hydrochloride, arotinolol mexazolam, medazepam, ethyl loflazepate, lorazepam, hydrochloride, aprindine hydrochloride, amiodarone hydro lormetazepam. chloride, Sotalol hydrochloride, pilsicainide hydrochloride, US 8,900,602 B2 9 10 propafenone hydrochloride, bepridil hydrochloride, Oxpre trimetoquinol hydrochloride hydrate, procaterol hydrochlo nolol hydrochloride, carteolol hydrochloride, quinidine sul ride hydrate, formoterol fumarate hydrate. fate hydrate, cibenzoline Succinate, flecainide acetate, dis Oral rinse includes aZulene Sodium Sulfonate. opyramide, nadolol, pindolol, bufetolol hydrochloride, Antidiarrheals or antiflatulents among the agents affecting bisoprolol fumarate, procainamide hydrochloride, propra digestive organs include loperamide hydrochloride, dimethi nolol hydrochloride, Verapamil hydrochloride, mexiletine cone, resistant lactobacillus preparation, bifidobacteria hydrochloride. preparation, berberine chloride hydrate, preparation for Diuretics include aZosemide, chlorthalidone, spironolac butyric acid bacteria. tone, torasemide, triamterene, trichlormethiazide, hydrochlo Agents for peptic ulcer include aZulene Sodium Sulfonate, rothiazide, piretanide, bumetanide, furosemide, benzylhy 10 aldioxa, benexate hydrochloride betadex, omeprazole, orno drochlorothiazide, mefruside, mozavaptain hydrochloride. prostil, gefarnate, cimetidine, Sucralfate hydrate, Sulpiride, Hypotensive agents include azelnidipine, alacepril, arani cetraxate hydrochloride, Sofalcone, teprenone, troXipide, dipine, indapamide, amoSulalol hydrochloride, imidapril nizatidine, pirenzepine hydrochloride hydrate, famotidine, hydrochloride, efonidipine hydrochloride, quinapril hydro plaunotol, proglumide, polaprezinc, irsogladine maleate, chloride, celiprolol hydrochloride, tilisolol hydrochloride, 15 misoprostol, methylmethioninesulfonium chloride, raniti temocapril hydrochloride, terazosin hydrochloride, delapril dine hydrochloride, lafutidine, Sodium rabeprazole, lanSopra Zole, clebopride malate, rebamipide, roXatidine acetate hydrochloride, barnidipine hydrochloride, prazosin hydro hydrochloride. chloride, betaxolol hydrochloride, benazepril hydrochloride, Acid Suppressants include magnesium oxide, magnesium bevantolol hydrochloride, manidipine hydrochloride, labe hydroxide, Sodium hydrogen carbonate, precipitated calcium talol hydrochloride, olmesartan medoxomil, cadralazine, carbonate, magnesium aluminometasilicate. captopril, carteolol hydrochloride, carvedilol, candesartan Laxatives include Senna extract, Sennoside, Sodium pico cilexetil, guanabenZ acetate, clonidine hydrochloride, cilaza sulfate hydrate. pril, cilnidipine, telmisartan, todralazine hydrochloride Choleretic agents include anetholtrithione, urSodeoxy hydrate, trandolapril, tripamide, nicardipine hydrochloride, cholic acid, trepibutone, nicotinic acid, naphthylacetic acid. nipradillol, nilvadipine, Valsartan, hydralazine hydrochloride, 25 Other agents affecting digestive organs include Mallotus pindolol, felodipine, budralazine, bunazosin hydrochloride, japonicus extract, azulene Sodium sulfonate, cetylpyridinium propranolol hydrochloride, perindopril erbumine, penbutolol chloride, dequalinium chloride, aZasetron hydrochloride, ito Sulfate, enalapril maleate, bopindolol malonate, doxazosin pride hydrochloride, indisetron hydrochloride, granisetron mesilate, meticrane, methyl-DOPA hydrate, metoprolol tar hydrochloride, cevimeline hydrochloride hydrate, tropisetron trate, lisinopril hydrate, rescinnamine, reserpine, losartan 30 hdyrochloride, ramosetron hydrochloride, ondansetron, potassium. kitasamycin acetate, mosapride citrate, domiphen bromide, Vasoconstrictive agents include rizatriptan benzoate, dexamethasone, trimebutine maleate, domperidone, pilo midodrine hydrochloride, dihydroergotamine mesylate, elet carpine hydrochloride, polycarbophil calcium, mesalazine, riptan hydrobromide, Sumatriptan, Zolmitriptan. metoclopramide. Vasodilators include isosorbide mononitrate, inositol Salivary gland hormone preparations orthyroid or parathy hexanicotinate, isoXSuprine hydrochloride, dipyridamole, 35 roid hormonal agents include dried thyroid, thiamazole, pro isosorbide dinitrate, dilazephydrochloride hydrate, diltiazem pylthiouracil, liothyronine Sodium, levothyroxine Sodium hydrochloride, trapidil, trimetazidine hydrochloride, nic hydrate. orandil, nisoldipine, nitrendipine, nitroglycerin, nifedipine, Anabolic steroids include mestanolone, methenolone. amlodipine besylate, benidipine hydrochloride, hepronicate, Adrenal hormonal agents include cortisone acetate, fluidro Verapamil hydrochloride. 40 cortisone acetate, dexamethasone, triamcinolone, hydrocor Antihyperlipidemic agents include atorvastatincalcium tisone, prednisolone, betamesone, methylprednisolone. hydrate, ezetimibe, elastase ES, clinofibrate, clofibrate, Androgenic hormonal agents include methyl testosterone. colestimide, simvastatin, Soysterol, Sodium dextran Sulfate, Estrogenic hormonal and progestational hormonal agents nicomol, niceritrol, pitavastatin calcium, fenofibrate, pravas include allylestrenol, estriol, ethinyl estradiol, chlormadi tatin Sodium, fluvastatin Sodium, probucol, beZafibrate, poly 45 none acetate, conjugated estrogen, medroxyprogesterone enephosphatidylcholine, rosuvastatin calcium. acetate, dydrogesterone, norethisterone, pregnanediol, fos Other agents affecting circulatory organs include ifen festrol. prodil tartrate, indomethacin, sevelamer hydrochloride, Other hormonal agents include kallidinogenase, clomi fasudil hydrochloride hydrate, lomerizine hydrochloride, phene citrate, cyclophenyl, danazol, triloStane, finasteride. gamma-aminobutanoic acid, dihydroergotoxine mesylate, 50 Agents affecting reproductive tract among the agents tocopherolnicotinic acid ester, nicergoline, bosentanhydrate, affecting genitourinary apparatus include estriol, clotrima meclofenoxate hydrochloride, amezinium methyl Sulfate. Zole, chloramphenicol, tinidazole, metronidazole. Antitussive agents among the agents affecting respiratory Oxytocics include methylergometrine maleate. organs include ephedrine hydrochloride, clo?edanol hydro Contraceptive agents include ethinyl estradiol norethister chloride, cloperastine, dimenorfan phosphate, dextrometho 55 one, ethinyl estradiol levonorgestrel, desogestrel ethinyl rphan hydrobromide hydrate, pentoxyverine citrate, benpro estradiol. perine phosphate. Agents for hemorrhoidal disease include venous plexus Expectorantagents include L-ethylcysteine hydrochloride, extract, tribenoside, bromelain tocopherol acetate, melilot L-methylcysteine hydrochloride, L-carbocysteine, ambroXol eXtract. hydrochloride, fudosteine, bromhexine hydrochloride. Other agents affecting genitourinary apparatus include Antitussive expectorant agents include eprazinone hydro 60 imidafenacin, Quercus salicina extract, oxybutynin hydro chloride, guaifenesin, codeine phosphate hydrate, tipepidine chloride, Vardenafil hydrochloride hydrate, propiverine hibenzate. hydrochloride, sildenafil citrate, Solifenacin Succinate, Bronchodilator agents include aminophylline hydrate, iso tolterodine tartrate, silodosin, cernitin pollen extract, tamsu proterenol hydrochloride, clenbuterol hydrochloride, losin hydrochloride, naftopidil, flavoxate hydrochloride, rito mabuterol hydrochloride, methoxyphenamine hydrochlo 65 drine hydrochloride. ride, orciprenaline sulfate, salbutamol sulfate, fenoterol Other agents for each organ include gamma-ory Zanol, hydrobromide, tulobuterol, theophylline, terbutaline sulfate, cepharanthine. US 8,900,602 B2 11 12 Vitamin A and D preparations among the vitamin prepara difumarate, pranlukast hydrate, bepotastine besylate, pemiro tions include alfacalcidol, calcitriol, VitaminA, falecalcitriol. last potassium, montelukast sodium, ramatroban, repirinast, Vitamin B1 preparations include dicethiamine hydrochlo loratadine. ride, octothiamine, thiamine disulfide, bisbentiamine, fursul Antibiotic agents include Vancomycin hydrochloride, tiamine, benfotiamine. amoxicillin hydrate, cephalexin, cefaclor, cefixime, cefcap Vitamin B preparations include cobamamide, nicotinic ene pivoxilhydrochloride hydrate, cefdinir, cefteram pivoxil, acid, pantethine, hydroxocobalamin acetate, pyridoxine cefpodoxime proxetil, azithromycin, enoxacin, clarithromy hydrochloride, flavin adenine dinucleotide, mecobalamin, cin, ciclacillin, josamycin, roXithromycin, levofloxacin. folic acid, riboflavin butyrate, pyridoxal phosphate. Synthetic antibacterials include moxifloxacin hydrochlo Vitamin C preparations include ascorbic acid, and vitamin 10 ride, lomefloxacin hydrochloride, ofloxacin, ciprofloxacin, E preparations include tocopherol calcium Succinate, toco nalidixic acid, norfloxacin, pipemidic acid hydrate, fleroxa pherol acetate. C1. Vitamin K preparations include phytonadione, menate Antivirus agents include aciclovir, adefovir pivoxil, trenone. efavirenz, emitricitabine, Valaciclovir hydrochloride, ente Other vitamin preparations include astaxanthin, fucoxan 15 cavir hydrate, Zanamivir hydrate, sanilvudin, didanosine, thin, lutein. Zidovudine, nevirapine, palivizumab, fosamprenavir cal Calcium preparations among the revitalizers include cal cium, saquinavir mesylate, delavirdine mesylate, lamivudine, cium L-aspartate, calcium lactate hydrate. ritonavir, ribavirin, abacavir Sulfate, oseltamivir phosphate, Mineral preparations include potassium L-aspartate, lopinavir ritonavir. potassium chloride, Sodium ferrous citrate, potassium glu Other chemotherapeutic agents include itraconazole, ter conate, iodine lecithin, iron Sulfate hydrate. binafine hydrochloride, furconazole. Hemostatic agents among the agents for blood or body Other effective ingredients may be, for example, one or fluid include carbazochrome sodium sulfonate hydrate, tran more agents selected from the group consisting of deoxyri examic acid, adrenochrome monoaminoguanidine mesilate. bonucleic acid and a salt thereof, an adenylic acid derivative Agents for inhibiting blood coagulation include warfarin including adenosine triphosphate, adenosine monophosphate potassium. 25 and a salt thereof, ribonucleic acid and a salt thereof, a nucleic Other agents for blood or body fluid include aspirin, ethyl acid-related material including guanine, Xanthine and a icosapentate, Sarpogrelate hydrochloride, ciloStaZol, ticlopi derivative thereofanda salt thereofananimal-derived extract dine hydrochloride, beraprost sodium, limaprostalfadex, clo including deproteinized blood serum extract, splenic extract, pidogrel Sulfate. placental extract, cock's comb extract, royal jelly; a microbi Agents for liver disorders among the other metabolized 30 ally-derived extract including yeast extract, lactic bacterium drugs include liver hydrolysate, diisopylamine dichloroac extract, bifidus extract, ganoderma lucidum extract; a plant etate, tiopronin, protoporphyrin disodium, malotilate. derived extract including carrot extract, Swertia japonica Detoxifying agents include calcium disodium edetate, glu extract, rosemary extract, Phellodendoronamurense Rupre tathione, sodium hydrogen carbonate, calcium folinate. cht extract, garlic extract, aloe extract, Salvia extract, arnica Arthrifuges include allopurinol, colchicine, probenecid, 35 extract, chamomilla recutita extract, Japanese white birch benzbromarone. extract, Hypericaceae extract, eucalyptus extract, Soapberry Enzyme preparations include semi-alkaline proteinase, extract, Inula britannica extract, Spatholobus Suberectus Serrapeptase, pronase, bromelain, lysozyme hydrochloride. extract, Cassia mimosoides extract, Morus alba extract, dong Diabetes drugs include acarbose, acetohexamide, pioglita quai extract, adders-wort extract, Sophora Angustifolia Zone hydrochloride, buformin hydrochloride, gliclazide, gly extract, Crataegi fructus extract, white lily extract, hop clopyramide, glybuzole, glibenclamide, glimepiride, chlor 40 extract, polyantha extract, Coix Lachryma-Jobi extract, loofa propamide, tolbutamide, nateglinide, Voglibose, miglitol, extract, Cnidium Officinale extract, blueberry extract, hae mitiglinide calcium hydrate, metformin hydrochloride. matococcus extract, Pfaffia extract, ginkgo leaf extract, Asian Other metabolized drugs include azathioprine, adenosine ginseng extract, Hinokitiol, cepharanthine; Cl- or Y-linolenic triphosphate disodium salt, alendronate Sodium hydrate, acid, eicosapentaenoic acid. Succinic acid, estradiol, glycolic inosine pranobex, ipriflavone, etidronate disodium, epalr 45 acid, lactic acid, malic acid, citric acid, , glycyr estat, everolimus, L-cysteine, levocarnitine chloride, ralox rhizinic acid, glycyrrhetinic acid, , allantoin, ifene hydrochloride, camo.stat mesylate, cyclosporin, tacroli guaiaZulene, e-aminocaproic acid, hyaluronic acid, chon mus, mizoribine, methotrexate, Sodium resedronate hydrate, droitin, , dermatan Sulfate, heparan Sul leflunomide. fate, heparin, keratan Sulfate, cysteine and a derivative thereof Cellular stimulants include adenine. 50 and a salt thereof collagen, elastin, keratin, deep seawater, Antineoplastic agents include cyclophosphamide hydrate, papaya powder, Zinc, DHA, glutathione, flavonoid, polyphe melphalan, estramustine phosphate sodium, capecitabine, nol, tannin, elagic acid, nucleic acids, Chinese herbs, sea carmofur, tegafur, fluorouracil, methotrexate, fludarabine weeds, inorganic Substances, and a mixture thereof. phosphate, etoposide, aceglatone, anastroZole, exemestane, When the active ingredient has a bitter taste or is needed to fadrozole hydrochloride hydrate, tamoxifen citrate, be released in the gastrointestinal tract may be used, the toremifene citrate, tamibarotene, gefitinib, tamibarotene, 55 ingredient treated by known method such as coating may be bicalutamide, flutamide, procarbazine hydrochloride, ima used. For example, the active ingredient may be coated by the tinib mesylate, letrozole. method of JP-A-11-263723, i.e., spray-drying fluidized-bed Anti-allergic agents include alimemazine, triprolidine granulation, agitation granulation, or kneading granulation of hydrochloride, clemastine fumarate, chlorpheniramine male the active ingredient with an easily soluble agent including ate, diphenhydramine hydrochloride, cyproheptadine hydro 60 Xylitol, Sorbitol. Sucrose, an aqueous binder including poly chloride hydrate, promethazine hydrochloride, homochlor vinylpyrrolidone, pullulan, hydroxypropylcellulose, hydrox cyclizine hydrochloride, meduitazine, auranofin, ypropyl methylcellulose, gum arabic, gelatin, and mannitol, bucillamine, amlexanox, ibudilast, ebastine, azelastine lactose or mannose. It may be also coated by the method of hydrochloride, epinastine hydrochloride, OZagrel hydrochlo JP-A-2002-275054, i.e., coating of the active ingredient with ride, olopatadine hydrochloride, cetirizine hydrochloride, 65 a gelling agent, a binder and Sugar alcohol. fexofenadine hydrochloride, oxatomide, ketotifen fumarate, If hard taste, acid taste or bitter taste derived from starting Zafirlukast, seratrodast, splatast tosilate, tranilast, emedastine materials may be suppressed by seasoning or flavoring, US 8,900,602 B2 13 14 acidulant (e.g., citric acid, tartaric acid, malic acid, ascorbic The orally rapidly disintegrating tablet of the present acid, etc.). Sweetening agent (e.g., Sodium saccharin, dipotas invention has usually 20 to 200N, preferably 30 to 100N, of sium glycyrrhizinate, aspartame, Stevia, thaumatin, etc.), fla hardness. The tableting pressure varies according to the tablet sizes, but for example, the tablet has 30 to 150N of hardness Voring Substance, perfume (e.g., various fruit perfumes con when the tableting pressure is 100 to 1200 kgf, and the tablet taining lemon oil, orange oil or strawberry, and yoghurt, mint, has 30 to 80N of hardness when the tableting pressure is 100 menthol, etc.) may be blended. to 1000 kgf, in case that 200 mg of tablet is tableted by using The other ingredients to be blended without impairing pestle with 8 mm of diameter. disintegrating properties may be any agents which are gener The orally rapidly disintegrating tablet of the present ally acceptable as a phamaceutical additive, and include, for invention may be also used as a solid preparation other than example, acidulant, Sweetener, flavoring Substance, perfume, 10 tablets intended for rapid disintegrating properties (e.g., a colorant, Surfactant, excipient, binder, stabilizing agent, chewable tablet). The orally rapidly disintegrating tablet of blowing agent. the present invention may be also used as food Such as healthy food or food for specified health uses, pet food or feedstuff, The lubricant used in the present invention includes, for agrichemical, as well as medicine, due to rapid disintegrating example, gum arabic powder, cacao butter, carnauba wax, properties by a small amount of water. carmelloSecalcium, carmelloSesodium, caropeptide, aqueous 15 silicon dioxide, dried aluminum hydroxide gel, glycerin, EXAMPLES magnesium silicate, light anhydrous silicic acid, light liquid paraffin, crystalline cellulose, hardened oil, synthetic alumi The present invention is illustrated by Examples as fol num silicate, sesame oil, flour starch, white beeswax, mag lows, but the scope of the present invention is not intended to nesium oxide, dimethyl polysiloxane, potassium sodium tar be limited thereto. trate. Sucrose fatty acid ester, glycerin fatty acid ester, silicon Each tablet obtained in each Example was evaluated in the resin, aluminum hydroxide gel, Stearyl alcohol, Stearic acid, following manner. aluminum Stearate, calcium Stearate, polyoxyl Stearate, mag Disintegration Time in the Oral Cavity nesium Stearate, cetanol, gelatin, talc, magnesium carbonate, The time for a tablet to completely disintegrate on the precipitated calcium carbonate, cornstarch, lactose, hard fat, 25 tongue in the oral cavity (n-6 per a tablet) was measured for saccharose, potato starch, hydroxypropylcellulose, fumaric to 8 subjects, of which the average time provided the disinte acid, Sodium Stearyl fumarate, polyethylene glycol, polyoxy gration time in the oral cavity. ethylene polyoxypropylene glycol, polysorbate, beeswax, Sensory Test magnesium aluminometasilicate, methylcellulose, Japan A tablet was naturally disintegrated on the tongue in the wax, glycerin monostearate, Sodium lauryl Sulfate, calcium 30 oral cavity for 5 subjects. After that, a questionnaire about Sulfate, magnesium Sulfate, liquid paraffin, phosphoric acid. texture and taste was carried out. Preferable one includes stearic acid, magnesium stearate, Hardness of Tablet calcium Stearate. Sucrose fatty acid ester, polyethylene gly It was measured by using Load-cell type tablet hardness col, Sodium Stearyl fumarate or talc. testerPC-30, manufactured by OKADA SEIKO CO.,LTD.). The orally rapidly disintegrating tablet of the present Tableting Difficulties invention may be prepared by mixing the disintegrating par 35 The mortar and pestle of a tableting machine and a tablet ticle composition with additives of at least one or more agents after tableting were observed, and Sticking and capping, selected from lubricant, excipient, disintegrating aid and/or adherence and weight variation were analyzed. binding aid, an active ingredient, and other ingredients which can be blended in medicine, followed by compressing to Reference Example 1 mold. The compression molding is preferably carried out by 40 a direct tableting method, in which the tableting pressure is Preparation of Masking Particles usually 200 to 2000 kgf, preferably 250 to 1600 kgf, more preferably 250 to 1200 kgf, but varies according to the tablet Mosapride citrate was used as a bitter-tasting active ingre S17S. dient to prepare masking particles according to the method of The orally rapidly disintegrating tablet of the present 45 WO2005/55989. Specifically, 10 parts by weight of water invention may be also prepared by wet-granulating at least was sprayed into 21 parts by weight of mosapride citrate 2 one or more agents selected from the disintegrating particle hydrate, 20 parts by weight of methylcellulose and 59 parts by composition, a disintegrant, the active ingredient or a binder, weight of D-mannitol to be granuled by an agitation granu and the active ingredient, followed by compressing to mold. lation machine, dried at 80° C. overnight, and filtered by 32 The wet-granulation includes spray drying, fluidized-bed 50 mesh sieve to prepare a masking particle. granulation drying, agitation granulation or wet-extrusion Mosapride citrate was manufactured by Dainippon Sumi granulation. The orally rapidly disintegrating tablet may also tomo Pharma Co., Ltd., and Metolose SM-25 (2.53 mm/S of obtain the desired hardness or disintegrating properties by viscosity (2% aqueous viscosity at 20°C. (Japanese Pharma aging such as warming and/or humidifying according to the copoeia))) manufactured by Shin-Etsu Chemical Co., Ltd. conventional method after compression molding. was used as methylcellulose and Mannite P manufactured by In the preparation of the orally rapidly disintegrating tablet 55 Mitsubishi Foodtech Co., Ltd. was used as mannitol. of the present invention, lubricant may be mixed with other ingredients, followed by compressing to mold, as mentioned Examples 1-3 above, but the tablet may be also prepared by a method (i.e., external lubrication) wherein lubricant is preliminarily Preparation of Disintegrating Particle Compositions applied to the surface of pestle and wall surface of mortar in 60 a compression molding machine without mixing with other The ingredients of the prescriptions of Table 1 were homo ingredients and a compression molding is carried out. By this geneously dispersed by water so as to be 35 parts by weight method, the orally rapidly disintegrating tablet may obtain the per 100 parts by weight of the entire dispersion, followed by desired hardness and disintegrating properties. The method spray-dried by using a spray drying machine (type L-8, manu applying lubricant to pestle and mortar may be carried out 65 factured by Ohkawara Kakohki Co., Ltd.) with 80° C. of the according to the conventional known methods and by using outlet temperature to give a fluid white spherical granulated conventional machines. particle. US 8,900,602 B2 15 16 TABLE 1.

(Unit: parts by weight) Calcium Magnesium Rice Mannitol Xylitol silicate aluminometasilicate Cornstarch starch HPS L-HPC

Example 1 78 2 6 6 9 Example 2 78 2 6 6 9 Example 3 78 2 6

HPS refers to hydroxypropylstarch. L-HPC refers to low-substituted hydroxypropylcellulose. XyliteXC manufactured by Mitsubishi Foodtech Co., Ltd. was used as xylitol, FlowLite RE manufactured by Eisai Food & Chemical Co., Ltd. was used as calcium silicate, Neusilin UFL2(R) manufactured by Fuji Chemical Industry Co., Ltd. was used as magnesium aluminometasilicate, Cornstarch W manufactured by Nihon Cornstarch corporation was used as corn starch, Micropearl manufactured by Shimada Industry Co., Ltd. was used as rice starch, HPS101 manufactured by Freund Corporation was used as HPS (hydroxypropylstarch), and low-substituted hydroxypropylcellulose (LH-21 manufactured by Shin-Etsu Chemical Co.,Ltd.) was used as L-HPC.

Examples 4-12 machine as 50N of setting hardness to give a tablet with 240 mg of weight, 8 mm of diameter, and 9R (Examples 4-9 and Preparation of Orally Rapidly Disintegrating Tablets 11-12). To the disintegrating particle composition prepared in Example 3 were added the ingredients of Table 2 and 0.4 parts To the disintegrating particle composition prepared in 25 by weight of magnesium Stearate, and the mixture was com Example 1 or 2 were added the ingredients of Table 2, 0.4 bined, and then tableted by a rotary tableting machine with parts by weight of magnesium Stearate, 0.2 parts by weight of 50N of setting hardness to give a tablet with 240 mg of aspartame and 0.2 parts by weight of menthol, and the mix weight, 8 mm of diameter, and 9R (Example 10). ture was combined, and then tableted by a rotary tableting Formulation TABLE 2

(Unit: parts by weight) Disintegrating Particle of particle Reference Rice Crystalline composition example 1 Acetaminophen HPS starch Crospovidone cellulose CMC

Example 4 61.2 25 10 3 (Example 1) Example 5 54.2 25 7 10 3 (Example 1) Example 6 54.2 25 7 7 5 (Example 1) Example 7 63.7 25 7 3 O.S (Example 2) Example 8 61.4 25 7 5 O.8 (Example 2) Example 9 58.2 25 10 5 1 (Example 2) Example 10 59.6 10 2O 10 (Example 3) Example 11 39.2 30 2O 10 (Example 2) Example 12 642 30 5 (Example 2)

CMC refers to carmellose. Acetaminophen fine powder manufactured by Fuji Chemicals Ltd. was used as acetaminophen, carboxymethylcellulose NS-300 manufactured by Gotoku Chemical Company Ltd. was used as CMC, Kollidon CL manufactured by BASF Japan Ltd. was used as crospovidone, and Ceolus KG-802 manufactured by Asahi Kasei Chemicals Corporation was used as crystalline cellulose KG-802. US 8,900,602 B2 17 18 Comparative Example 1 The tablets using the disintegrating particle compositions of Examples 4-12 had moderate molding pressure and hard 78 Parts by weight of mannitol. 2 parts by weight of xylitol, ness for use in tablet, and the disintegration time in the oral 6 parts by weight of calcium silicate, and 14 parts by weight cavity was 60 seconds or below and the tablets had sufficient of cornstarch were mixed. 67.6 Parts by weight of the mix 5 disintegrating properties in the oral cavity. It was difficult for ture, 25 parts by weight of the masking particles prepared in tableting in the preparations of Comparative examples 1 and Reference example 1, 7 parts by weight of hydroxypropyl 2. It was difficult to prepare a tablet in the preparations of starch and 0.4 parts by weight of magnesium Stearate were Comparative examples 1 and 2. mixed. Since the resulted powders for tableting have low density and low fluidity, any setting tablets similar to the 10 The invention claimed is: Examples could not be obtained due to the difficulty to load 1. A disintegrating particle composition, which is prepared into a mortar although the resulted powders were tried to be by homogeneously dispersing inorganic excipient(s) and tableted by a rotary tableting machine as 50N of setting hard starch(es) in complex particles which are composed of man CSS. nitol and xylitol, wherein 15 Comparative Example 2 (a) the sum of mannitol and xylitol is 70 to 90 parts by weight; 78 Parts by weight of mannitol. 2 parts by weight of xylitol, (b) the inorganic excipient(s) are in the amount of 2 to 15 6 parts by weight of calcium silicate, and 14 parts by weight parts by weight; of cornstarch were put into a mortar, and thereto was added an (c) the starch(es) are in the amount of 5 to 25 parts by appropriate amount of water. The mixture was kneaded, fol weight, and the total amount of the ingredients (a), (b) lowed by filtering through 32 mesh sieve to granulate. The and (c) is 100 parts by weight, resultant was dried at 80°C. overnight. 67.6 Parts by weight wherein the starch(es) are at least one selected from the of the mixture, 25 parts by weight of the masking particles group consisting of potato starch, flour starch, Sticky prepared in Reference example 1, 7 parts by weight of 25 rice starch, Sweet potato starch, tapioca starch, rice hydroxypropylstarch and 0.4 parts by weight of magnesium starch, cornstarch and waxy cornstarch, and Stearate were mixed. Any setting tablets similar to the Examples could not be obtained due to the adherence and the wherein the composition is obtained by a spraying broad weight variation of tablet, although the resulted pow method. ders were tried to be tableted by a rotary tableting machine as 30 2. The composition of claim 1, wherein 50N of setting hardness. (a) the sum of mannitol and xylitol is 75 to 85 parts by Tableting Results weight; (b) the inorganic excipient(s) are in the amount of 3 to 9 TABLE 3 parts by weight; and 35 Disintegration (c) the starch(es) are in the amount of 10 to 15 parts by Molding time in the weight. pressure Tableting Hardness oral cavity kgf property N seconds 3. The composition of claim 2, wherein the ratio by weight of mannitol to xylitol is 99:1 to 90:10. Comparative difficult for tableting example 1 40 4. The composition of claim 2, wherein the ratio by weight Comparative difficult for preparing tablet of mannitol to xylitol is 99:1 to 95:5. example 2 Example 4 610-670 good 52.9 50 5. The composition of claim 1, wherein the inorganic Example 5 660-720 good SO.2 40 excipient(s) are at least one selected from the group consist Example 6 630-690 good SO.1 35 ing of magnesium aluminometasilicate, magnesium alumi Example 7 660-730 good SO.1 44 45 Example 8 590-650 good 49.1 30 nosilicate, anhydrous silicic acid, calcium silicate, calcium Example 9 620-680 good 47.4 42 hydrogen phosphate, calcium carbonate and talc. Example 10 490–540 good 47.7 2O 6. A method for preparing the composition of claim 1, Example 11 680-78O good 48.1 24 comprising a step wherein a dispersion comprising the ingre Example 12 850-950 good 45.8 12 dients (a) to (c) is spray-dried. k k k k k