Europäisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`(cid:6)(cid:27)&(cid:11)(cid:11)(cid:12)(cid:17)(cid:20)(cid:16)(cid:17)(cid:20)(cid:20)(cid:23)(cid:12)(cid:6)
`EP 1 695 699 A1
`
`(11)
`
`(19)
`
`(12)
`
`A61K47/38(2006.01)
`A61K47/10(2006.01)
`
`(43) Date of publication:
`30.08.2006 Bulletin 2006/35
`
`(21) Application number: 04820201.4
`
`EUROPEAN PATENT APPLICATION
`published in accordance with Art. 158(cid:3)(3) EPC
`(51) Int Cl.:(cid:3)
`A61K9/20(2006.01)
`A61K9/14(2006.01)
`A61K31/5375(2006.01)
`
`(22) Date of filing: 07.12.2004
`
`(86) International application number:
`PCT/JP2004/018204
`
`(84) Designated Contracting States:
`AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
`HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR
`
`(30) Priority: 09.12.2003 JP 2003410961
`(71) Applicant: Dainippon Sumitomo Pharma Co., Ltd.(cid:3)
`Osaka 541-8524 (JP)(cid:3)
`
`(87) International publication number:
`WO 2005/055989 (23.06.2005 Gazette 2005/25)(cid:3)
`• OKAMOTO, S.(cid:3)
`c/o Dainippon Sumitomo Pharma Co.,(cid:3)Ltd
`Fukushima-(cid:3)ku, Osaka-(cid:3)shi, Osaka 553-0001 (JP)(cid:3)
`• SHIBAMORI, K.(cid:3)
`c/o Dainippon Sumitomo Pharma Co.Ltd
`Osaka-(cid:3)shi, Osaka 541-8524 (JP)(cid:3)
`• SHIMONO, N.(cid:3)
`c/o Dainippon Sumitomo Pharma Co.,(cid:3)Ltd
`Ibaraki-(cid:3)shi, Osaka 567-0878 (JP)(cid:3)
`
`(74) Representative: Vossius & Partner
`Siebertstrasse 4
`81675 München (DE)(cid:3)
`
`(72) Inventors:
`• FUJIWARA, K.(cid:3)
`c/o Dainippon Sumitomo Pharma Co.,(cid:3)Ltd
`Ibaraki-(cid:3)shi, Osaka 567-0878 (JP)(cid:3)
`• SOGO, Kiyomi
`c/o Dainippon Sumitomo Pharma Co.,(cid:3)Ltd
`Fukushima-(cid:3)ku, Osaka-(cid:3)shi, Osaka 553-0001 (JP)(cid:3)
`DRUG-(cid:3)CONTAINING GRAINS AND SOLID PREPARATION CONTAINING THE GRAINS
`The invention provides a medicament-(cid:3)containing particle wherein an unpleasant taste of the medicament is
`(57)
`alleviated, which is obtainable by mixing and granulating the following ingredients: (1) the medicament with an unpleasant
`taste, (2) methylcellulose and (3)(cid:3)mannitol; and a solid preparation including the particle. The invention can make an
`unpleasant taste of the medicament alleviated and furthermore when the formulation including the particle is administered,
`the unpleasant taste can be masked and the formulation has a good dissolvability in gastrointestinal tract.
`
`(54)
`
`Printed by Jouve, 75001 PARIS (FR)
`
`EP1 695 699A1
`
`Par Pharm., Inc.
`Exhibit 1036
`Page 001
`
`

`

`Description
`
`EP 1 695 699 A1
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`TECHNICAL FIELD
`(cid:3)[0001] The present invention relates to a medicament-(cid:3)containing particle and a solid preparation containing the particle.
`More particularly, it relates to a medicament-(cid:3)containing particle wherein an unpleasant taste of the medicament having
`the unpleasant taste is alleviated in buccal cavity, and "a solid preparation containing the particle" which does not
`substantially induce an unpleasant taste of the medicament and has a good dissolvability in gastrointestinal tract.
`
`BACKGROUND ART
`(cid:3)[0002] A lot of medicaments contained in pharmaceutical products induce an unpleasant taste such as bitter taste,
`astringent taste and pungent taste when the pharmaceutical product is orally administered. In case that a medicament
`has such an unpleasant taste, it is very difficult for a patient to take a pharmaceutical product containing the medicament.
`A big problem to be solved for the preparation thereof is how to mask such an unpleasant taste of the medicament in
`the preparation. In order to solve this problem, i.e. in order to mask the unpleasant taste of the medicament when the
`medicament is orally administered, a sweater or a flavor has hitherto usually been used as an additive, but sometimes
`an increased amount of the sweater is required to fully mask a bitter taste. Alternatively, a coating of a medicament or
`a medicament-(cid:3)containing granule, and so on has been applied with a water-(cid:3)insoluble polymer base such as ethyl
`cellulose. With respect to this method, however, in order to more effectively depress an unpleasant taste of the medi-
`cament, it is necessary to coat it in more coating amount. As a result, the coating may affect a releasing amount of the
`medicament transferred into gastrointestinal tract and the desired release of the medicament can not be obtained, which
`is another problem.
`(cid:3)[0003] For example, in case of an intrabuccally rapidly disintegrating tablet, it has been desired to produce a tablet
`having good disintegrability in buccal cavity and good dissolubility in gastrointestinal tract. However, when the intrabuc-
`cally rapidly disintegrating tablet contains a medicament having an unpleasant taste, it is difficult to simultaneously satisfy
`above the two conditions of rapid disintegrability in buccal cavity and alleviation of an unpleasant taste in buccal cavity
`because these conditions are inconsistent to each other, and it is furthermore difficult to simultaneously satisfy the
`condition of alleviating an unpleasant taste in buccal cavity and the condition of good dissolubility in gastrointestinal
`tract, because these conditions are also inconsistent to each other. Furthermore, it is also difficult to simultaneously
`satisfy all these conditions mentioned above.
`(cid:3)[0004] The present inventors have studied for obtaining the desired preparation, and during which they have given in
`attention to previously granulate the medicament with the other ingredients and further to use a water-(cid:3)soluble polymer
`in the granulating procedure. It is already known that a particle (or granule) obtained by granulating a medicament is
`formulated into a drug preparation, for example, WO 2002/002083 discloses "a quick disintegrating tablet in buccal
`cavity, said quick disintegrating tablet comprising: spray-(cid:3)dried drug-(cid:3)containing particles, wherein each particle comprises
`a bitter tasting drug and/or a drug of inferior fluidity and a pharmaceutical preparation carrier, wherein each particle has
`a mean diameter of approximately 50 Pm to approximately 250 Pm and an apparent specific gravity of approximately
`0.5 to approximately 1.2, and a saccharide." The pharmaceutical preparation carrier in this reference includes water-
`insoluble polymers, gastrosoluble polymers, enterosoluble polymers, wax-(cid:3)like substances and saccharides as an ex-
`ample, in detail, the reference discloses a working example using a water-(cid:3)insoluble polymer. Thus it is disclosed in the
`patent gazette that such "a particle-(cid:3)form containing a medicament" which includes a water-(cid:3)insoluble polymer such as
`ethylcellulose may make a bitter thereof masked. In addition, it is disclosed in the patent gazette as "the fluidity of a drug
`that is not bitter tasting can be improved by the present invention, and in this case, the above-(cid:3)mentioned polymer
`substances, such as water-(cid:3)insoluble polymer, gastrosoluble polymer, enterosoluble polymer, etc., and wax-(cid:3)like sub-
`stances, etc., a water soluble polymer, saccharide, etc., can be used as the above-(cid:3)mentioned carrier. Examples of the
`water-(cid:3)soluble polymers as the carrier are hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone,
`polyvinyl alcohol, etc." Thus, this publication suggests that even if a medicament-(cid:3)containing particle which includes the
`medicament with a bitter taste and a water-(cid:3)soluble polymer is produced, the bitter taste thereof cannot be masked.
`In addition, JP-(cid:3)A-(cid:3)2001-039861 discloses, for example, "a tablet obtained by mixing (1)(cid:3)(a) a granule in which
`(cid:3)[0005]
`a medicament is included in a water-(cid:3)soluble polymer matrix or a wax matrix and/or (b) a granule prepared by coating a
`medicament-(cid:3)containing granule with a water-(cid:3)soluble polymer or a water-(cid:3)insoluble polymer film, with (2) an excipient,
`(3) adding a solvent thereto, kneading the resultant mixture, and (4) placing the kneaded mixture in a mold, and then
`molding the kneaded mixture to form a tablet." In the reference, hydroxypropyl cellulose, hydroxypropylmethylcellulose,
`methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone, polyvinyl alcohol are exemplified as a water-
`soluble polymer. However, the granule mentioned in patent the gazette has a feature that a medicament can be gradually
`released in water or in gastrointestinal tract. Accordingly, the problem of the reference is contrary to that of the present
`invention.
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`2
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`Par Pharm., Inc.
`Exhibit 1036
`Page 002
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`

`

`EP 1 695 699 A1
`In addition, WO 2000/024379 discloses a preparation method of drug-(cid:3)containing spherical fine particles that
`(cid:3)[0006]
`are useful in the production of easily-(cid:3)swallowed, controlled-(cid:3)release preparations. In detail, it discloses that "a preparation
`method of drug-(cid:3)containing spherical fine particles having a mean particle size of 200 Pm or less comprising: adding a
`binder solution to a mixture containing an excipient powder having the property of retaining a solvent and a drug powder,
`and granulating by high-(cid:3)speed mixing." In the reference, celluloses such as microcrystalline cellulose, methylcellulose,
`carmellose sodium, carmellose calcium, and low-(cid:3)substituted hydroxypropyl cellulose, and various starches are exem-
`plified as an excipient having the property of retaining a solvent. However, the patent gazette discloses neither any
`masking of a bitter taste of a medicament nor any combination of a medicament having an unpleasant taste, methylcel-
`lulose and mannitol as in the present invention mentioned hereinafter.
`In addition, JP-(cid:3)A-(cid:3)2000-191518 discloses that "a method for preparing an intrabuccally quickly disintegrating
`(cid:3)[0007]
`tablet, which comprises dissolving a difficultly soluble pharmaceutical agent together with a surfactant and/or a water-
`soluble polymer in an organic solvent or an water-(cid:3)containing organic solvent, coating an excipient with the solution or
`granulating the excipient with the solution to obtain molded products, mixing a saccharide with them, adding an organic
`solvent, water or an water-(cid:3)containing organic solvent thereto, followed by kneading, and subjecting it to a compression-
`molding." However, the patent gazette discloses the improvement of dissolubility of a difficultly soluble medicament, but
`does not disclose a masking of a bitter taste. Additionally, the example section discloses examples only using surfactants,
`but does not disclose any example using a water-(cid:3)soluble polymer. Furthermore, the patent gazette does not disclose
`anything about a combination of a medicament with an unpleasant taste, methylcellulose and mannitol as the present
`invention discloses.
`
`DISCLOSURE OF INVENTION
`
`(Problem to be solved by the invention)
`(cid:3)[0008] As mentioned above, with regard to a solid preparation containing a medicament with an unpleasant taste, it
`had been difficult to mask an unpleasant taste of a medicament and carry out a rapid dissolution in gastrointestinal tract
`by now.
`
`(Means to solve the problem)
`(cid:3)[0009] Under such situation, the present inventors have found that a bitter taste of a medicament in buccal cavity
`could be alleviated by preparing a medicament-(cid:3)containing particle with methylcellulose which has been used as a
`conventional base for sustained release or for coating among various water-(cid:3)soluble polymers and a specific sugar
`alcohol, and furthermore that a rapid dissolution in gastrointestinal tract and a masking of an unpleasant taste could
`simultaneously be carried out when taking a preparation containing the particle; thereby they have succeeded in resolving
`the above problem, then have accomplished the present invention. Furthermore, with regard to an intrabuccally rapidly
`disintegrating preparation, they have found that the present invention make the drug preparation intrabuccally rapidly
`integrated and also make a bitter taste of the intrabuccal medicament alleviated.
`(cid:3)[0010] The present invention provides various embodiments of the invention as mentioned below.(cid:3)
`[1] A medicament-(cid:3)containing particle wherein an unpleasant taste of the medicament is alleviated, which is obtainable
`by mixing and granulating the following ingredients:(cid:3)
`
`(1) the medicament with an unpleasant taste,
`(2) methylcellulose, and
`(3) mannitol.
`[2] The medicament-(cid:3)containing particle according to the above [1] wherein the amount of the methylcellulose is
`about 0.05 to about 10 parts by weight per 1 part by weight of the medicament with an unpleasant taste.
`[3] The medicament-(cid:3)containing particle according to the above [1] wherein the amount of the methylcellulose is
`about 0.15 to about 7 parts by weight per 1 part by weight of the medicament with an unpleasant taste.
`[4] The medicament-(cid:3)containing particle according to the above [1] wherein the amount of the methylcellulose is
`about 0.8 to about 5 parts by weight per 1 part by weight of the medicament with an unpleasant taste.
`[5] The medicament-(cid:3)containing particle according to any one of the above [1] - [4] wherein the amount of the mannitol
`is about 0.3 to about 50 parts by weight per 1 part by weight of the methylcellulose.
`[6] The medicament-(cid:3)containing particle according to any one of the above [1] - [4] wherein the amount of the mannitol
`is about 0.5 to about 12 parts by weight per 1 part by weight of the methylcellulose.
`[7] The medicament-(cid:3)containing particle according to any one of the above [1] - [4] wherein the amount of the mannitol
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`Par Pharm., Inc.
`Exhibit 1036
`Page 003
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`EP 1 695 699 A1
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`is about 0.7 to about 7.5 parts by weight per 1 part by weight of the methylcellulose.
`[8] The medicament-(cid:3)containing particle according to any one of the above [1] - [7] wherein the mannitol is D-(cid:3)mannitol.
`[9] The medicament-(cid:3)containing particle according to any one of the above [1] - [8] wherein the medicament with an
`unpleasant taste is 4-(cid:3)amino-(cid:3)5-(cid:3)chloro-(cid:3)2-(cid:3)ethoxy-(cid:3)N-[[4-(4-(cid:3)fluorobenzyl)-(cid:3)2-(cid:3)morpholinyl](cid:3)methyl](cid:3)benzamide or a phar-
`maceutically acceptable salt thereof.
`[10] The medicament-(cid:3)containing particle according to the above [1], which is obtainable by mixing and granulating
`the following ingredients:(cid:3)
`(1) ((cid:25))-(cid:3)4-(cid:3)amino-(cid:3)5-(cid:3)chloro-(cid:3)2-(cid:3)ethoxy-(cid:3)N-[[4-(4-(cid:3)fluorobenzyl)-(cid:3)2-(cid:3)morpholinyl](cid:3)methyl](cid:3)benzamide citrate dihydrate as
`a medicament,
`(2) methylcellulose, and
`(3) D-(cid:3)mannitol, wherein the amount of the methylcellulose is about 0.15 to about 7 parts by weight per 1 part
`by weight of ((cid:25))-(cid:3)4-(cid:3)amino-(cid:3)5-(cid:3)chloro-(cid:3)2-(cid:3)ethoxy-(cid:3)N-[[4-(4-(cid:3)fluorobenzyl)-(cid:3)2-(cid:3)morpholinyl](cid:3)methyl](cid:3)benzamide citrate, and
`the amount of the D-(cid:3)mannitol is about 0.5 to about 12 parts by weight per 1 part by weight of the methylcellulose.
`[11] A solid preparation comprising the medicament-(cid:3)containing particle set forth in any one of the above [1] - [10]
`and other ingredients for pharmaceutical preparation.
`[12] The solid preparation according to the above [11] which is a tablet-(cid:3)like preparation or a granule-(cid:3)like preparation.
`[13] The solid preparation according to the above [12] wherein the tablet-(cid:3)like preparation is in the form of a tablet
`or a pill.
`[14] The solid preparation according to the above [12] wherein the granule-(cid:3)like preparation is in the form of a granule,
`a fine granule or a powder.
`[15] The solid preparation according to any one of the above [11] - [14] which is an intrabuccally rapidly disintegrating
`preparation.
`[16] The solid preparation according to the above [15] wherein the intrabuccally rapidly disintegrating preparation
`is in the form of a tablet.
`[17] The solid preparation according to the above [15] wherein the intrabuccally rapidly disintegrating preparation
`is a granule-(cid:3)like preparation.
`[18] The intrabuccally rapidly disintegrating preparation set forth in any one of the above [15] - [17] which is char-
`acterized by the following properties:(cid:3)
`
`(i) disintegrating within 40 seconds on a tongue of a healthy adult with his mouth closed and without chewing,
`(ii) dissolving at a substantial dissolution rate of 85% or more after 15 minutes according to the dissolution test
`described in the Japanese Pharmacopoeia XIV [using Method 2 (50 rpm) for tablets or Method 1 (50 rpm) for
`granule-(cid:3)like preparation, resolution medium : 900 mL of water], and
`(iii) not substantially feeling an unpleasant taste on setting the preparation in buccal cavity.
`
`[19] A composition for preparing the intrabuccally rapidly disintegrating preparation set forth in the above [15], which
`comprises
`a medicament-(cid:3)containing particle wherein an unpleasant taste of the medicament is alleviated, which is obtainable
`by mixing and granulating the medicament with an unpleasant taste, methylcellulose and mannitol;(cid:3)
`an excipient; and
`a disintegrator.
`[20] A process for preparing a medicament-(cid:3)containing particle wherein an unpleasant taste of the medicament is
`alleviated, which is obtainable by mixing (1) the medicament with an unpleasant taste, (2) methylcellulose and (3)
`mannitol, and granulating the mixture with water or a water-(cid:3)containing solvent.
`[21] A commercial package which comprises the solid preparation set forth in the above [11] comprising 4-(cid:3)amino-
`5-(cid:3)chloro-(cid:3)2-(cid:3)ethoxy-(cid:3)N-[[4-(4-(cid:3)fluorobenzyl)-(cid:3)2-(cid:3)morpholinyl]-methyl](cid:3)benzamide or a pharmaceutically acceptable salt
`thereof as a medicament with an unpleasant taste; and a written matter as to the solid preparation, including a
`description on the outside of the package or the written matter inside the package which intends that the solid
`preparation can/(cid:3)should be used for promoting gastrointestinal motility, improving postgastrectomy condition, or
`preventing/(cid:3)treating gastroesophageal reflux disease (GERD).
`
`BRIEF DESCRIPTION OF DRAWINGS
`(cid:3)[0011] Fig 1 shows results of the dissolution test using each tablet in Example 1 and Comparative Example 1.
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`Par Pharm., Inc.
`Exhibit 1036
`Page 004
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`

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`EP 1 695 699 A1
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`BEST MODE FOR CARRYING OUT THE INVENTION
`(cid:3)[0012] The "average particle size" used in the present claims and specification, unless otherwise indicated, is denoted
`as a value measured, for example, by means of a laser diffraction particle size analyzer (HELOS & RODOS) (SYMPATEC
`Inc.).
`(cid:3)[0013] The "per 1 part by weight of the medicament" used in the present claims and specification is based on a form
`of "pharmaceutically active ingredient" which is generally used in pharmaceutical field. Regarding a medicament as a
`salt form, it is based on 1 part by weight of the salt thereof. However, when a medicament has crystal water, it is the
`residual amount by subtracting the amount of crystal water therefrom.
`(cid:3)[0014] The medicament-(cid:3)containing particle of the invention is essentially a medicament-(cid:3)containing particle wherein
`an unpleasant taste of the medicament is alleviated, which is obtainable by mixing and granulating the following ingre-
`dients:(cid:3)
`
`(1) the medicament with an unpleasant taste,
`(2) methylcellulose, and
`(3) mannitol; and each of the ingredients is explained as follows.
`(cid:3)(1) A medicament with an unpleasant taste
`(cid:3)[0015] There are no special restriction to the "medicament with an unpleasant taste" used in the present invention as
`long as it is a one that is used for treating or preventing a disease as a pharmaceutically active ingredient, and it is a
`one with an unpleasant taste such as bitter taste, astringent taste and pungent taste. The medicaments include antipyretic-
`analgesic-(cid:3)antiinflammatory drugs, quinolone antibacterial agents, antibiotics, antitumor agents, gastrointestinal agents,
`antidiarrheals, antidepressants, antiepileptics, antihypertensives and so on. The examples of the medicaments include
`mosapride citrate shown below, quinine sulfate, morphine sulfate, morphine hydrochloride, caffeine, ethenzamide, co-
`deine phosphate, dihydrocodeine phosphate, berberine chloride, acrinol, zonisamide, loperamide hydrochloride, gati-
`floxacin, sparfloxacin, alacepril, clarithromycin and so on. As mentioned above, the medicament may be in the form of
`a salt-(cid:3)free or a salt. Additionally it may be in the form of a hydrate.
`(cid:3)[0016] Especially, the preferable medicament with an unpleasant taste which is adapted for the present invention is
`4-(cid:3)amino-(cid:3)5-(cid:3)chloro-(cid:3)2-(cid:3)ethoxy-(cid:3)N-[[4-(4-(cid:3)fluorobenzyl)-(cid:3)2-(cid:3)morpholinyl](cid:3)methyl](cid:3)benzamide or a pharmaceutically acceptable
`salt thereof, which is shown in the following formula. The compound (or the acid addition salt or the hydrate thereof) is
`a selective agonist of serotonin 4 receptor, which can exhibit an acceptable effect promoting gastrointestinal motility (US
`4,870,074). The compound can be prepared according to, for example, the method described in US 4,870,074 or a
`modified method thereof. In addition, the compound is also useful as a medicament for treating gastroesophageal reflux
`
`disease, postgastrectomy syndrome, or the other gastrointestinal symptom.(cid:3)(cid:3)[0017] The citrate·dihydrate of the above racemic mixture (hereinafter, occasionally referred to as "mosapride") have
`
`already been practically used for improving gastrointestinal symptom accompanied with chronic gastritis, and tablets
`containing 2.5 mg or 5 mg of mosapride citrate (anhydride) (1.72 mg or 3.44 mg of mosapride) have been marketed
`under the trade name "Gasmotin" in Japan. These tablets are sold as a film-(cid:3)coating tablet since mosapride is a bitter
`medicament.
`(cid:3)[0018] As another solid preparation containing mosapride; US 4,870,074 discloses a solid preparation containing
`mosapride citrate, corn starch, lactose, crystalline cellulose, hydroxypropyl cellulose, light anhydrous silicic acid and
`magnesium stearate in Example 245.
`(cid:3)[0019]
`In addition, WO 2004/066913 discloses a solid preparation (except orally disintegrating tablets) free of film
`coating, which is substantially free of light anhydrous silicic acid and which comprises mosapride or a salt thereof.
`(cid:3)[0020] On the other hand, as an intrabuccally rapidly disintegrating tablet containing mosapride citrate, JP-(cid:3)A-
`1999-349475 discloses a process for preparing an intrabuccally rapidly disintegrating tablet containing mosapride citrate
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`Exhibit 1036
`Page 005
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`EP 1 695 699 A1
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`which comprises leaving tablets containing amorphous lactose and molded under a low pressure under the relative
`humidity of about 60% to about 90%, and converting the amorphous lactose into the crystalline lactose. Furthermore,
`US 6,413,541 discloses a process for preparing an intrabuccally rapidly disintegrating tablet containing mosapride citrate
`which comprises the following Steps (a), (b) and (c), wherein a medicament is mixed before granulation or tabletting (b):
`(a) a step of dissolving at least one saccharide having a high solubility in water and at least one water-(cid:3)soluble binder in
`water alone or in water and an alcohol; (b) a step of mixing the solution obtained in the above Step (a) with at least one
`excipient, granulating, drying and tabletting the mixture under a low compression pressure; (c) a step of aging the tablets
`obtained in Step (b).
`(cid:3)[0021] However, any gazettes do not disclose any description about a particle containing mosapride citrate.
`4-(cid:3)Amino-(cid:3)5-(cid:3)chloro-(cid:3)2-(cid:3)ethoxy-(cid:3)N-[[4-(4-(cid:3)fluorobenzyl)-(cid:3)2-(cid:3)morpholinyl](cid:3)methyl](cid:3)benzamide may be in the form of ra-
`(cid:3)[0022]
`cemic mixture or in either enantiomeric form thereof, however, the racemic compound thereof (i.e. "mosapride") is
`preferable. In addition, mosapride may be in a free form thereof or in the form of a pharmaceutically acceptable salt
`thereof. The preferable salt is an acid addition salt. The acid addition salt with an organic acid includes, for example,
`formate, acetate, lactate, adipate, citrate, tartrate, fumarate, methanesulfonate, maleate, etc.; and the acid addition salt
`with an inorganic acid includes, for example, hydrochloride, sulfate, nitrate, phosphate, etc. Especially, citrate is preferable
`among them. Furthermore, mosapride or a pharmaceutically acceptable salt thereof may exist in the form of a solvate,
`a hydrate, or a non-(cid:3)hydrate. A hydrate of citrate is preferable, especially the citrate·dihydrate thereof is more preferable.
`(cid:3)(2) Methylcellulose
`(cid:3)[0023] The "methylcellulose" formulated in the medicament-(cid:3)containing particle of the present invention has an action
`masking an unpleasant taste of the medicament by the specific combination with mannitol. It had not been thought that
`methylcellulose is useful for masking an unpleasant taste as mentioned the following gazettes. For example, JP-(cid:3)A-
`56-164122 discloses that it was failed to mask a bitter taste with methylcellulose (the reference formulation C in JP-(cid:3)A-
`56-164122). Additionally, WO 2002/002083 also discloses it was failed to alleviate a bitter taste of a medicament having
`a bitter taste by a granulation with a water-(cid:3)soluble polymer as mentioned above.
`(cid:3)[0024]
`In the present invention, it has been found that the combination of mannitol with methylcellulose which is
`selected among a lot of kinds of water-(cid:3)soluble polymers can provide the desired effect. In other words, the desired effect
`could not be obtained when using the other water-(cid:3)soluble polymer which is used for known granulation, such as hydrox-
`ypropyl cellulose, hydroxypropylmethylcellulose, pullulan, polyvinylpyrrolidone and polyvinyl alcohol; however, the de-
`sired effect could be exhibited when using methylcellulose (see below, Comparative Example).
`(cid:3)[0025] The amount of the methylcellulose may be about 0.05 to about 10 parts by weight, preferably about 0.15 to
`about 7 parts by weight, more preferably about 0.8 to about 5 parts by weight, per 1 part by weight of the medicament.
`(cid:3)(3) Mannitol
`(cid:3)[0026] Mannitol is one of essential ingredients in the medicament-(cid:3)containing particle of the present invention. The
`sugar or sugar alcohol which can exhibit the desired effect in combination with methylcellulose is the above-(cid:3)mentioned
`mannitol. In other words, the desired effect could not be obtained by using the other sugars or sugar alcohols, however,
`has been incipiently accomplished by using mannitol (see below, Comparative Example). The preferable mannitol is D-
`mannitol.
`(cid:3)[0027] The amount of the mannitol may be about 0.3 to about 50 parts by weight, preferably about 0.5 to about 12
`parts by weight, more preferably about 0.7 to about 7.5 parts by weight, per 1 part by weight of methylcellulose.
`Medicament-(cid:3)containing particle
`(cid:3)[0028] The particles are prepared by mixing and granulating the above ingredients (1)-(3). In more detail, they are
`obtainable by mixing the above ingredients (1)-(3) and granulating the mixture with water or water-(cid:3)containing solvent.
`The method include a method for mixing the ingredients and then granulating the mixture with water or water-(cid:3)containing
`solvent; or a method for dissolving a part of methylcellulose in water, adding the solution to the mixture and then
`granulating it. Furthermore, the method also includes a method for mixing the ingredients, adding water or water-(cid:3)con-
`taining solvent which includes the other conventional binder within the range of the amount that could not influence the
`effect of the invention, and then granulating it. The method of the granulation includes a conventional method such as
`an agitation granulation method, an extrusion granulation method, a fluidized bed granulation method, a dry granulation
`method and the like.
`(cid:3)[0029] The average particle size of a medicament-(cid:3)containing particle may be about 500 Pm or less, for example, about
`5 to about 500 Pm, preferably about 10 to about 400 Pm, more preferably about 10 to about 300 Pm. The average
`particle size thereof can be determined under a consideration of the feeling in buccal cavity when administered and the
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`6
`
`Par Pharm., Inc.
`Exhibit 1036
`Page 006
`
`

`

`EP 1 695 699 A1
`
`dissolvability as well as the effect masking an unpleasant taste.
`In the medicament-(cid:3)containing particle of the invention, the amount of the methylcellulose may be about 0.05
`(cid:3)[0030]
`to about 10 parts by weight per 1 part by weight of the medicament with an unpleasant taste. Preferably, the amount of
`the methylcellulose in the medicament-(cid:3)containing particle may be about 0.15 to about 7 parts by weight per 1 part by
`weight of the medicament with an unpleasant taste. More preferably, the amount of the methylcellulose formulated in
`the medicament-(cid:3)containing particle may be about 0.8 to about 5 parts by weight per 1 part by weight of the medicament
`with an unpleasant taste.
`In addition, the amount of the mannitol in the medicament-(cid:3)containing particle may be about 0.3 to about 50
`(cid:3)[0031]
`parts by weight per 1 part by weight of the methylcellulose. Preferably, the amount of the mannitol formulated in the
`medicament-(cid:3)containing particle may be about 0.5 to about 12 parts by weight per 1 part by weight of the methylcellulose.
`More preferably, the amount of the mannitol formulated in the medicament-(cid:3)containing particle may be about 0.7 to about
`7.5 parts by weight per 1 part by weight of the methylcellulose.
`(cid:3)[0032] The "medicament-(cid:3)containing particle" of the present invention is intended to mean that methylcellulose does
`not overall covers over the medicament, but a part of the medicament can exist on the surface of the particle. The
`medicament-(cid:3)containing particle thus obtained can make the unpleasant taste of the medicament itself alleviated.
`(cid:3)[0033] The medicament-(cid:3)containing particle of the invention may further include corrigents, fluidization agents, stabi-
`lizers, surfactants, disintegrants, coloring agents, etc in the particle. These ingredients are exemplified in the following
`solid preparation, which can be used as the above ingredients.
`
`Solid preparation of the present invention
`(cid:3)[0034] Using the medicament-(cid:3)containing particle of the present invention, a solid preparation can be prepared. An
`applicable formulation thereof is, for example, a tablet-(cid:3)like preparation or a granule-(cid:3)like preparation. The tablet-(cid:3)like
`preparation includes, for example, tablets and pills; and the granule-(cid:3)like preparation includes, for example, granules,
`fine granules and powders. In addition,(cid:3) the solid preparation may include an intrabuccally rapidly disintegrating prepa-
`ration which includes tablets (intrabuccally rapidly disintegrating tablets) and a granule-(cid:3)like preparation (intrabuccally
`rapidly disintegrating granules or intrabuccally rapidly disintegrating powders).
`In addition to a medicament-(cid:3)containing particle, the solid preparation of the invention may contain a pharma-
`(cid:3)[0035]
`ceutically acceptable ingredient for pharmaceutical preparation which is ordinarily used for preparing a pharmaceutical
`solid preparation as long as there is no particular inconvenience. As to the "ingredient for pharmaceutical preparation",
`any ingredients which give no bad effect on the preparation and have a necessity to be formulated are available, which
`include, for example, an excipient, a binder, a lubricant, a disintegrant and the like.
`(cid:3)[0036] Examples of the excipients are lactose, sucrose, D-(cid:3)mannitol, starch, crystalline cellulose, erythritol, trehalose,
`anhydrous calcium hydrogen phosphate, calcium sulfate and the like. Examples of the binders are gum arabic, starch,
`hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylalcohol, pullulan, gelatin, ethylcellulose, methylcellu-
`lose, carmellose sodium, dextrin, polyvinylpyrrolidone and the like.
`(cid:3)[0037] Examples of the lubricants are stearic acid and a metallic stearate such as magnesium stearate and calcium
`stearat