CA2323680C

CA2323680C - Orally disintegrable tablets

Info

Publication number: CA2323680C
Application number: CA002323680A
Authority: CA
Inventors: Toshihiro Shimizu; Shuji Morimoto; Tetsuro Tabata
Original assignee: Takeda Pharmaceutical Co Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 1998-05-18
Filing date: 1999-05-17
Publication date: 2007-05-22
Anticipated expiration: 2019-05-17
Also published as: HK1096021A1; CY1119153T1; ES2559766T3; US7875292B2; KR100554924B1; EP2263660A3; JP2000302681A; EP1121103A2; JP3746167B2; DK2263660T3; JP4454791B2; PT1736144E; CA2323680A1; US9901546B2; ATE348601T1; DE69934505T2; US7431942B2; AU3731699A; CN1195500C; KR20050010070A

Abstract

An orally disintegrable tablet, of the present invention, which comprises (i ) fine granules having an average particle diameter of 400 .mu.m or less, which fine granules comprise a composition coated by an enter ic coating layer, said composition having 10 weight % or more of an acid-labile physiologically active substance and (ii) an additive, has superior disintegrability or dissolution in the oral cavity so that it can be used for treatment or prevention of various diseases, as an orally disintegrable tablet capable of being administered to the aged or children and easily administered without water. Also, because the tablet of the present invention contains fine granules having the average particle diameter such that it will not impart roughness in mouth, it can be administered easily without discomfort at the administration.

Description

DESCRIPTION
Orally Disintegrable Tablets TECHNICAL FIELD

The present invention relates to an orally disintegrable tablet containing an acid-labile physiologically active substance such as lansoprazole, and having a characteristic of fast disintegration in the oral cavity even without water. The present invention also relates to fine granules containing the acid-labile physiologically active substance such as lansoprazole which may be used for producing the orally disintegrable tablet.
BACKGROUND ART

Pharmaceutical solid preparations, for example, tablets, usually are prepared to make pharmaceutically active ingredients to be absorbed in a digestive organ by disintegration or dissolution through oral administration, without fast disintegration or dissolution in the oral cavity.

JP-A-6-502194 (published in 1998, equivalent to U.S. Patent No. 5,464,632) discloses a rapidly disintegrable multiparticulate tablet, the excipient mixture of which is suitable for imparting a disintegration rate such that the tablet disintegrates in the mouth in less than sixty seconds, characterized by the fact that the active substance is present in the form of coated microcrystals or coated or uncoated microgranules. However, there is no disclosure of an acid-labile physiologically active substance with a basic inorganic salt as the active substance, weight percentage of the active substance in the excipient mixture, or the size of the coated microgranule.

la On the other hand, JP-A-5-92918 (published in 1987) discloses a powder consisting of a fine-particle core coated with a water-soluble high molecular compound and at least one physiologically active substance, and having a granule size of practically up to 500 pm. However, there is no disclosure of an acid-labile physiologically active substance with a basic inorganic salt as the physiologically active substance, weight percentage of the active substance in the coated granule or the size of the coated granule.

JP-A-63-301816 and U.S. Patent No. 5,026,560 disclose spherical granules having a core coated with spraying powder containing a drug and low substituted hydroxypropylcellulose. However, there is no disclosure of orally disintegrable tablet.
EP-A-0452862 discloses a spherical granule obtained by coating a pharmacologically inactive spherical seed core having at least 50 weight % microcrystalline cellulose and an average particle size of 100-1000 m, with a powder comprising an active ingredient, by using an aqueous binding solution, and spraying an aqueous solution or suspension of a coating agent thereon. However, most of the particle sizes of thus obtained granules are 500 Eun or more.

JP-A-1-268627, JP-A-1-268628 and JP-A-8-27033 disclose pharmaceutical compositions using erythritol, respectively.
However, there is no disclosure of solid pharmaceutical composition characterized fast disintegration in the oral cavity.

JP-A-9-48726 discloses a buccal formulation consisting of a drug and a substance wetting in a mouldable way on humidifying, and retaining a shape after moulding and drying.
As such substance, sugars, sugar alcohols and water-soluble polymers are exemplified.
JP-A-5-271054 discloses production of fast dissolving tablets comprising an active ingredient and sugars.
JP-A-9-71523 discloses a tablet with rapid disintegration in the oral cavity comprising medicine, crystalline cellulose, low-substituted hydroxypropyl cellulose and lubricant.
However, these prior art references nowhere disclose an acid-labile physiologically active substance with a basic inorganic salt as an active substance, weight percentage of the active substance in the tablet or the size of the coated fine granule.
To accompany an aging population and their changes in life environment, it is desired to develop an orally disintegrable solid preparation capable of being administered without water, retaining the convenience for use which is a characteristic of a tablet, and being administered on demand easily, anytime and anywhere, without water.
Conventional granules have large particle diameters, which results in inferior workability when dispensing, and also results in difficulties in consistently adding a regular amount of the granules when they are combined into tablets or capsules. Granules having a large particle diameter (400 m or more of average particle diameter) also produce a feeling of roughness in the mouth. Accordingly, especially when used in an orally disintegrable tablet, the average particle diameter of the included granules must be about 400 Eun or less, preferably about 350 m.
For many reasons, such as, masking a bitter taste, or providing enteric abilities or release abilities, it is desirable to prepare the solid pharmaceutical preparations as granules (or fine granules). In particular, in case of granules or fine granules in which the active ingredient of the drug is enteric coated to impart enteric dissolution, there is a need for enteric coating to prevent dissolution by stomach acid (i.e., to make the preparation acid-resistance). It is necessary to coat the whole surface of the particle -before the enteric coating- (including a case of the crystal of physiologically active substance only, and a case of the granule produced by granulation), with the enteric coating.
Namely, at least some uniform thickness (at least 20 Eun or more) of the coating layer is needed. Even a portion of thin and weak coating, is undesirable because acid-resistance is lowered. Accordingly, before the enteric coating, it is necessary that the particle is as spherical with smooth surface as possible in form, as uniform as possible in size, and has less cavity.
It is very difficult to produce an enteric coated fine granule with an average particle diameter of 400 Eun or less, when the coating is performed so that at least 20 Nm thickness of coating layer may coat the whole particle, and the enteric coated particle contains a basic inorganic salt for stabilization of an acid-labile physiologically active substance, and where it contains binders for maintaining the strength of the particle and/or disintegrants for maintaining the disintegrability (dissolution) of the particles. Further, in the case where the content of the acid-labile physiologically active substance is increased, it is necessary to also increase the content of the excipients such as basic inorganic salt, binders and disintegrants. Furthermore, it is very difficult to produce a small enteric coated fine granule containing the physiologically active substance in high content.
Accordingly, it is desired to develop a fine granule which is coated with the enteric coating layer on the composition containing the physiologically active substance such as a physiologically active substance containing a basic inorganic salt and which has a particle diameter so that roughness or oral discomfort is not felt, to develop a fine granule containing the physiologically active substance, i.e., the active ingredients of drugs, and so forth, in high content, to develop a fine granule keeping enteric dissolution, a disintegrability and dissolution and suitable strength, and to develop an orally disintegrable preparation containing such a fine granule, being a fast disintegration type, showing superior oral disintegrability and dissolution and having suitable strength (hardness) so that it will not be damaged through production processes or handling.
In particular, there is a need to combine an acid-labile physiologically active substance, with basic inorganic salts and so forth for stability, and further to coat with coating layers such as an enteric layer. In such cases, it is an important problem to produce an small enteric coated fine granule, even though it contains the acid-labile physiologically active substance in high concentration and in high content.

DISCLOSURE OF INVENTION

The present invention relates to:

5 [1] an orally disintegrable tablet, which comprises:

(i) fine granules having an average particle diameter of 400 pm or less, which fine granules comprise a composition coated by an enteric coating layer, the composition having 10 weight % or more of an acid-labile physiologically active substance (such as lansoprazole) and (ii) an additive, wherein the enteric coating layer preferably contains a first component that is an enteric coating agent and a second component that is a sustained-release agent;

[2] an orally disintegrable tablet of the above [1], wherein the average particle diameter of the fine granules is 300 to 400 pm;

[3] an orally disintegrable tablet of the above [1], wherein the fine granules further comprise a basic inorganic salt;

[4] an orally disintegrable tablet of the above [1], wherein the additive comprises a water-soluble sugar alcohol;

[5] an orally disintegrable tablet of the above [1], wherein the composition coated by an enteric coating layer is further coated by a coating layer which comprises a water-soluble sugar alcohol;

5a [6] an orally disintegrable tablet of the above [4], wherein the additive comprises (i) crystalline cellulose and/or (ii) low-substituted hydroxypropyl cellulose;

[7] an orally disintegrable tablet of the above [1], wherein the particle diameter of the fine granules is practically 425 pm or less;

[8] an orally disintegrable tablet of the above [1], wherein the particle diameter of the fine granules is practically 400 pm or less;

[9] an orally disintegrable tablet of the above [1], wherein the acid-labile physiologically active substance is a benzimidazole compound or a salt thereof;

[10] an orally disintegrable tablet of the above [9], wherein the benzimidazole compound is lansoprazole;

[11] an orally disintegrable tablet of the above [3], wherein the basic inorganic salt is a salt of magnesium and/or a salt of calcium;

[12] an orally disintegrable tablet of the above [1], wherein the composition comprises a core being coated by a benzimidazole compound and a basic inorganic salt, said core comprising crystalline cellulose and lactose;

[13] an orally disintegrable tablet of the above [12], wherein the core comprises 50 weight % or more of lactose;

[14] an orally disintegrable tablet of the above [12], wherein the core comprises 40 to 50 weight % of crystalline cellulose and 50 to 60 weight % of lactose;

[15] an orally disintegrable tablet of the above [1], wherein the composition comprises 20 weight % or more of an acid-labile physiologically active substance;

[16] an orally disintegrable tablet of the above [1], wherein the composition comprises 20 to 50 weight % of an acid-labile physiologically active substance;

[17] an orally disintegrable tablet of the above [1], wherein the fine granules are produced by fluidized-bed granulation method;

[18] an orally disintegrable tablet of the above [1], wherein the enteric coating layer comprises an aqueous enteric polymer agent;

[19] an orally disintegrable tablet of the above [18], wherein the aqueous enteric polymer agent is a methacrylate copolymer;

[20] an orally disintegrable tablet of the above [18], wherein the enteric coating layer further comprises a sustained-release agent;

[21] an orally disintegrable tablet of the above [20], wherein the sustained-release agent is a methacrylate copolymer;

._.......~.~.,.....~.. _ . __ ____......~___. _.__.~_,_._ __ [22] an orall..y d.isinteY rable tablet of the above [20], wherein the sustained-release agent is in ari amount of 5 to 15 weight % relative to .100 weight % of the aqueous enteric polymer agent;
[2:3] an orally disintegrable tablet of the above [4], wherein the water--soluble s-~'zgar alcohol is erythritol;
[24] an orally disintegrable tablet of the above [4], wherein the water-soluble sugar alcohol is mannitol.;
[25] an orall.y, disintei-jrable tablet of the above [5], wherein the water-solubae sugar alcohol is in an amount of 5 to 97 weight % relative to 100 weight % of the orally disinteqrable tablet apart :f:rom the fine granules;
[26)] an orally dis intec;rable tablet of the above [41, wherein the crystalline cellulose is in an ainount of 3 to 50 weight % relative t::o :L00 weight % of the tablet apart from the fine granule;
[27] an orally disintegrable tablet of the above [6], wherein the content of hydroxypropoxyl group in the low-substituted hydroxypropyl cellulose is 7.0 to 9.9 weight %;
[28] an orally dis integrable tablet of the above [61, wherein the conten.t of hydroxypropoxyl group in the low-substituted hydroxypropyl cellulose i.s 5.0 t:o 7.0 weight o;
[29] an orally disintegrable tablet of the above [11, which further comprises crospovidone;
[30] an orally d.isintegrable tablet of the above [1], wherein the oral di_sintegrat:ion time is one minute or less;
[31] an orally disintegrab:Le tablet of the above [1], which comprises no, lubricant inside the tablet;
[32] fine granules having an average particle diameter of 400 m or less, which coinprise a composi_tion coated by an eriteric coating layer, the composition having (i) 25 weight % or more of an acid-labile physiologically active substance and (ii) a basic inorganic salt;
[ 33 ] f ine gra:r.iu.l.es of the above [ 32 ], wherein the average particle diameter of the f:ine granules is 300 to 400 m;

[34] fine granules of the above [32], wherein the particle diameter of the fine granules is practically 425 m or less;
[35] fine granules of the above [32], wherein the particle diameter of the fine granules is practically 400 Eun or less;
[36] fine granules of the above [32], wherein the acid-labile physiologically active substance is a benzimidazole compound or a salt thereof;
[37] fine granules of the above [36], wherein the benzimidazole compound is lansoprazole;
[381 fine granules of the above [321, wherein the basic inorganic salt is a salt of magnesium and/or a salt of calcium;
[39] fine granules of the above [32], wherein the composition comprises.a core being coated by a benzimidazole compound and a basic inorganic salt, said core comprising crystalline cellulose and lactose;
[40] fine granules of the above [39], wherein the core comprises 50 weight % or more of lactose;
[41] fine granules of the above [32], wherein the composition comprises 25 to 40 weight ~ of an acid-labile physiologically active substance;
[ 421 fine granules of the above [ 32 ], which are produced by fluidized-bed granulation method;
[ 43 ] fine granules of the above [ 32 ], wherein the enteric coating layer comprises an aqueous enteric polymer agent;
[ 44 ] fine granules of the above [ 43 ], wherein the aqueous enteric polymer agent is a methacrylate copolymer;
[ 45 ] fine granules of the above [ 43 ], wherein the enteric coating layer further comprise a sustained-release agent;
[46] fine granules of the above [45], wherein the sustained-release agent is a methacrylate copolymer;
[47] fine granules of the above [45], wherein the sustained-release agent is in an amount of 5 to 15 weight %
relative to 100 weight % of the aqueous enteric polymer agent ;

[ 48 ] f i_ne granules of the above [ 32 ], wherein the enteric coating layer is in an amount of 50 to 70 weight % relative to 100 weight % of t:he f ine granules;
[49] a tablet, granule, fine gr.anule, capsule, effervescent or suspension preparation which comprises the fine granules of the above [32], and so forth.

In the present specification, "coati_ng" means also partial coating and adhesion or adsorption in addition to coating the whole sittrface of an object (e.g., core) which is to be coated.
"Spherical" means also forms having a curved surface such as forms having elliptic cross sections, and forms in the shapes of eggplants and drops in addition to spheres.
"Average particle diameter" means volume based distribution median diameter (median diameter: 50% particle diameter from cumulative distri.bution), unless otherwise specif ied . It can be measured by, for example, a laser diffracti.on particle distribution measurement method.
Concretely exemplified i_s a method using Raser Diffraction Analyzer, type: HEROS RODOS [trade mark; manufactured by Sympatec (Germany)].

"An orally disintegrabletablet" of the present invention comprises (i) fine granul.es having an average particle diameter of 400 m or less, which fine granu:Les comprise a composition coated by an enteric coating layer, the cornposition having 1.0 weight % or more of an acid-labile physiologi.c;ally active substance and (ii) an additive.
In the present invention, "fine granules having an average particle diameter of 400 ~un or less, which fine granules comprise a composition coated by an enteric coating layer, the compositi.ori having 10 weight % or more of an acid-labile physiologically active substance" have an average particle diameter of about 400 f_un or less, in order that roughness is not felt in the mouth. Preferably, the average particle diameter of the fine granules is 300 to 400 Eun.
Aside from the average particle diameter of the above "fine granules", regarding the maximum particle size, the 5 particle diameter is practically 425 pm or less, and preferably practically 400 pm or less. Preferably, the particle diameter is practically 300 to 425 m, more preferably 300 to 400 m.
"Practically" as used in "the particle diameter is practically 425 pm or less" and "the particle diameter is 10 practically 400 m or less" means that the particles may include a small quantity (about 5 weight % or less) of particles whose particle diameter is out of above described range, to include the inevitably contaminant particles.

"An acid-labile physiologically active substance"
includes a compound being unstable in an acidic region and/or a compound inactivated by an acid, especially a pharmaceutical ingredient. Concretely mentioned are vitamins such as vitamin B12, fursultiamine, folic acid, vitamin A, vitamin D, as well as a known benzimidazole compound having an antiulcer activity of the formula ( I) below, or a salt thereof.

Formula (I):

~>--S N
H N (1O1 n Ra wherein ring A may be substituted; R1, R3 and R4 are the same or different and each is a hydrogen, an alkyl or an alkoxy;
R2 is C1_4 alkyl which may be substituted by a substituent(s) selected from the group consisting of halogen, hydroxy and C1-4 alkoxy; and n is 0 or 1.

In the above formula (I), "substituent(s)" of the "substituted ring A" include, for example, halogen, C1-10 alkyl which may be substituted, C3_7 cycloalkyl which may be substituted, C2_16 alkenyl which may be substituted, C1-10 alkoxy which may be substituted, cyano, carboxy, C1_7 alkoxycarbonyl, C1_4 alkoxycarbonyl-C1_4 alkyl, carbamoyl, carbamoyl-C1_4 alkyl, hydroxy, hydroxy-C1_7 alkyl, C1-6 acyl, carbamoyloxy, nitro, C2_6acyloxy,C6_12aryl,C6_12aryloxy, C1_6 alkylthio, C1_6 alkylsulfinyl, etc.

The "substituent" of the above "C1-10 alkyl which may be substituted", "C3_7 cycloalkyl which may be substituted", or "C2_16 alkenyl which may be substituted" includes, for example, (1) halogen, (2) nitro, (3) amino which may be substituted by 1 or 2 of CZ_4 alkyl and C1_4 acyl, etc. , (4) amidino, (5) guanidino, (6) carbamoyl, etc. The number of these substituent is 1 to 3.
The "substituent" of the above "C1-10 alkoxy which may be substituted" includes, for example, (1) halogen, (2) nitro, (3) amino which may be substituted by 1 or 2 of C1_4 alkyl and C1_4 acyl, etc., (4) amidino, (5) guanidino, etc. The number of these substituent is 1 to 3.
The above "C1_6 acyl" includes, for example, C2_6 alkanoyl such as formyl, acetyl, propionyl, etc.
The above "C1_4 acyl" includes, for example, formyl and C2_4 alkanoyl such as acetyl, propionyl, etc.

The above "C2_6 acyloxy" includes, for example, C2_6 alkanoyloxy such as acetyloxyl, etc.
The above "C6_12 aryl" includes, for example, phenyl, naphthyl, etc.

The above "C6_12 aryloxy" includes, for example, phenoxy, naphthyloxy, etc.

The "alkyl" for R1, R3 or R4 includes, for example, a straight-chain or branched C1-10 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Among others, preferred is a straight-chain or branched C1-6 alkyl. More preferred is a straight-chain or branched C1-3 alkyl.

The "alkoxy" for R1, R3 or R4 includes, for example, C1-10 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.
Among others, preferred is C1- 6 alkoxy. More preferred is C1- 3 alkoxy.
The "C1-4 alkyl" of the "C1-4 alkyl which may be substituted by a substituent(s) selected from the group consisting of halogen, hydroxy and C1-4 alkoxy" for R2 includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.
The "C1-4 alkoxy" of the above "C1-4 alkyl which may be substituted by a C1-4 alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.
The number of the substituents which the "C1-4 alkyl" has is preferably 1 to 3.

Salts of the benzimidazole compound include pharmaceutically acceptable salts such as alkali metal salts, e. g. , sodium salts and potassium salts, alkaline earth metal salts e. g., calcium salts and magnesium salts, etc.
Such benzimidazole compounds having an antiulcer .y_._._.._..r.... _._..._,....-..,..~._ activity, or salts thereof include, for example, a compound or a salt thereof disclosed in JP-A-52-62275, JP-A-54-141783, JP-A-57-53406, JP-A-58-135881, JP-A-58-192880, JP-A-59-181277, JP-A-61-50978, JP-A-62-116576, JP-A-62-277322, JP-A-62-258320, JP-A-62-258316, JP-A-64-6270, JP-A-64-79177, JP-A-5-59043, JP-A-62-111980, JP-A-5-117268, EP-A-166287, EP-A-519365, and so forth.

The "physiologically active substance" of the present invention preferably is a benzimidazole compound or a salt thereof such as lansoprazole, omeprazole, rabeprazole, pantoprazole, perprazole, leminoprazole, TU-199, etc.
Preferred is lansoprazole and omeprazole, etc. More preferred is lansoprazole.

The amount of the "acid-labile physiologically active substance" in the "composition" is, for example, about 10 weight % or more, preferably about 20 weight % or more, more preferably about 23 weight % or more, especially preferably about 25 weight % or more. Among others, preferred is 20 to 50 weight %.

In the "composition", a basic inorganic salt is preferably incorporated with the acid-labile physiologically active substance.
The "basic inorganic salt" includes, for example, a basic inorganic salt of sodium, potassium, magnesium and/or calcium, preferably a basic inorganic salt of magnesium and/or calcium.
Among others, preferred is a basic inorganic salt of magnesium.
The basic inorganic salt of sodium includes, for example, sodium carbonate, sodium hydrogencarbonate, etc.
The basic inorganic salt of potassium includes, for example, potassium carbonate, potassium hydrogencarbonate, etc.

The basic inorganic salt of magnesium includes, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6Al2(OH)16=CO3=4H2O], aluminum magnesium hydroxide [2.5MgO=Al2O3=xH2O], etc. Among others, preferred is heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, etc.
The basic inorganic salt of calcium includes, for example, precipitated calcium carbonate, calcium hydroxide, etc.
The preferable examples of the "basic inorganic salt"
include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, etc.
Such basic inorganic salt of magnesium or calcium, etc.
has a basic pH (not less than 7) when it is in the form of a 1t aqueous solution or suspension.
Two or more of these basic inorganic salts (preferably a basic inorganic salt of magnesium, a basic inorganic salt of calcium, etc.) can be used as a mixture in a given ratio.
The amount of the basic inorganic salt to be used is appropriately selected depending on the kind of the basic inorganic salt and is, for instance, about 0.3 to 200 weight %, preferably about 1 to 100 weight %, more preferably about 10 to 50 weight %, especially preferably about 20 to 40 weight ~ relative to the benzimidazole compound or a salt thereof.
The "composition" may contain water-soluble polymers, the following binders, lubricants, and excipients, etc. in common use as pharmaceutical materials. The amount of such water-soluble polymers, binders, lubricants, and excipients is selected from amounts commonly employed in the manufacture of preparations in general dosage forms.
The "water-soluble polymer" includes, for example, a water-soluble polymer which is soluble in ethanol (i.e., an ethanol-soluble water-soluble polymer) such as a cellulose derivative (e.g., hydroxypropyl cellulose, which may be referred to as "HPC" hereinafter), poly(vinylpyrrolidone), etc.; a water-soluble polymer which is insoluble in ethanol 5 (i.e., an ethanol-insoluble water-soluble polymer) such as a cellulose derivative (e.g., hydroxypropylmethyl cellulose, which may be referred to as "HPMC" hereinafter, methyl cellulose, carboxymethyl cellulose sodium, etc.), sodium polyacrylate, polyvinyl alcohol, sodium alginate, and guar 10 gum, etc.
When such water-soluble polymers are used, the dissolution of drugs (physiologically active substances) can be controlled by employing them in combination with the ethanol-soluble water-soluble polymer and ethanol-insoluble 15 water-soluble polymer or by employing them in combination with some water-soluble polymers having different viscosity.
In the present invention, the "water-soluble polymer is preferably, a cellulose derivative such as HPC, HPMC, and methyl cellulose, and polyvinyl alcohol. More preferred is a cellulose derivative such as HPC, HPMC.
The "HPC" contains, for example, about 53 . 4 to 77 . 5 weight more preferably about 60 to 70 weight %, of hydroxypropoxyl group. The viscosity of 2 weight % aqueous solution of HPC
at 20 C is usually about 1 to 150,000 cps (centipoise). As the above HPC, hydroxypropyl cellulose defined in Japanese Pharmacopoeia may be employed. Hereinafter, all viscosity of HPC is a value of 2 weight % aqueous solution at 20 C.
The "HPMC" is a mixed ether which is connected by a methoxy group and a hydroxypropoxy group. The content of the methoxy group of HPMC is, for example, about 19 to 30 weight %. The content of the hydroxypropoxy group is, for example, about 4 to 12 weight t. The viscosity of 2 weight % aqueous solution of HPMC at 20 C is usually about 1 to 40 , 000 centistokes. As such HPMC may be employed hydroxypropylmethyl cellulose 2208 defined by Japanese Pharmacopoeia, hydroxypropylmethyl cellulose 2906 defined by Japanese Pharniacopoeia, hydroxypropylmethyl cellulose 2910 defirred by Japanese Pharmacopoeia, and so forth. Eiydroxypropyl cellulose(s) may be employed alone or in admixture of two or more thereof.
The content of the water-soluble polymer such as HPC
and/or HPMC is usually about 0.1 to 50 weight o, preferably about 1 to 30 weight %, as against the whole "composition"
containing the physiologically active substance, in order to control thE: dissolution of the physiologically active substance in the composition containing the physiologically active substance and retain a high content of the physiologically active substance.

The above "enteric coating layer" which coats the:
"composition having 1.0 wei_ght % or more of an acid-labile physiologically active substance" includes, for example, an aqueous enteric polyrner agent such as celltilose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate (hereinafter, referred to as HP-55), hydroxyrnethyl cellulose acetate succinate, methacrylate copo:Lymer [e.g., Eudragit L30D-55etc.(trade mark; manufactured by Rohm GmbH(Germany)), KollICoat MAE30DP (trade mark; manufactured by BASF
(Germany)), Polyquid PA-30 (trade mark; manufactured by SanyoKasei (Japan)), etc.carboxymethyl cel.lulose,shellac, etc.; a sustained-release agent such asmethacrylate copolymer [e.g., Eudragit NE30D (trade mark), Eudragit RL30D (trade mark), Eudragit RS30D (trade mark), etc.]; a water-soluble polymer; plasticizers such as triethyl citrate, polyeth,ylene glycol, acetylated monoglyceride, triacetin, castor oil, etc.
and mixtures thereof.
The "aqueous enteric polymer agent" is preferably a methacrylate copolymer. The "sustained-release agent" is preferably a methaci.rvylate copolymer.

The "sustained-release agent" is used in an amount of 5 to 30 weight o, preferably 5 to 15 weight o, relative to 100 24205-1241 (S) weight o of the "aqueous enteric polymer agent". The "plasticizers is used in an amount of 5 to 30 weight % relative to 100 weight o of the "aqueous enteric polymer agent".

.5 The "additives" of the "orally disintegrable tablet which.
comprises (i) fine granules having an average particle diameter of 400 p.m or less, which fine granules comprise a composition coated by an enteric coating layer, the composition having 10 weight % or more of an acid-labile physiologically.active substance and (ii) an additive" may be ones commonly employed as pharmaceutical materials. The amount of such additives to be used is selected from amounts commonly employed in the manufacture of preparations. in general dosage forms.
The "additives" include, for example, a water-soluble sugar alcohol, a crystalline cellulose, a low-substituted hydroxypropyl cellulose, as well as, binders,.acids, artificial sweeteners, flavorants, lubricants, colorants, stabilizers, excipients, disintegrants, and so forth.
The "water-soluble sugar alcohol" means a water-soluble sugar alcohol which needs water in an amount of less than :30 ml when 1 g of water-soluble sugar alcohol is added to water and dissolved within about 30 minutes at 20 C by strongly shaking every 5 minutes for 30 seconds.
The "water-soluble sugar alcohol" includes, for example, sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose, erythritol, etc. Two or more of these water-soluble sugar alcohols can be used as a mixture in a given ratio.

The "water-soluble sugar alcohol" is preferably mannitol, xylitol and erythritol. More preferred is mannitol and erythritol. Especially preferred is mannitol. As erythritol, one that is produced by fermentation with yeasts using glucose as the starting material, and that has a particle size of at most 50 mesh is used. Such erythritol is available on the market, e.g. as mariufactured by Nikken Chemical Co., Ltd. (Japart) .
The "water.-soluble sugar alcohol" is usually employed in an amount of about 5 to 97 wei.ght 5s, preferably about 10 to 90 weight o relative to 100 weight o of the orally disintegrable tablet apart from the fine g.r,_inules,:in order to obtain sufficient strength of the preparation and sufficient dis.integration or da.ssolution in the oral cavity.
For example, mannitol or e.rythritol is usually employed in an amount of about 5 to 90 weight %, preferably about 10 to 80 weight %, more preferably about 20 to 80 weight %, especially preferably about 50 to 80 weight % relative to 100 weight % of the orally disintegrable tablet apart from the fine granules.
The "crystalline cellulose" includes refined one having partially cx-cellulose depolymerization. Such crystalline cellulose includes one called microcrystalline cellulose.
Examples of the"crysta_lLine cellulose"include CEOLUS KG801, Avicel PH101, Avicel PH102,Avicel PH301, AvicelPH302,Avicel RC-591 (crystalline cellulosec;armellose sodium), etc. Among *
these, preferably employed is CEOT.,US KG801 which is also called crystalline cellulose of high compressibility. Two or more of the crystalline cellulose can be used as a n-ixture in a given ratio. Such crystalline cellulose:isa.vailable on the market, for example, as manufactured by Asahi Chemical Co., Ltd.
(Japan).
The "crystalline cellulose" is used, for instance, in an amount of about. 3 to 50 weight %, preferably about 5 to 40 weight more preferably about 5 to 20 weight % relative to 100 weight $ of the orally disitZtegrable tablet apart from the fine granules.
The "low-substituted hydroxypropyl cellulose" means a low-substituted hydroxypropyl cellulose wherei_n the content of hydroxypropoxyl g_r.oup in the hydroxypropyl cellulose *Trade-mark (hereinafter, may be abbreviated to "the content of HPC group") is about 5.0 to 9.9 weight %, preferably a low-substituted hydroxypropyl cellulose wherein the content of HPC group is about 5.0 to 7.0 weight %, a low-substituted hydroxypropyl cellulose wherein the content of HPC group is about 7.0 to 9.9 weight %, and so forth.
The"low- substituted hydroxypropyl cellulose wherein the content of HPC group is about 7.0 to 9. 9 % includes, for example, LH-22, LH-32 and mixtures thereof, which are commercially available [Shin-Etsu Chemical Co., Ltd. (Japan)]. Also, they can be produced in accordance with per se known methods, for example, methods described in JP-B-82 53100 or analogous thereto.
The low-substituted hydroxypropyl cellulose wherein the content of HPC group is about 5.0 to 7.0 % includes, f or example, LH-23, LH-33 and mixtures thereof, described in the following Reference Examples. They can be produced in accordance with per se known methods,for example, methods described in JP-B-82 53100 or analogous thereto.
At f irst, alkaline cellulose containing free alkaline and propylene oxide is reacted to obtain the crude low-substituted hydroxypropyl cellulose containing free alkaline.
Concretely, for example, raw material pulp such as wood pulp and cotton leader is immersed in about 10 to 50 t concentration of an aqueous solution of sodium hydroxide, and pressed to obtain alkaline cellulose of which NaOH/cellulose ratio is about 0.1 to 1.2 (ratio by weight). Next, crude low-substituted hydroxypropyl cellulose containing free alkaline is obtained by reacting the resulting alkaline cellulose and propylene oxide with stirring at about 20 to 90 C for about 2 to 8 hours. Propylene oxide is used in an amount so that the content of hydroxypropoxyl group in the desired low-substituted hydroxypropyl cellulose can be 5 or more weight % to less than 7 weight % (in case of the low-substituted hydroxypropyl cellulose wherein the content of HPC group is about 5.0 to 7.0 weight %), 7 or more weight $ to less than 9.9 weight % (in case of the low-substituted hydroxypropyl cellulose wherein the content of HPC group is about 7.0 to 9.9 weight %).
5 The crude low-substituted hydroxypropyl cellulose containing free alkaline is dispersed in water or hot water containing about 5 to 80 % of acid necessary to neutralize all the alkaline, and a part of the crude low-substituted hydroxypropyl cellulose containing free alkaline is dissolved 10 therein. Acid is further added to neutralize the remaining alkaline.
After the neutralization, some processes such as drainage, drying and grinding are performed in accordance with conventional methods to obtain the desired low-substituted 15 hydroxypropyl cellulose.
The particle diameter of "the low-substituted hydroxypropyl celluloses wherein the content of hydroxypropoxyl group is 5.0 to 7.0 weight V to be used in the present invention is, for example, about 5 to 60 Eun, 20 preferably about 10 to 40 m, as a average particle diameter.
In the above ranges, in case that low-substituted hydroxypropyl celluloses (L-HPC) having a relatively large particle diameter (for example, L-HPC having about 26 to 40 m of the average particle diameter) is employed, a pharmaceutical preparation superior in disintegrability can be produced. On the other hand, in case that L-HPC having a relatively small particle diameter (for example, L-HPC having about 10 to 25 pm of the average particle diameter) is employed, a pharmaceutical preparation superior in strength of the preparation can be produced. Accordingly, the particle diameter of L-HPC can be suitably selected according to the characteristics of the desired pharmaceutical preparation.
The "low- substituted hydroxypropyl cellulose wherein the content of HPC group is 5.0 to 7.0 weight V or the "low-substituted hydroxypropyl cellulose wherein the content of HPC

24205-1241 (S) group is 7 . 0 to 9. 9%" is usually employed in an amount of about 3 to 50 weight %, preferably about 5 to 40 weight %, relative to 100 weight % of the orally disintegrable tablet apart from the fine granules, in order to obtain sufficient oral disintegrability and sufficient strength of the preparation.
The "binders" include, for example, hydroxypropyl cellulose, hydroxypropylmethylcellulose, crystalline cellulose, a starch (pregelatinized starch), polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, low-substituted hydroxypropyl cellulose, etc. The use of crystalline cellulose as the binders provides a solid preparation which exhibits more excellent strength of a preparation while retaining excellent disintegration and dissolution in the oral cavity.
The "acids" include, for example, citric acid (e.g., citric acid anhydrous), tartaric acid, malic acid, etc.
The "artificial sweeteners" include, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, etc.
The "flavorants" include synthetic flavorants or natural flavorants, such as lemon, lime, orange, menthol, strawberry, etc.
The "lubricants" include, for example, magnesium stearate, sucrose fatty acid ester, polyethyleneglycol, talc, stearic acid, etc.
The "colorants" include, for example, various food colorants such as Food Yellow No. 5, Food RED No. 2, Food Blue:
No.2, etc., food lakes, red iron oxide, etc.
The "stabilizers" include, for example, the above-mentioned "basic inorganic salt".
The "excipients" include,for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride, titanium oxide, etc.

The "disintegrants" include those conventionally used in the pharmaceutical field, such as (1) crospovidone, (2) super disintegrarlts such as c:roscarme:Llose sodium [FMC-Asahi 'Chemical Co., Ltd. (Japan)], c,armell.ose calcium [Gotoku :5 Chemical(Yakuhin), (Japari)], (3) carboxymethyl.starch sodium [ e . g . , Matsutani Chemi.ca_l Co. , Ltd. ( Japan ) ] , ( 4 ) low-substituted hydroxypropyl.ce.llulose[e.g., Shin-Etsu Chemical Co., Ltd. (Japan)], (5) corn starch, etc. Among others, preferred is, for example, crospovidone.
The "c:rospovidone" iricludes polyvinylpolypyrrolidone (PVPP), 1-vinyl-2-pyrrolidinone homopolymer, 1-etheny'l-2-pyrrolidinone homopolymer, etc, such as Kollidon*CL
[manufactured by BASF (Ger_many) ] , Polyplasdone* XL
[manufactui-ed by IS1' Ltd. (Japan) ], Polyplasdone XL-10 [manufactured by ISP Ltd. (Japan)], Polyplasdone*INF-10 [manufactured by ISP Ltd. ( Japan )], etc. iJsually crospoiFidone having a molecular weight of at least 1,000,000 is used.
Two or more of these disintegrants can be as a mi.xture in a given ratio. F"or examplF:,( i) crospovidone solely, or (ii) crospovidone and another disintegrant(s) is preferably employed.
The "disintegrants" are used, for instance, in an eimount of about 1 to 15 weight %, preferably about 1 to 10 weight -%, more preferably about 3 to 7 weight %, relative to 100 weight % of the orally dis.integr.able tablet apart from the fine granules.
In the present invention, the "fine granules" may contain, for example, titanium oxide as a masking agent.
The diameter of tt-ie "orally disintegrable tablet" of the present invention is about 5 to 20 mm, preferably about 7 to 15 mm, more preferably about 8 to 13 mm.
The "orally disintegrable tablet" may comprise no lubricant :inside thrl tablet.
The orally disintegrable tablet of the present invention exhibits fast disintegrabi.l.i ty or dissolubility in *Trade-mark the oral cavity, and also an appropriate strength of preparation.
The oral disintegration time of the "orally disintegrable tablet" of the present invention (the time for healthy male or female adults to complete disintegration by buccal saliva) is one minute or less, usually about 50 seconds or less, preferably about 40 seconds or less, more preferably about 30 seconds or less.
The strength of the "orally disintegrable tablet" of the present invention (measurement with a tablet hardness tester) is usually about 1 to 20 kg, preferably about 2 to 15 kg, more preferably 3 to 8 kg.
In the above-mentioned fine granules, "fine granules having an average particle diameter of 400 m or less, which comprise a composition coated by an enteric coating layer, said composition having (1) 25 weight % or more of an acid-labile physiologically active substance and (ii) a basic inorganic salt" are novel.
The "fine granules" have an average particle diameter of about 400 m or less, preferably 350 Eun or less. Preferably, the average particle diameter of the fine granules is 300 to 400 m. Aside from the average particle diameter of the "fine granules", regarding the maximum particle size, the particle diameter is practically 425 pm or less, and preferably practically 400 m or less. Preferably, the particle diameter is practically 300 to 400 Eun or less.

Regarding the fine granule of the present invention, the dissolution of the physiologically active substance can be controlled by formulating the coat (coating layer) to have different viscosity or content of the water-soluble polymer (e. g., HPC, HPMC and so f orth ) or by f ormulating the coat to have a controlled ratio of the ethanol-soluble water-soluble polymer (e.g., HPC) and the ethanol-insoluble water-soluble polymer (e.g., HPMC). The dissolution of the physiologically 24205-1241 (S) active substance is not very influenced by liquidity, which can be suitably controlled.
As a pharmaceutical preparation which comprises the"fine granules" of the present invention, there may be employed, for example a solid preparation such as tablet, granule, fine granule, capsule, effervescent, etc; a liquid preparation such as suspension preparation, etc. Among others, preferred is a tablet, more preferred is an orally disintegrable tablet.

When the "fine granule" of the present invention is used for a tablet except for an orally disintegrable tablet, the diameter of the tablet is about 5 to 10 mm, preferably about 5 to 8 mm. When the fine granule of the present invention is used for a capsule, the size of the capsule is preferably a #2 capsule or less.

24205-1241(S) The "composition" in the present invention can be produced by a known granulation method.
The "granulation method" includes, for example, rolling granulation method (e.g., centrifugal rolling granulation, 5 etc.), fluidized-bed granulation (e.g., rolling fluidized-bed granulation, fluidized granulation, etc.), stirring granulation and so forth. Among others, preferred is fluidized-bed granulation method, more preferred is rolling fluidized-bed granulation method.
10 Concrete example of the "rolling granulation method"
includes a method using "CF apparatus" manufactured by Freund Industrial Co., Ltd. (Japan) and so forth. Concrete examples of the "rolling fluidized-bed granulation method" include *
methods using "SPIR-A-FLOW", "multi plex" manufactured by 15 Powrex Corp. (U. S. A.), "New-Marurnerizer" manufactured by Fuji Paudal Co., Ltd. (Japan), and so forth. The method for spraying the mixture can be suitably selected in accordance with the kind of granulator, and may be, for example, any ane *Trade-mark of a tap spray method, a bottom spray method, a tangential spray method, and so forth. Fi-niong others, a tangential spray method is preferred.
The "compositioi i" in the present invention can be produced in accordance with, for example, a method which comprises coiiting a core comprising crystalline cellulose and lactose with an acid-labile physiologically active substance.
For example, employed is a method described in JP-A-5-92918 (coating methio(i) , whicti comprl.ses coating a core comprising crystalline cellulose and lactose with an acid-labile physiologically active substance, if necessary together with a basic: inorganic salt, binders, lubricants, excipients, a water-Soluble polyrner, etc. (hereinafter, may be abbreviated to "coating layer"). For example, employed is a method whi_ch comprises coating a core with an acid-labile physiologically active substance and a basic inorganic salt, and then fu7-ther with binders, lubricants, excipients, a water-soluble polymer, etc.
The ave:rage particle diameter of the "cores" is about 250 p.m or less, preferably about 50 to 250 m, more preferably about 100 to 250 E.un, especially preferably about 100 to 200 m. The "cores" having the above average particle diameter include particles which all pass through a#50 sieve (300 pun) , particles where about 5 w/w -W or less of the total remain on a #60 sieve (250 m), and particles where about 10 w/w o or less of the total pass through a #282 sieve (53 m) . The specific volume of the "core" is about 5 ml/g or less, preferably about 3 ml/g or less.
Examples of the "core" include (1) a spherica:L granulated product comprising crystalline cellulose and lactose, (2) a spherical granulated product being about 150 to 250 ~un and coniprisirig crystalline cellulose *
(Avicel SP, manufactured by Asahi Cheinical Co., Ltd. ( Japan )), (3) a stirr:ina granulated product being about 50 to 250 m and *Trade-mark comprising :Lactose (9 parts ) and a starch (1 part ), (4) a micro particle bc:>ing about 250 Itm or l_ess classified as a spherical granule comprising micro crystalline cellulose described in JP-A-61-213201 ,( 5) a processed product such as wax formed to a sphere by spraying or melting ciranulat ion ,( 6) a processed product such as gelatin beads comprising oi.l component, (7) calcium silicate, (8) starch, (9) a porous particle such as chitin, cellulose, ch:itosan, etc, and (10) a bulk product such as granulated sugar, crystalline lactose or sodium chloride, 1.0 and processed preparat:ions thereof. Further, these cores may be produced in accordance with per se known grinding method or granulation method, and sifted to prepare the particles having the desired particle diameter.
The above "sphe:lrical gr_anulated product comprising crystalline cellulose and lactose" includes, for example (i) a spherica:L granulated product being 1.00 to 200 m arrd comprisinq crystalline cellulose (3 parts) and lactose (7 parts) [e.cf. , Nonpareil*105 (70-L40) (partic:Le diameter of 100 to 200 m), ma.nufactured by Freund Industrial Co., Ltd.
( Japan )], ( ii ) a spheri.cal granulated product being about 150 to 250 ~i.m and comprising crystalline cellulose (3 parts) and lactose (7 parts) (.e.g., Nonpare.il*NP-7:3, manufactured by Freund Industrial Co., Ltd. (Japan)], (iii) a spherical granulated. product being 100 to 200 Eun and comprising crystalline cellulose (4.5 parts) and lactose (5.5 parts) [e.g., Nonpareil 105T (70-1.40) (particle diameter of 100 to 200 m) , manufactured by Freund Industrial Co. , Ltd. (Japan) ], (iv) a spherical grariulated product. bei_ng about 150 to 250 m and comprising crystalline cellulose (5 parts) and lactose (5 parts) [ e. g., Nonpcire_i.l. NP- 5: 5, manuf actur. ed by Freund Industria.l. Co., Ltc'i. ( Japan )], and so forth.
In order to p~~oduce a pliarmaceuti.ca'l preparation which is superior in dissolution while retai.ning suitable strength, the "core" include::13, f or example, preferably the spherical *Trade-mark granulated product comprising crystalline cellulose and lactose, more preferably the spherical granulated material comprising crystalline cellulose and lactose and containing 50 weight t or more of lactose. Among others, preferred is a core comprising 40 to 50 weight % of crystalline cellulose and 50 to 60 weight % of lactose.
As the "core" employed in the present invention, in particular, there may be employed the spherical granulated product comprising crystalline cellulose and lactose, more preferably the spherical granulated product with a diameter of about 100 to 200 m and comprising crystalline cellulose (4.5 parts) and lactose (5.5 parts).
The "core" may contain the physiologically active substance such as the above described pharmaceutical ingredient. Also, the "core" may not contain the physiologically active substance because the release of the physiologically active substance can be controlled by a coating layer containing the physiologically active substance.
The "core" is preferably as uniform a sphere as possible, for reducing the irregularity of the coating, in addition to being a powdery core.
The ratio of the "coating layer" to the "core" can be selected within the range in which it is possible to control dissolution of the physiologically active substance and particle size of the composition, for example, usually about 50 to 400 weight % relative to 100 weight % of the core.
The coating layer may be constructed by plural layers.
At least one layer of the plural layers must contain the physiologically active substance. The combination of various layers such as a coating layer not containing the active ingredient, a base coating layer, and an enteric coating layer which constitute the coating layer can be suitably selected.
In case that the "core" is coated, for example, the above physiologically active substance and the water-soluble -..-~-......._ . _.~._. _ polymer can be employed in admixture thereof. The admixture may be a solution or a dispersion, and can be prepared by using an organic solvent such as water or ethanol or an admixture thereof.
The concentration of the water-soluble polymer in the admixture varies according to the ratio of the physiologically active substance and the excipients, and is usually about 0.1 to 50 weight %, preferably about 0.5 to 10 weight %, in order to retain the binding strength of the physiologically active substance to the core and maintain the viscosity of the mixture so as not to reduce the workability.
Where the coating layer comprises plural layers, the concentration of the physiologically active substance in each layer may be changed successively or gradually by selecting for the content ratio or viscosity of the water-soluble polymer or by successive coating with mixtures varying in the ratio of the physiologically active substance and the other excipients. In the above case, it may be coated with a mixture in which the content ratio of the water-soluble polymer is out of the range of about 0.1 to 50 weight %, as long as the coating layer as a whole contains about 0.1 to 50 weight t of the water-soluble polymer. Further, in forming the inactive coat according to known methods, the coating layer may comprise some layers such that the inactive layer may block each layer containing the physiologically active substance.
Also, in case of two or more physiologically active substances not suited in the compatibility, the core may be coated by employing each mixture together or separately.
The above coated material is dried, and passed through sieves to obtain a"composition" having uniform size. Because the form of the powder is usually according to the core, a fine granule being in the form of a rough sphere may be obtained.
As the sieve may be employed, for example a #50 circular sieve (300 m). The composition is obtained by selecting those which pass through the #50 circular sieve.

The "fine granule" in the present invention can be produced in accordance with in the same manner as above granulation method, for example, a method which comprises 5 coating the composition with an enteric coating layer, in order to protect the acid-labile physiologically active substance or to impart enteric dissolution. If necessary, the composition coated with an enteric coating layer may be further coated by a water-soluble sugar alcohol, preferably mannitol.
10 In such case, the strength of the orally disintegrable tablet comprising fine granules is improved.
The "enteric coating layer" is preferably a layer having about 20 to 70 Eun, preferably about 30 to 50 m of thickness and coating the whole surface of the composition containing 15 the physiologically active substance. Accordingly, the smaller particle diameter of the composition, the higher the weight $ of the enteric coating layer in the whole fine granule.
In the fine granule of the present invention, the "enteric coating layer" is about 30 to 70 weight %, preferably about 20 50 to 70 weight %, of the fine granule as a whole.
The "enteric coating layer" may be constructed by plural (e. g., 2 or 3) layers. For example, employed is a method which comprises coating a composition with an enteric coating layer having polyethyleneglycol, and then with an enteric coating 25 layer having triethyl citrate, followed by being coated with an enteric coating layer having polyethyleneglycol.

The "orally disintegrable tablet" of the present invention can be produced in accordance with a conventional 30 method in the pharmaceutical field. Such methods include,for instance, a method which comprises blending the "fine granules" and the "additives", and molding, if necessary followed by drying. Concretely mentioned is a method which comprises blending the fine granules and the additives, if necessary with water, and molding, if necessary followed by _,..._,_...~._._ _ ..--..-.~ .._ _ . _ .......,v. _ _ drying.
The "blending procedure" can be carried out by any of the conventional blending techniques such as admixing, kneading, granulating, etc. The above "blending procedure" is carried out, for instance, by using an apparatus such as Vertical Granulator GV10.[manufactured by Powrex Corp. (Japan)], Universal Kneader [manufactured by Hata Iron Works Co., Ltd.
(Japan)], fluidized bed granulator LAB-1 and FD-3S
[manufactured by Powrex Corp. (Japan)], V-shape mixer, tumbling mixer, and so forth.
Preferred example of the method for the "orally disintegrable tablet" of the present invention is a method which comprises:
(i) coating a core comprising crystalline cellulose and lactose with an acid-labile physiologically active substance and a basic inorganic salt, followed by being coated with a coating layer comprising a water-soluble polymer to obtain a composition, (ii) coating the resultant composition with an enteric coating layer having polyethyleneglycol, and then with an enteric coating layer having triethyl citrate, and then with an enteric coating layer having polyethyleneglycol, followed by being coated by mannitol to obtain fine granule, and (iii) blending the resultant fine granule with an additive, followed by molding.

Where the pharmaceutical preparation of the present invention, especially an orally disintegrable tablet, is one which comprises no lubricant inside the preparation or tablet, such preparation can be preferably produced in accordance with methods described in JP-A-56-14098, Japanese Patent No.
2681601, etc. Such preparation, especially an orally disintegrable tablet, has sufficient strength. The above lubricant includes, for example, magnesium stearate, sucrose fatty acid ester, polyethyleneglycol, talc, stearic acid, etc.

The pharmaceutical preparations such as solid preparation (e.g., tablets, granules, fine granules, capsules, effervescents, etc.) and liquid preparation such as suspending preparation, which comprises the "fine granules"
of the present invention can be produced in accordance with a conventional method.
The solid pharmaceutical preparation containing the "fine granules" of the present invention and the "orally disintegrable tablet" of the invention can also be produced by the wet tabletting method. As the above method, it is preferably employed the methods described in JP-A-5-271054and so forth. They can also be produced by drying after humidification. As the above method, preferably employed are the methods described in JP-A-9-48726, JP-A-8-291051 and so forth. Namely, it is effective to humidify before tabletting or after tabletting and then to dry, in order to enhance the hardness.
The "molding procedure" can be carried out, for instance, by tabletting with a pressure of 0.5 to 3 ton/cm2 , preferably 1 to 2 ton/cm2 by using a single-punch tabletting machine [Kikusui Seisakusho (Japan)] or a rotary type tabletting machine [Kikusui Seisakusho (Japan)] when a solid preparation is a tablet, especially an orally disintegrable tablet.
The "drying procedure" can be carried out by any of the techniques used commonly in the art, such as vacuum drying, fluidized-bed drying, etc.

The "fine granules" of the invention can be used for a pharmaceutical preparation. The pharmaceutical preparation includes, for example, a solid preparation such as tablet, granule, fine granule, capsule, effervescent, etc.; a liquid preparation such as a suspension preparation, etc. Among others, a tablet is preferred. Such tablet preferably has suitable strength so as to be stable through production , _ __.._.._..,~_......_ _...,,.,._.....- ,. ~,_..... _ .__._.__~..,_.... _ _ __ .

processes and distributions.
A solid pharmaceutical preparation comprising the fine granule of the invention is used for an orally disintegrable tablet and can be administered without water or together with water.
As administration methods, there are listed (1) a method of administration by dissolution or disintegration together with a little water, or without water and with saliva in the oral cavity, not to be swallowed as it is, or (2) a method of administration with water, where it is swallowed as it is.
Also, the tablet may be administered dissolved or disintegrated with water.
The "orally disintegrable tablet" of the present invention is advantageously used in (a) cases where administration without water is necessary, (b) cases of administration to a patients who have difficulty in swallowing tablets, or (c) cases of administration to the aged or to children where there is a fear of blocking the throat if it is in usual tablet form.
In case of the above (a), the orally disintegrable tablet is preferably used for antipyretic agents, analgesic agents, anti-inflammatory agents, antianxiety drugs, antitussive-expectorants, anti motion sickness agents, drugs for prevention and treatment for car-sickness, and so forth.
In case of the above (b), the orally disintegrable tablet is preferably used for preventing and/or treating hypertension, hyperlipemia, diabetes, bronchial asthma, cerebrovascular diseases, and so forth.

The "orally disintegrable tablet" of the present invention and the pharmaceutical preparation which comprises the "fine granules" of the present invention can be safely administered orally to mammals such as mice, rats, rabbits, cats, dogs, bovines, horses, monkeys, humans, etc.
With the dosage of the "orally disintegrable tablet" of the present invention and the pharmaceutical preparation which comprises the "fine granules" of the present invention, varies depending on the pharmaceutically active ingredient, subject, kinds of diseases, etc., the dosage can be selected so that the dosage of the pharmaceutically active ingredient is an effective amount.
For instance, when a benzimidazole compound (I) or a salt thereof such as lansoprazole is employed as an acid-labile physiologically active substance, especially a pharmaceutically active ingredient, the "orally disintegrable tablet" of the present invention and the pharmaceutical preparation which comprises the "fine granules" of the present invention is useful for treatment and prevention of digestive ulcer (e.g., gastric ulcer, duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome, etc), gastritis, reflux esophagitis, etc.; eradication of H. pylori; suppression of gastrointestinal bleeding caused by digestive ulcer, acute stress ulcer and hemorrhagic gastritis; suppression of gastrointestinal bleeding caused by invasive stress (e.g., stress caused by cerebrovascular disease, head injury, f ailure of many organs, burn injury of a wide range, which necessitate a large-scale operation necessitating the following intensive management, or intensive care); treatment and prevention of ulcer caused by non-steroidal anti-inflammatory agent;
treatment and prevention of gastric hyperacidity and ulcer caused by postoperative stress; administration before anesthesia, etc. The dosage of the preparation per an adult (body weight : 60 kg) is about 0. 5 to 1, 500 mg/day, preferably about 5 to 150 mg/day, as a benzimidazole compound (I) or a salt thereof such as lansoprazole.
The "orally disintegrable tablet" of the present invention and the pharmaceutical preparation which comprises the "fine granules" of the present invention can be administered once a day, or two or three times separately a day.

BEST MODE FOR CARRYING OUT THE INVENTION
The following Examples and Reference Examples are further illustrative but by no means limitative of the present 5 invention.
Unless otherwise specifically indicated, the following "%" means weight %.
Also, the content of the hydroxypropoxyl group is measured in accordance with the methods described in Japanese 10 Pharmacopoeia (13th edition).
The physical properties of the tablets and granules prepared in Examples were determined by the following test methods.
(1) Hardness test 15 Determination was carried out with a tablet hardness tester [manufactured by Toyama Sangyo, Co. Ltd. (Japan)]. The test was performed in 10 runs and mean values were shown.
(2) Oral disintegration time Time for complete disintegration only by saliva in the 20 oral cavity was determined.
(3) Remaining ratio According to the 2nd method of the dissolution test defined in Japanese Pharmacopoeia, the dissolution test was performed by using 500 ml of 0. 1N HC1 (75 rpm) for 1 hour. Then, 25 the enteric fine granule was collected by means of the sieve.
The content of the drug in the collected fine granule was measured by the HPLC method. The remaining ratio was calculated according to the following expression with the content of the drug in the tablet which is measured separately 30 by HPLC method.
Remaining ratio = (Content of the drug in the collected fine granule after the dissolution test using 0.1N HC1 for 1 hour)/(Content of the drug in the tablet) 35 (4) Acid-resistance: Dissolution using 0.1N HC1 According to the 2nd method of the dissolution test defined in Japanese Pharmacopoeia, the dissolution test was performed by using 500 ma of 0. 1N HCl (75 rpm) for 1 hour. Then, test mediuni was collected and filtered by using a 0.45 pm membrane filter. The rabsor.bance was measured to calculate the dissolution, of the drug into 0.1N HC:l.
(5) Average particle diameter: Volume based, distribution median diameter (median diameter: 50% particle diameter from cumulative dist:ribut::.ion) Determination was carried out with Raser Diffraction Analyzer, type: HEROS RODOS [trade mark, manufactured by Sympatec (i:yermany)]_ Examples Example 1 (1) Production of granules having a core A cent_rifugal f)_uidized coating granulator [manufactured by Powrex Gorp.( Japan ), MP -10 (Type 2)] is charged with 300 *
g of Nonpareil 105 ( 70-140 )( particle diameter of 100 to 200 m) . With the inlet air temperature and the temperature of the loading being controlled at 85 C and about 28 C respectively, *
the Nonpareil is coated by spraying a bulk liquid of the following composition prepared in advance in accordance with the tangential spray method at a spray rate of 20 g/min. The spraying operation i..s stopped when the specified amount of the bulk liquid has beeri sprayed, and then drying is carried out in the granulator for 7 minutes. The resulting granules are sieved through a #60 circular si_eve (250 Ftm) and a #100 circular sieve (150 m) to provide 750 g of granules having a core.
Bulk liquid:
Lansoprazole 300 g Magnesium cax bonate 100 g L-HPC 5t) g *Trade-mark HPC (Type SSL) 100 g Water 1650 g (2) Production of fiim-undercoated granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2) ] is charged with 680 g of the above granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 70 C and about 36 C, respectively, an undercoating liquid of the following composition prepared in advance is sprayed in accordance with the tangential spray method at a spray rate of 10 g/min. to provide 650 g of film-undercoated granules having a core.

Undercoating liquid:
HPMC 32 g (Type 2910, viscosity: 3 centistokes) Talc 8 g Water 760 g (3) Production of enteric coated granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] is charged with 450 g of the above film-undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 65 C and about 36 C, respectively, an enteric film coating liquid of the following composition prepared in advance is sprayed in accordance with the tangential spray method at a spray rate of 17 g/min . The coated powders are dried in vacuum at 40 C for 16 hours, and sieved through a #42 circular sieve (355 pm) and a #80 circular sieve (177 m) to provide 950 g of enteric coated granules having a core.

Enteric film coating liquid:

Eudragit::* L30U-55 1078. 3 g Eudragit NE30D 138.5 q Triethyl. citi.ate 46.0 g Glyce.ryl monostearate 23.1 g Talc 16.0 g Polysorbate 80 9.0 g Yellow iron oxide 0.5 g Water 2038.5 g Sieve weight ratio #18 (850 lim ) o n -- ---~ 0 9 --Y~
#30 (500 Eim) on 0 ~

#2010 (75 tn) on 100 0 #200 (75 m) pass 0 (4) Production of granulated powders A fluidized beci granulator [manufactured by Powrex Corp.
(Japan), LAB-1] is charged with 1321.2 g of erythritol [manufactur_ed by Nikken Chemical Co. , Ltd. (Japan) ], 360.0 g of low-substit::uted hydroxypropyl cellulose LH-32 [hydroxypropoxyl g:-:oup contents of 8.8 %, inanufactured by Shin-EtsuC'hemical Co., Ltd. (Japan)], 18.0 g of citric acid anhydrous, and. 1.8 q- of aspartame, and granulation is carried out while spraying a. solution wh:ich is prepared by dissolving 3.6 g of po]..yethylene glycol ( PEG- 6000 ) in 896 . 4 ml of purified water. The granule::> are dried to provide granulated powders.
To the granulated powders are added 90.0 g of crospovidone and 5.4 g ef magnes.um stearate, which is admixed in a bag to give mixed powders.

(5) Production of orally disintegrable tablets Hereinafter, the above "enteric coated granules having a core" is referreG to as "enteric coated powders".
200.0 g of the above enteric coated powders and 300.0 g of the above mixed powders are tablette.d using Autograph (trade *Trade -mark:

mark; compressing force measurement a.pparat-us) with a punch having a beveled ecl.ge, 11 nun in diameter, at a tabletting pressure of 1.0 ton/cm2 to provide tablets each weighing 500 mg.
Ref erence Exarnple 1..
An alkaline cellulose comprising 24.1 0 of NaOH, 1.7 -t of Na2CO3, 42.9 % of cellulose, 31.8 ?r of H20 was obtained by immersing a wood pi.ll.p in 49% aqueous solution of sodium 1.0 hydroxide and then by pressing it. A reactor was charged with 100 weight parts olff ttie alkaline cellulose. Then, nitrogen gas replacement was carried out. After the replacement, 5 weight parts of propy_Lene oxide was charged i.n 'the reactor and reacted with stirring at 40 C for 1 hour, at 50 C for 1 hour and at 70 (.' for 1 hoUr to obtairi 103 wei.ght parts of a reactant.
On the other side, a kneader was charged with 2.5 weight parts of hot water at 65 C and 0.13 weight parts of glacial acetic acid (about 40 weight % against equivalent for neutralizzition, in.:it_i_al neutralized acid) and therein, 1 weight part of the above resulting alkaline cellulose was dispersed. TYien, the temperature was set at 30 C to dissolve a part of t:he reactiAnt, and 0.20 weight part of glacial acetic acid (the remainder of an equivalent for rieutralization, complete neutralized acid) to obtain a processed fiber product containinq a part of dissolution and a part of deposit.
The :resulting product was washed with hot water at about 80 C, drai_ned, dried, ground by means of a high rolling impact grinder, and sifted by means of a 100 mesh sieve to obtain the powder of low-=subsi:it:uted hydroxypropyl cellulose LH-33 (the content of hydroxypropoxyl group: 5.8 weight o, the average particle diameter: 17.8 lum).

ReferencE: Exanlple :2 Powders of low-substituted hydroxyp.r.opyl. cellulose LH-23 (hydroxypropoxyl gx-oup contents: 5.7 weight %, average particle diameter: 30.8 lim) were obtained in the same manner as in Reference Exampl e 1. .

5 Example 2 (1) Production of granules having a core A cent:rifugal #:luidized coating granulator [manufactured by Powrex Corp.( Japan ), MP- ]. 0( Type 2)] was charged with 300 g of Nonpareil 105 [( trade mark) particle diameter: 100 to 200 10 m]. With the inlet air temperature and the temperature of the loading being controlled at '70 O C and about 30 C, respective,Ly, the Nonparei.l was coated by spraying a spray liquid of the followirig composition prepared in advance in accordance with thea tangential spray method at a spray rate 15 of 22 g/miii. , and then drying was carried out in the granulator for 10 minutes. The resulti_ng granules were sieved through a #48 circ'ular sieve (300 m) and a #100 circular sieve (150 m) to provide 2186 g of powders (150 to 300 [tm) having a core.
20, Spray liquid:
Lansoprazole 927 g Magnesium carbonatfs 309 g Low-substituted hydroxypropyl cellulose LH-32 154.5 g (hydrox117propoxyl group contents: 8.8 wt (average particle diameter: 17.57 [.im) Hydroxypropyl cellulose (Type SSL) 309 g PurifiecI water 3955 g (2) Production of film-undercoated granules having a core A centrifugal.E:luidized coating granulator [manufactured by Powrex (;orp.( Japa.n ), MP-10 (Type 2)] was charged with 2040 25 g of the above grariu].es having a core. With the inlet air temperature and thr:: temperature of the loading being controlled at 75 and about 40 C:, respectively, an undercoating liquid of the fo.llowing composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 13 g/miri. to provide 2145 g of film-undercoated griariu_les havi_ng a c,or.e.

Undercoating l.i_quid :
Hydroxypropylmethylcellulose 264 g (Type 2910, viscosity: 3 centistokes) Purified wate.r. 5016 g (3) Production of enteric coated granules having a core A centrifugaltluidized coating granulator[manufactured by Powrex C.orp.( Japan ), MP-10 (Type 2) ) was charged with 1710 g of the above film-undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 70 C and about 40 C, respectively, an enteric film coati_rig liquid of the following composikion prepared i.n advancE: was sprayed in accordance with the tangential spray met-hod at a spray rate of 17 g/min ., and dried for 7 minul:.es, and then sieved through a #42 circular sieve (355 p,m) and a #80 c:ircular sieve (177 m) to provide 2393 g of enteric, coated powders (177 to 355 m) having a core.

Enteric f:ilm coatin.g liquid:
Eudragit* L30D-55 5016.4 g Eudr.<:igit*NE30D 559.0 g Triel;.hyl citrate 3.33.7 g Glyceryl monostearate 106.5 g PolySorbate 80 34.8 g Red :iron oxide 1.8 g Purified water 2547.1 g (4) Production of enteric coated and mannitol coated granules having a core A centrifugaZ flu.idized coating granulator [manufactured by Powrex Corp.( Japan ), MP -10 (Type 2)) was charged with 600 *Trade-mark g of the above, entE:::ric coated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 65 C and about 32 C, respectively, an film coatirig ].iquid" of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rat:e of 11 g/niin ., and t:hen dried for 7 minutes to provide. 617 g of enteric coated and mannitol coated granules t.aving a c;ore.
The average p,:article diameter of the obtained granules was 334.1 m.

Film coating liquid:
Mann=itol. 33 g Purified water 297 g (5) Production of mannitol-granulated powders A flu_Ldized bed granulator [manufactured by Powrex Corp.
(Japan), T,AB-1] was charged with 800 g of mannitol [manufactured by Merck Japan Co. , I,t:d. ], and granulation was carried out while spraying 315 g of purified water. The granules were drie(l to provide 727 . 3 g of grariulated powders.
(6) Production of mixed powders To 97.3 g of the above mannitol-granulated powders were added 105 g of the above enteric coated and mannitol coated granules having a core, 15.0 g of low-substituted hydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8 weig}.zt %, average particle di.ameter: 17.8 .m) , 22.5 g of orystalli ne cellulose [CEOLUS KG-801 (trade mark), manufactured by As.ahi. Chemical Co., Ltd. (Japan)], 7.5 g of crospovidone, 1.5 g of citric acid anhydrous, 0.45 g of aspartame and 0.75 g of magnesium stearate, which was admixed in a bag 1. o give ir,.i_xe:d powders.

(7) Production of orally disintegrable tablets 250.0 g of the above mixed powders were tabletted using Autograph (trade m~.~xrk.; compressing force measurement apparatus) with a punch (15R), 11 mm in dianieter, at a tabletting pressure of 1.5 ton/cm2, to provide tablets each weighing 500 mg.
The hardness and oral disintegration time of each tablet thus obtained were 5.9 kg and 30 secorids, respectively.
Example 3 (1) Production of granules having a core A centrifugal a~luidized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged wi_th 900 g of Nonpar..eil. 105 (trade mark) (particle diameter of 100 to 200 m). With the inlet air temperature and the temperature of the loading being controlled at 75 C and about 29 C
respectively, the IVonpareil was coated by spraying a bulk liquid of' the following composition prepared in advance in accordance with the tangential spray niethod at a spray rate of 22 g/niin. The spraying operation was stopped when the specified amount 5654.7 g of the bulk liquid had been sprayed, and then drying was carried out in the grantilator for 10 minutes. The resulting granules were sieved through a #60 circular sieve (250 tim) and a #100 circular sieve (150 m) to provide 2424 g of granules having a core.
Bulk liquid:
Lansop:r:~azole 1080 g Magnesium carbonate 360 g Low-substituted hydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8 weight o) Hydroxypropyl cellulose (Type SSL) 360 g Purif_L.:d water 4608 g (2) Production of iilrn-undercoateci granules having a core A centrifugal fluidizedcoating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 2337 . 5 g of the above granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 80 C and about 41 C, respectively, an undercoating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 18 g/min. The spraying operation was stopped when the specified amount 6050 g of the undercoating liquid had been sprayed, and then drying was carried out in the granulator for 10 minutes to provide 2551 g of film-undercoated granules having a core.

Undercoating liquid:
Hydroxypropyl methylcellulose 332.5 g (Type 2910, viscosity: 3 centistokes) Low-substituted hydroxypropyl cellulose LH-32 17.5 g (hydroxypropoxyl group contents: 8.8 weight (average particle diameter: 17.57 Eun) Purified water 6650 g (3) Production of enteric coated granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 570 g of the above film-undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 75 C and about 40 C, respectively, an enteric film coating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 18 g/min. The spraying operation was stopped when the specified amount 2646 g of the enteric film coating liquid had been sprayed, and then drying was carried out in the granulator for 8 minutes. The coated powders were sieved through a #42 circular sieve (355 m) and a #70 circular sieve (212 m) to provide 1116 g of ....__,-...,,~... _.m_..~.~...._... _._ _ _..__ enteric coated granules having a core.
The average par.:=ticle diameter of the obtained granules was 326.9 pin.

5 Enteric film coating liquid:
Eudragit* L30D--55 1911 g Eudragit*NE30I.:, 212.9 g Triethyl. citra.te 127.1 g Glyceryl monostearate 40.6 g Polysorbate 8() 13.3 g Red iron oxide 0.8 g Purified watex 970.3 g (4) Production of mixed powders To 200 g of th}=: above enteric coated granules having a core were added 189.7 g of mannitol, 30.0 g of low-substituted 10 hydroxypropyl cellulose LH-23 (hydroxypropoxyl group contents :5. 8 weight:, o, average particle diameter: 17 . 8pm ), 60.0 g of crystalline cellulose [CEOLUS KG-801 (trade niark ), manufactured by Asabi. Chemica:L Co., Ltd.( Japari )], 15. 0 g of crospovidorie, 2.8 g of citric acid anhydrous and 25 g of 15 magnesium stearate, which was admixed in a bag to give mixed powders.

(5) Production of orally c3isintegrable tablets 250.0 g of the above mixed powders were tabletted using 20 Autograph i;trade mark; compressing force measurement apparatus) with a punch (15R), 11 nun in diameter, at a tabletting pressure of 1.5 ton/cm2, to provide tablets each weighing 500 mg.
The hFardness ar,d oral disintegration time of each tablet 25 thus obtained were 4.2 kg and 24 seconds, respectively.
Example 4 *Trade-mark (1) Production of granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 900 g of Nonpareil 105 (trade name) (particle diameter of 100 to 200 m).

With the inlet air temperature and the temperature of the loading being controlled at 75 C and about 32 C respectively, the Nonpareil was coated by spraying a bulk liquid of the following composition prepared in advance in accordance with the tangential spray method at a spray rate of 20 g/min. The spraying operation was stopped when the specified amount 5654.7 g of the bulk liquid had been sprayed, and then drying was carried out in the granulator for 10 minutes. The resulting granules were sieved through a #48 circular sieve (300 m) and a #100 circular sieve (150 m) to provide 2280 g of granules having a core.

Bulk liquid:
Lansoprazole 1080 g Magnesium carbonate 360 g Low-substituted hydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8 weight %) Hydroxypropyl cellulose (Type SSL) 360 g Purified water 4608 g (2) Production of film-undercoated granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 1020 g of the above granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 85 C and about 40 C, respectively, an undercoating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 15 g/min. The spraying operation was stopped when the specified amount 1980 g of the undercoating liquid hail been sprayed, and then drying was carried otit in the granulator for 10 minutes t.o provide 1330.5 g of film-undercoated granules having a core.

Undercoating liquid:
Hydroxypropylmc,thylcelluLose 120 g (Type 2910, vi:::,cosity: 3 centistokes) Titan.itim oxide (Ti02) 240 g Sterilized Talc (trade mark) 240 g [produced by Matsumura Sangyo Co. Ltd. (Japan)]
Magnesium carbonate 120 g Purified water 2880 g (3) Production of enteri.c coated granules having a core A cen-trifugal fl.uidized coating granulator [manufactured by Powrex Corp. (Japan) , MP-10 (Type 2) ] was charged with 460 g of the above film - un.c3er.coated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 80 C and about 41 C, respectively, an enteric film eoating :Liquid of the following composition prepared i.n advance was sprayed in accordance with the 1.5 tangentia.]. spray methad at.a spray rate of 13 g/min. The spraying operation was stopped when 'the specified amourit 2205 g of the E:nteric f.ilm coating liquid had been sprayed.
Enteric film coating liquid:
Eudrag:Lt* L30D-55 2290 g Eudraq:i_t* NE30D 253 g Triethl(l citrat.e 153 g Glycer~~l monostearate 20 g Polyso_r_bate 80 8 g Titanium oxide ( Ti.Oz ) 53 g Sterilized Talc H(t:rade mark) 53 g [produ(,.;ed by Matsumu.ra Sangyo Co. Ltd. (Japan)]
Purifio3d water 2420 g *Trade-mark (4) Production of enteric coated and mannitol coated granules having a core Following (3), with the inlet air temperature and the temperature of the loading being coritrolled at 80 C and about 35 C, respectively, an film coating li_quid of the following composition prepared:in advance was sprayed in accordance with the tangential spray method at a spray rate of 16 g/min. using a centrifud,:rl fluid:i zed coating granulator [manufactured by 113 Powrex Corp.( Japan ), MP -10 (Type 2) ]. Tl-le spraying operation was stopped when the specified arnount 824 g of the film coating liquid had been sprayed, and then drying was carried out in the granulator for 10 rninutes. The resultirig granules were sieved through cr #42 circular sieve (355 tcrn) and a #60 circular, sieve (250 p,m) to provide 806 q of enteric coated and mannitol coated granules hav.ing a core.
The av~:rage particle dianieter of the obtained granules was 326.6 ,:n.

Film coating liqu.id, Mannitol 320 g Purified water 2880 g (5) Production of mixed powders To 120 g of the above enteric coated and mannitol coated granules having a core were added 87.75 g of mannitol, 8.5 g of low-substituted hydroxypropyl cellulose LH-23 (hydroxypropoxyl graup contents: 5.8 weight %), 4.5 g of low-substituted hydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8 weight %), 19.5 g of crystalline cellulo:_>e [CEOLUS KG-801 (trade mark), manufactured by Asatii Chemical Co., I.t:d.( Japan ) j , 6. 5 g of crospovido.ne, 1. 3 g of citric acid anhydrous, 1. 3 g of aspartame and 0.65 g of magnesium stearate, whicti was admixed in a bag to give mixed powders.

(6) Product_Lon of orally disintegrable tablets 250.0 q of the above mixed powders were tabletted using Autograph ( t.rade mark; compressing force measurement apparatus) with a punch (15R), 11 mm in diarneter, at a.
tabletting pressure of 1.5 ton/cm2, to provide tablets each weighing 500 mg.
The hardness anct. oral disintegration time of each tablet thus obtained were 3.9 kg and 20.5 seconds, respectively.
The remaining rat:io of the obtained tablet after acid-resistance test was 97%.
Example 5 (1) Production of granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp.( Japzn ), MP-10 (Type 2) ] was charged with 900 g of Nonpareil 105 (t:rade mark) (particle diameter of 100 to 200 p.m). With the iY:,lr-~t air temperature and the temperature of the loading being controlled at 65' C and about 30 O C
respectivel..~t, the Ncnpareil was coated by spraying a bulk liquid of the following compos:it,ion prepared in advance in accordance with the tangential spray method at a spray rate of 22 g/min. 'Phe spraying operation was stopped when the specified anlount 566:1 g of the bu.lk liquid had been sprayed, and theri drying was carried out in the granulator for 8 minutes.
The result:ing granules were sieved through a #42 circular sieve (350 pLm) and a #100 c.ircula.r sieve (150 m) to provide 2074 g of granules having a core.

Bulk liquid:
Lansoprazole 1080 g Magnesium carbonate 360 g Low-substituted ri.ydroxypr_opyl cellulose LH-32 180 g (hydroxy;propoxyl group contents: 8.8 weight o) *Trade-mark Hydroxypropyl ce:l.lu_l_ose ( Typc: SSL) 360 g Purified. water 4680 g (2) Production of ,.f ilm-undercoated granules having a core A centrifugal f:luidized coating granulator [manufactured by Powrex Corp. ( Japan ), MP--10 (Type 2)] was charged with 2074 5 g of the above granules having a core. With the irilet air temperature and the ternperature of the loading being controlled at '78 C and about 40 C, respectively, an undercoating liquid of the following cornposition prepared in advance was sprayed in accordance with the tangential spray 10 method at a spray ratc: of 22 g/min. The spraying operation was stopped when the :-,pecified amount 1980 g of the undercoating liquid had been spriiyed, and then drying was carried out in the granulator for 9 minutes. The resulting granules were sieved through a #42 ~:~i.rcular sieve (350 E.cm) and a #100 circular 15 sieve (150 i.am) to provide 2555 g of film-undercoated granules having a core.

Undercoating liquid:
Hydroxypropylmethylcellulose 252 g (Type 2910, viscosity: 3 centistokes) Titanium oxide ( T-i0z ) 108 g Sterilized Talc (trade mark) 108 g [produced by Matsumura Sangyo Co. Ltd. ( Japan )]
Low-substituted hydroxypropyl cellulose LH-32 180 g (hydroxypropoxy]. group coritent:s: 8.8 weight %) Mannit(:).1 252 g Purified water 3600 g 20 (3) Production of enteric coated granules having a core A centrifi_igal -f:lu,idized coating grarlulator [manufactured by Powrex Corp. (Japari) , MP-10 (Type 2) ] was charged with 1320 g of the above film-undercoated granules having a core. With the inlet air temperaLure and the ternperature of the loading being controlled at: 80 C and about 42 C, respectively, an enteric film coating liquid (A) of the following composition prepared i.n advance was sprayed in accordance with the tangential. spray mF:thod at a spray rate of' 22 g/min. The specified amount 16:38 g of the erite.ric film coating liquid had been sprayecl.

Enteric film coatirig liquid (A):
Eudragit*L30D-55 1219.2 g Eudragit*NE3GD 134.4 g Polyethylene glycol 6000 40.8 g Glyr..e~r.yl moncrstearate 24.0 g Polysorbate 80 7.2 g Ferric oxide 0.24 g Ferr ic oxide ( yel low ) 0.24 g Citric acid anl:lydr.ous 0.48 g Purified water 1693 g Following this, with the inlet air temperature and the temperatu:r_e of the 7..oading being controlled at 76 C and about 42 C, respectively,, an enteric film coating liquid (B) of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 22 g/mi.n. The specified amount 6552 g of the enteric film coating liquid had been sprayed.

Enteric film coating liquid (B):
Eudragit~kL30D-55 4032 g Eudragit*NE30D 447.8 g Triethyl citrate 269.3 q Glyceryl monostearate 86.4 g Polysorbate 80 25.9 g Ferric oxide 0.86 g Ferric oxide (yellow) 0.86 q *Trade-mark Citric acid anhydrous 0.72 g Purified water 2624 g Following this, with the inlet air temperature and the temperature of the loading being controlled at 80 C and about 42 C, respectively, an enteric film coating liquid (A) of the above mentioned composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 22 g/min. The specified amount 819 g of the enteric film coating liquid had been sprayed.

(4) Production of enteric coated and mannitol coated granules having a core Following (3), with the inlet air temperature and the temperature of the loading being controlled at 85 C and about 35 C, respectively, an film coating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 22 g/min. using a centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)]. The spraying operation was stopped when the specified amount 882 g of the film coating liquid had been sprayed, and then drying was carried out in the granulator for 10 minutes. The resulting granules were sieved through a #35 circular sieve (420 m) and a #60 circular sieve (250 m) to provide 1964 g of enteric coated and mannitol coated granules having a core.
The average particle diameter of the obtained granules was 333.7 m.

Film coating liquid:
Mannitol 180 g Purified water 1080 g (5) Production of mixed powders To 270 g of the above enteric coated and mannitol coated ~~ ~ ....,_ _,. , ...._.,...__ ._ .

granules having a core were added 204.0 g of mannitol, 30 g of low-substituted hydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8 weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade niark), manufactured by Asalai Cherrtical Co., Ltd. (Japan)], 15 g of crospovidone, 3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magneSium stearate arid 3 g of flavor [STRAWBERRY DURAROME
(trade mark), manufactured by Nihon Filmenich Co., Ltd.
(Japan)], which was admixed in a bag to give mixed powders.
(6) Production of o-cally disintegrable tablets 570 g of the above rni_xed powders were tabletted using Autograph (trade narr-e; compressing force measurement apparatus) with a punch having a beveled edge, 13 mrn i.n diameter, at atabletting pressure of 1.5 ton/cm2, to provide tablets each weighing 570 mg.
The hardness and oral disintegration time of each tablet thus obtained were 2.6 kg and 20 seconds, respectively.
The acid-resist_.ance of the obtained tab.Iet was 3.5 -%.
Example 6 (1) Production of granules having a core A cent:a:ifugal fluidized coating granulator [manufactured by Powrex Corp. ( Japan ), MP-10 (Type 2)] was charged with 750 g of Nonpareil 105 ( trade name )( particle diameter of 100 to 200 m). With the iralet air temperature and the temperature of the loading beinq controlled at 65 C and about 30 C
respectively, the Nonpareil was coated by spraying a bulk liquid of the follow:ing composition prepared in advance in accordance with the tangential spray ntethod at a spray rate of 22 g/m:in. The s;prayi.ng operatiort was stopped when the specified amount 4717.5 g of ti-ie bulk liquid had been sprayed, and then drying was car:ried out in the grariulator for 8 minutes.
The resulting grani,_Les were sieved through a #42 circular sieve (350 Fun) and a #100 circular sieve (150 m) to provide 1811 g of g.ranules having a core.
Bulk liquid:
Lansoprazole 900 g Magnesium carbonate 300 g Low-substituted hydroxypropyl cellulose LH-32 150 g (hydroxypropoxyl group contents: 8.8 weight %) Hydroxypropyl cellulose (Type SSL) 300 g Purified water 3900 g (2) Production of fil_m-undercoated granules having a core A centrifugal f:Lu:i.di.zed coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 1811 g of the above granal.es having a core. With the inlet air temperature and the temperature of the loading being 1.0 controlled at 78 C and about 38 C, respectively, an undercoating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rUte of 22 g/min. The spraying operation was stopped when the ;:,pecified amount 5274 g of the undercoating 1.5 liquid had been sprayed, and then dry_ing was carried out in the granulator for 9 rni.riutes. The resulting granules were sieved through a#42 ~.,i.rcuLar sieve (350 p,m) and a #100 circular sieve (150 Eun) to provide 2628 g of f.ilm-undercoated granules having a core.
Undercoating liquidr.
Hydroxypropylmethyicellulose 378 g (Type 2910, viscosity: 3 centistokes) Titaniuni oxide (Ti02) 162 g Sterilized Talc (trade mark) 162 g [produced by Matsu.mura Sangyo Co. Ltd. (Japan) ) Low-substituted hydroxypropyl cellulose LH-32 270 g (hydroxypropoxyl qroup contents: 8.8 weight o) Mannitol.. 378 g Purified water 5400 g (3) Production of enteric coated granules having a core A centrifugalflu.idized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 1560 5 g of the above film--undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 70 C and about 40 C, respectively, an enteric film coating liquid (A) of the following composition prepared in advance was sprayed i_n accordance with the 10 tangential spray method at a spray rate of 19 g/min. The specified amount 6048 g of the enteric film coating liquid had been sprayed.

Enteric filcn coating liquid (A):
Eudragit*L30D-55 4032 g Eudragit* NE30D 447.8 g Triethyl citrate 269.3 g Glyceryl mon(:)stearate 86.4 g Polysorbate 80 25 _ !) g Ferric oxide 0.86 g F'erric oxide (yellow), 0.86 g Citric acid anhydrous 0.72 g Pur:ified water 2624 g Following this, with the inlet air ternperature and the temperature of the loading being controlled at 72 C and about 42 C, respectively, an enteric film coating liquid (B) of the following compositiori prepared in advance was sprayed in accordance with the tangential spray rriethod at a spray rate - of 19 g/min. The specified amount 819 g of the enteric film coating liquid had been sprayed.

Enteric film coating .Li:quid ( B ) :
Eudragii* L301:)-55 609.6 g *Trade-ma.rk Eudragit* NE301_) 68.0 g Polyethylene <<.Lycol 6000 20.4 g Glyceryl rnonostearate 12.0 g Polysorbate 80 3.6 g Ferric oxide 0.12 g Ferric oxide Oyellow ) 0.12 g Citric acid anhydrous 0.24 g Purified water 846.7 g (4) Production of en.t:eri.c coated and mannitol coated granules having a core Following (3), while the inlet air temperature and the temperature of the loading being controlled at 65 0 C and about 38 C, respectively, an film coating liquid of the following compositiori prepared. in advance was sprayed in accordance with the tangential spray inethoci at a spray rate of 19 g/min. using a centrifugal fluidized coating granulator [manufactured by Powrex Corp.. ( Japan ),. MP- 10 (Type 2)]. The spraying operation was stopped wheri the :_>pecifi_ed amount 882 g of the film coating liquid had been sprayed, and then drying was carried out in the granulator for 1.7 minutes.. The resulting granules were sieved through a #35 ~;i.rcular sieve (420 m) and a #60 circular sieve (250 u.m) to pro,,;,i_do 2825 g of enteric coated and mannitol coated granules havi..ng a core.
The average part:iclc_, di.amoter of the obtained granules was 330.5 E.un.

Film coating liquid:
Mannitol 180 g Purified water 1080 g (5) Produci::ion of mixed powders To 270 g of the i,above enteri.c coated and mannitol coated granules having a core were added 204., 0 g of mannitol, 30 g of low-substituted hydroxypropyl cellulose LH-33 * Trade -mark (hydroxyprapoxyl group contents: 5.8 weight %), 30 g of crystalline; cellulose [CEOLUS KG-801 (trade mark), manufacture:d by Asahi. Chemical. Co., Ltd. (Japan) ], 15 g of crospovidor..e, 3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesium stearate and 3 q of flavor [STRAWBERRY DURAROME
(trade marh:) , rnanufac:tured by Nihon Filmenich Co. , Ltd.
(Japan)], which was adcnixed in a bag to give mixed powders.
(6) Production of orally disintegrable tablets 1.0 570 gof the allaove mixed powders were tabletted using Autograph (trade mark; compressing force measurement apparatus) with a punch Ziaving a beveled edge, 13 mm in diameter, at a table'tting pressure of 1.5 ton/cm2, to provide tablets each weighing 570 mg.
The hardness artd oral disintegration time of each tablet thus obtai.ried were 3.1 kg and 22 seconds, respectively.
The acid-resistance of the obtained tablet was 2.5 0.
Example 7 (1) Production of granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2) ] was charged with 750 g of Nonpareil 105 (trade mark: )(parti.cle diameter of 100 to 200 m) . With the inlet air temperature and the temperature of the loading being coritrolled at "75 O C and about 30 'C
respective]_y, the Nonpareil. was coated by spraying a bulk liquid of the following composition prepared in advance in accordance with the tangential spray method at a spray rate of 20 g/m~-n. The spraying operation was stopped when the :30 specified amount 471.7. 5 q of the bulk liquid had been sprayed, and then drying was car. r. ied out in the granulator for 10 minutes to provide 1842 g of granules having a core.

Bulk liquid:
Lansoprazole 900 g Magnesium carbonate 300 g Low-substituted hydroxypropyl cellulose LH-32 150 g (hydroxypropoxyl (iroup contents: 8.8 weight %) Hydroxypropyl ce.L:tulose (Type SSL) 300 g Purified water 3900 g (2) Production of film-undercoated granules having a core A centrifugal fiuidized coatirig granulator [manufactured by Powrex Cor_p.( Japan ), MP-10 (Type 2)] was charged with 1842 g of the above granules having a core. With the inlet air temperaturc: and the temperature of the loading being controlled at 74 C and about 38 C, respectively, an undercoating liquid of the following composition prepared i.n advance was sprayed in accordance with the tangential spray 1.0 method at a. spray rate of 19 g/min. The spraying operation was stopped when the spcci.fied arnount 5365 g of the undercoating liquid had been sprayed, and then dryi.ng was carried out in the granulator for 9 rninutes. The resulting granules were sieved through a #42 circular sieve (350 l,im) and a #100 circular sieve (150 prn) to provide 2770 g of film-undercoated granules having a core.

Undercoating liquid:
Hydroxypr_opylmet:hylcellulose 378 g (Type 2910, viscosity: 3 ceritistokes) Titanium oxide ( T.iOz ) 162 g Sterilized Talc (trade mark) 162 g [produced by Matsurnura Sangyo Co. Ltd. (Japan) ]
Low-substituted hydroxypropyl cel.lulose LH-32 270 g (hydrox,ypropoxyl group contents: 8.8 weight a) Mannitol 378 g Purified water 5400 g (3) Production of enteric coated granules having a core A centrifugal f.lu.idized coating granulator [manufactured by Powrex Cor.-p .(Japan ) , MP-10 ( Type 2)] was charged with 1300 g of the above film-undercoated g-canules havirig a core. With the inlet air temperature and. the temperature of the loading being controlled at 78 C and about 39 C, respectively, an enteric film coating liquid (A) of the following composition prepared in advance was sprayed in accordance with the .
tangential spray methc~id at a spray rate of 21 g/min. The spraying operation was stopped when the specified. amount 5040 g of the enteric f ilm coating liquid had been sprayed, and then drying was ca._,ried out :i.n the grariuLator for 16 minutes. The resulting granules were sieved through a #35 circular sieve (420 m) and a#60 circular sieve (2'.50 i,Lm) to provide 2453 g of enteric coated granules hav;i.ng a core.

Enteric film coating a.iqui_d (A) :
Eudrag.it*L30D-5_')' 4032 g Eudrag.it* NE30D 447.8 g Triethyl citrate 269.3 g Glyceryl monostearate 86.4 g Polysorbate 80 25.9 g Ferric oxide 0.86 g Ferric oxide ( yE.l l.ow ) 0.86 g Citric acid anhydrous 0.72 g Purified water 2624 g A centrifugal flu=i_dized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 1000 g of the above enteric coated gr_anules having a core. With the inlet air temperature and the temperature of the loading being controlled at 80 C and about 38 'C, respectively, an enteric film coating liquid (B) of the f:ollowing composition prepared in advance w,::Ls sprayed iri acco.r.dance with the tangential spray methud at a spray rate of 19 g/min. The specified amount 273 q of the enteri.c film coat.i..ng liquid had been sprayed.

*Trade-mark .24205-1241 Enteric film coating liquid (B) :
Eudragit* L30D-55 610.4 g Eudragit*NE30D 68.0 g Polyethylene glycol 6000 20.4 g Glycery:L monostearate 12.0 q Polysorbate 80 3.6 g Ferric: oxide 0.12 q Ferric: oxide ( yellow ) 0.12 g Citric acid anhydrous 0.24 g Purified water 845.12 g (4) Production of enk_e.ri.c coated and mannitol coated 5 granules having a core.
Following (3), while the inlet air temperature and the temperature of the loading being cont.rolled at 75 C and about 35 C, respectively, an film coating liquid of the following composition prepared in advance was sprayed in accordance with 10 the tangential spray method at a spray rate of 20 g/min. using a centrifuga.l fluidizc.d coating granulator [manufactured by Powrex Corp.;Japan), MP-10 (Type 2)]. The spraying operation was stopped when the sx7eci.fied amount 294 g of the film coating liquid had been sprayed, and then drying was carried out in 15 the granulator for 10 mi_nt.ites. The resulting granules were sieved throuqh a #35 circular sieve (420 m) and a #60 circu..lar sieve (250 [un) to provi,de 1061 g of enteric coated and mannitol coated grarniles having a core.
The average particle diameter of the obtained granules 20 was 307.1 ~un.

Film coating liquid:
Mannitol 120 q Purifiod water 720 q (5) Production of m:i.xed powders *Trade-mark.

To 270 g of the above enteric coated and mannitol coated granules having a cc:)re were added 207 g of mannitol, 30 g of low-substituted hydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8 weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade mark), manufactured by Asahi Cheniical Co., Ltd. (Japan)], 15 g of crospovidone, 3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesium stearate and 3 g of: flavor [ STRAWBERRY DURAROME
(trade mark), manuf.:Ictured by Nihon Filmenich Co., Ltd.
(Japan)which was adniixed in a bag to give mixed powders.
(6) Production of oz-al.ly disintegrable tablets 570 g of the above mixed powders were tabletted using Autograph (trade mark; compressing force measurement apparatus) with a pcinch having a beve i_ed ecige, 13 mm in diameter, at a tablett:_l.rig pressure of 1.5 ton/cm2 , to provide tablets each weighing 570 mg.
The hardness an.d oral disintegration time of e rch tablet thus obtair.ied were :3.2 kg and 24 seconds, respectively.
Example 8 (1) Production of granules having a core A centrifugal f:luidized coating granulator [manufactured by Powrex Corp.( Japa:n ), MP-1.0 (Type 2)] was charged with 900 g of Nonpareil 105T (trade mark) (particle diameter of 100 to 200 m) . With the inlet air temper_ature and the temperature of the loading being controlled at 71 to 78 C and about 31 C respectively, the Nonpareil was coated by spraying a bulk liquid of the following composition prepared in advance in accordance with the tandentia.l. spr_ay method at a spray rate of 21 g/min. The spraying operation was stopped when the specified amourrt 5550 g of the bulk liquid had been sprayed, and then drying wa;, carried out:: in the granulator for 21 minutes. The resulting granules were sieved through a #42 circular sieve (350 [am )and a#100 circular sieve (150 pm) to provide 1723 g of g..r.cinules havirig a core.
Bulk liquid:
Lansopr.irzole 1080 g Magnesium carbonate 360 g Low-substituted liydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8 weight %) Hydroxypropyl ccll.ulose (Type SSL) 360 g Purified water 4680 g (2) Production of :f:ilm-undercoated granules having a core A centrifugal fl.uidized coating granulator [manufactured by Powrex Corp. ( Japan ), MP-10 (Type 2)] was charged with 2074 g of the above granules having a. core. With the inlet air temperature and the. temperature of the loading being :L0 controlled at 77 C: and about 41. C, respectively, an undercoating liquid of the following composition prepared in advance was sprayed in accordanc.e with the tangential spray method at a spray r.ate of 21 q/min. The spraying operation was stopped when the specifi.ed ainount 2787 g of the undercoating :L5 liquid had been sprayed, and Lhen drying was carried out in the granulator for 13 minutes. The resulting granules were sieved thrcugh a #42 circular sieve (350 E.un) and a #100 circular sieve (150 m) to provide 1958 g of fi_lm-undercoated granules having a core.
Undercoating liquid:
Hydroxypropylmethylcellulose 252 g (Type ,2910, viscosity: 3 centistokes) Titan_Lum oxide (Ti02) 108 g Sterilized Talc (trade mark ) 1.08 g [produced by Matsurnura Sangyo Co. Ltd. (Japan) ]
Low-sulostitutecil hydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl. g.roup contents: 8.8 weight o) Mannitol 252 g Purified water 3600 g (3) Production of eriteric coated granules having a core A centrifugal f:Luidized coating granulato.r [manufactured by Powrex C:orp.( Japan ), MP -10 (Type 2) ] was charged with 1100 g of the above film-undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 80 C and about 41 C, respectively, an enteric: film coatinq liquid (A) of the following composition prepared in advarice was sprayed in ac;cordance with the ~0 tangential spray method at a spray rate of 22 g /min. The specified amount 1365 g of the enteric E-i_lm coating liquid had been sprayed.

Enteric fi_7_m coating liquid (A):
Eudragit* L30D-55 1017 . 3 g Eudragit* NE30() 113.3 g Polyethylene glycol 6000 34.0 g Glyceryl monostF,.arate 20.0 g Polysorbate 80 6.0 g Ferr:ic oxide 0.2 g Ferr:ic oxide (yellow) 0.2 g Citric acid anhydrous 0.4 g Puri:Eied wate.i- 1410.8 g Following this, with the inlet air temperature and the temperature of the loading being controlled Eit 76 C and about 41 0 C, respectively, an enteric film c:oating liquid (B) of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 22 g/mi.n. ~Phe speci_fied amount 5040 g of the enteric film coating liquid had been sprayed.

Enteric film coating l.iquid (B):

*Trade-mark Eudragit*L3UD-55 3360 g Eudragit*NE30D 373,2 g Triethyl citratt'_-I 224.4 g Glyceryl monoste:arate 72.0 g Polysox-bate 80 21.6 g Ferric, oxide 0.72 g Ferric oxide (yellow) 0.72 g Citric acid anhydrous 0.6 g Purified water 1706.8 g Followirlg ttiis,;aith the inlet ai.r temperature and the temperature of the loading being controlled at 80 0 C and about 42 C, respectively, an enteric fiim coating liquid (A) of the above mentior.ted composi.t:i.on prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 21 g/min. The spec=ified amount 682.1i g of the enteric film coating liquid had been sprayed.

(4) Production of enteric coated and marrnitol coated granules having a core Followir.tg (3), with the inlet air temperature and the temperature of the loacling being controlled at 80 0 C and about 36 C, respectively, arr film coating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 22 g/min. using a centrifugal fluidized coating granulat:or [manufactured by Powrex Corp. (Japan) , r:P-10 (Type 2) ]. 'I'he spraying operation was stopped when the specified amount 735 g of the film coating liquid had been sprayed, and then drying was carried out in the granulator for 10 minutes. The resulting granules were sieved through a #35 circular sieve (420 }un) and a #60 circular sieve (250 [tm) to provide 2319.5 q of enteric coated and mannitol coated grant.i les having a core.
The average part_Acle diameter of the obtained granules was 392.7 m.

*Trade-mark Film coating liquid:
Mannitol 100 g Purified water 600 g (5) Production of mixed powders 5 To 270 g of the above enteric coated and mannitol coated granules having a core were added 204.0 g of rnannitol, 30 g of low-substituted hydr.oxypropy.:I cellulose LH-33 (hydroxypropoxyl grour) contents: 5.8 weight o), 30 g of crystalline cellulose [CEOLUS KG-801 (trade mark), 10 manufactured by Asahi. Chemical Co., Ltd. (Japan)], 15 g of crospovidorie, 3 g of c:::_t:r. i.c acid anhydr.aus, 9 g of aspartame, 6 g of magnesium s tearate and 3 g of flavor [STRAWBERRY DURAROME
(trade mark),, manufac*ur.ed by Nihon Fi.lmenich Co., Ltd.
( Japan )], which was admixed in a bag to give mixed powders.
(6) Producti_on of orally disintegrable tablets 570 g of the above mixed powders were tabletted using Autograph (trade mark; compressing force measurement apparatus) with a punch having a beveled edge, 12 mm in diameter, at a tablett:a.ng pressure of 1. 5 ton/cm2 , to provide tablets each weighing 570 mq.
The hardness and oral disintegration time of each tablet thus obtained were 3.7 kg and 35 seconds, respectively..
The acid-resistance of the obtained tablet was 3.4 %.
Example 9 (1) Produci: ion of granules having a core A centrifugal flu:id:ized coating granulator= [manufactured by Powrex Corp. (Japart), MP-10 (Type 2) ] was charged with 300 *
g of Nonpar.e_i.l 1.05 (70-1.40) (particle di.ameter of 100 to 200 in) . With the inlet air tc:mperature and the temperature of the loading being control<.ed at 85 C and about 28 C respectively, the Nonpare.ilwas coated by spraying a bulk liquid of the *Trade-marh_ following composition prepared in advance in accordance with the tangential spray method at a spray rate of 20 g/min. The spraying operation was stopped when the specified amount of the bulk liquid had been sprayed, and then drying was carried out in the granulator for 7 minutes. The resulting granules were sieved through a #48 circular sieve (300 m) and a #100 circular sieve (150 m) to provide 757 g of granules having a core.

Bulk liquid:
Lansoprazole 300 g Magnesium carbonate 100 g L-HPC 50 g HPC (Type SSL) 100 g Water 1650 g (2) Production of film-undercoated granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 680 g of the above granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 70 C and about 36 C, respectively, an undercoating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 10 g/min. to provide 672 g of film-undercoated granules having a core.

Undercoating liquid:
HPMC 32 g (Type 2910, viscosity: 3 centistokes) Talc 8 g Water 760 g (3) Production of enteric coated granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex -Corp.( Japan ), MP-10 (Type 2)] was charged with 450 g of the above film--undercoated granules having a core. With the inlet air temperature and the temperature of the loading being cont:r.ol:Led ai: 65 C and about 36 C, respectively, an enteric film coating liquid of the following composition prepared in advance was sprayed iri accordance with the tangentia.l spraymel:Lr.od at a spray rate of 17 g/min. The coated powders were dried in vacuum <.it 40 C: for 16 hours, and sieved through a442 circu:Lar si_eve (355 m) and a #80 circular sieve (177 m) to provide 950 g of enteric coated granules having a core.
The average p~article diameter of the obtained granules was 285.4 m.

1.5 Enteric fi_lm coating liquid:
Eudragit*L30D-55 1078.3 g Eudragit'"NE3c.;D 138.5 g Triethyl citi ate 46.0 g Glyceryl monostearate 16.5 g Talc 16.0 g Polysorbate 130 9.0 g Iron oxide 0.5 g Water 2038.5 g Sieve weight ratio #18 (850 on 0 #30 (500 pm) on 0 ~
#200 (75 Itm) on 100 ~
#200 (75 m) pass 0 ~

(4) Production of granulated powders A fltiii_dized bed granulator [mariufactured by Powrex Corp.
(Japan), LAB-1] was charged with 1321.2 g of erythritol [manufactured by Nikken Chemical Co., Ltd. ( Japan )], 360 . 0 g *Trade-mark of low-substituted hydroxypropyl cellulose LH-32 [hydroxypropoxyl group contents of 8.8 %, manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)], 18.0 g of citric acid anhydrous, and 1. 8 g of aspartame, and granulation was carried out while spraying a solution which was prepared by dissolving 3.6 g of polyethylene glycol ( PEG- 6000 ) in 896.4 ml of purified water. The granules were dried to provide granulated powders.
To the granulated powders were added 90.0 g of crospovidone and 5.4 g of magnesium stearate, which was admixed in a bag to give mixed powders.

(5) Production of orally disintegrable tablets 200. 0 g of the above enteric coated granules having a core and 300.0 g of the above mixed powders were tabletted using Autograph (trade name; compressing force measurement apparatus) with a punch having a beveled edge, 11 mm in diameter, at a tabletting pressure of 1.0 ton/cm2, to provide tablets each weighing 500 mg.
The hardness, the oral disintegration time and remaining ratio after acid-resistance test of each tablet thus obtained were 4.2 kg, 27 seconds and 96.3 %, respectively.

INDUSTRIAL APPLICABILITY
The orally disintegrable tablet of the present invention has superior disintegrability or dissolution so that it can be used for treatment or prevention of various diseases, as an orally disintegrable tablet capable of being administered to the aged or children and easily administered without water.
Also, because the orally disintegrable tablet of the present invention contains fine granules having the average particle diameter and an enteric coating layer such that it will not impart roughness in mouth, it can be administered easily without discomfort at the administration and has superior acid-resistance.
Further, because the orally disintegrable tablet of the present invention has a suitable strength such that it will not be substantially damaged through production processes or circulation processes, it is superior in stability for long-term storage and easy of use at the administration.
Further, because the fine granule of the present invention is characterized in that it stably retains the acid-labile physiologically active substance, contains the physiologically active substance in high content, be small and has superior stability, it can be used for producing various compact pharmaceutical preparations such as tablets, capsules, suspensions and so forth. Such preparations are easy of use at the administration. In addition, the fine granule of the present invention has superior acid-resistance after compression.

Claims

CLAIMS:

1. An orally disintegrable tablet, which comprises:
(i) fine granules having an average particle diameter of 400 µm or less, which fine granules comprise a composition coated by an enteric coating layer comprising a first component which is an enteric coating agent and a second component which is a sustained-release agent, the composition having 10 weight % or more of an acid-labile physiologically active substance, and (ii) an additive comprising a water-soluble sugar alcohol.

2. The orally disintegrable tablet of claim 1, wherein the average particle diameter of the fine granules is 300 to 400 µm.

3. The orally disintegrable tablet of claim 1 or 2, wherein the fine granules further comprise a basic inorganic salt.

4. The orally disintegrable tablet of claim 3, wherein the basic inorganic salt is at least one of a magnesium salt and a calcium salt.

5. The orally disintegrable tablet of any one of claims 1 to 4, wherein the water-soluble sugar alcohol is at least one member selected from the group consisting of sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose and erythritol.

6. The orally disintegrable tablet of any one of claims 1 to 5, wherein the additive further comprises at least one of (i) crystalline cellulose and (ii) low-substituted hydroxypropyl cellulose.

7. The orally disintegrable tablet of any one of claims 1 to 6, wherein the composition coated by an enteric coating layer is further coated by a coating layer which comprises a water-soluble sugar alcohol.

8. The orally disintegrable tablet of any one of claims 1 to 7, wherein 5 weight % or less of the fine granules have a particle diameter of more than 425 µm.

9. The orally disintegrable tablet of any one of claims 1 to 7, wherein 5 weight % or less of the fine granules have a particle diameter of more than 400 µm.

10. The orally disintegrable tablet of any one of claims 1 to 8, wherein the acid-labile physiologically active substance is a benzimidazole compound or a pharmaceutically acceptable salt thereof.

11. The orally disintegrable tablet of claim 10, wherein the benzimidazole compound has the formula:
wherein:

ring A may be substituted;

R1, R3 and R4 are the same or different and are each a hydrogen atom or an alkyl or alkoxy group;

R2 is a C1-4 alkyl group which is unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, hydroxyl and C1-4 alkoxy; and n is 0 or 1.

12. The orally disintegrable tablet of claim 3, wherein the composition comprises a core being coated by the basic inorganic salt and a benzimidazole compound as the acid-labile physiologically active substance, the core comprising crystalline cellulose and lactose.

13. The orally disintegrable tablet of claim 12, wherein the core comprises 50 weight % or more of lactose.

14. The orally disintegrable tablet of claim 12, wherein the core comprises 40 to 50 weight % of crystalline cellulose and 50 to 60 weight % of lactose.

15. The orally disintegrable tablet of any one of claims 1 to 14, wherein the composition comprises 20 weight % or more of the acid-labile physiologically active substance.

16. The orally disintegrable tablet of any one of claims 1 to 14, wherein the composition comprises 20 to 50 weight % of the acid-labile physiologically active substance.

17. The orally disintegrable tablet of any one of claims 1 to 16, wherein the fine granules are produced by a fluidized-bed granulation method.

18. The orally disintegrable tablet of any one of claims 1 to 17, wherein the enteric coating agent is an aqueous enteric polymer agent.

19. The orally disintegrable tablet of claim 18, wherein the aqueous enteric polymer agent is a methacrylate copolymer.

20. The orally disintegrable tablet of any one of claims 1 to 19, wherein the sustained-release agent is a methacrylate copolymer.

21. The orally disintegrable tablet of claim 18, wherein the sustained-release agent is contained in an amount of 5 to 15 weight % relative to 100 weight % of the aqueous enteric polymer agent.

22. The orally disintegrable tablet of any one of claims 1 to 21, which has a hardness strength of 1 to 20 kg.

23. The orally disintegrable tablet of claim 5, wherein the water-soluble sugar alcohol is erythritol.

24. The orally disintegrable tablet of claim 5, wherein the water-soluble sugar alcohol is mannitol.

25. The orally disintegrable tablet of claim 5 or 6, wherein the water-soluble sugar alcohol is contained in an amount of 5 to 97 weight % relative to 100 weight % of the orally disintegrable tablet apart from the fine granules.

26. The orally disintegrable tablet of claim 12, 13 or 14, wherein the crystalline cellulose is contained in an amount of 3 to 50 weight % relative to 100 weight % of the tablet apart from the fine granule.

27. The orally disintegrable tablet of any one of claims 1 to 26, which further comprises crospovidone.

28. The orally disintegrable tablet of any one of claims 1 to 26, having an oral disintegration time of one minute or less.

29. The orally disintegrable tablet of any one of claims 1 to 11, which is free of a lubricant inside the tablet.

30. The orally disintegrable tablet of any one of claims 12 to 17, which is free of a lubricant inside the tablet.

31. The orally disintegrable tablet of any one of claims 18 to 26, which is free of a lubricant inside the tablet.

32. Fine granules having an average particle diameter of 400 µm or less, which comprise a composition coated by an enteric coating layer, wherein the composition comprises (i) 25 weight % or more of an acid-labile physiologically active substance and (ii) a basic inorganic salt; and the enteric coating layer comprises a first component which is an enteric coating agent and a second component which is a sustained-release agent.

33. The fine granules of claim 32, wherein the average particle diameter of the fine granules is 300 to 400 µm.

34. The fine granules of claim 32 or 33, wherein weight % or less of the fine granules have a particle diameter of more than 425 µm.

35. The fine granules of claim 32 or 33, wherein 5 weight % or less of the fine granules have a particle diameter of more than 400 µm.

36. The fine granules of any one of claims 32 to 35, wherein the acid-labile physiologically active substance is a benzimidazole compound or a pharmaceutically acceptable salt thereof.

37. The fine granules of claim 36, wherein the benzimidazole compound has the formula:

wherein:

ring A may be substituted;

R1, R3 and R4 are the same or different and are each a hydrogen atom or an alkyl or alkoxy group;

R2 is a C1-4 alkyl group which is unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, hydroxyl and C1-4 alkoxy; and n is 0 or 1.

38. The fine granules of any one of claims 32 to 37, wherein the basic inorganic salt is at least one of a magnesium salt and a calcium salt.

39. The fine granules of any one of claims 32 to 35, wherein the composition comprises a core being coated by a benzimidazole compound as the acid-labile physiologically active substance and the basic inorganic salt, the core comprising crystalline cellulose and lactose.

40. The fine granules of claim 39, wherein the core comprises 50 weight % or more of lactose.

41. The fine granules of any one of claims 32 to 40, wherein the composition comprises 25 to 40 weight % of the acid-labile physiologically active substance.

42. The fine granules of any one of claims 32 to 41, which are produced by fluidized-bed granulation method.

43. The fine granules of any one of claims 32 to 42, wherein the enteric coating layer comprises an aqueous enteric polymer agent.

44. The fine granules of claim 43, wherein the aqueous enteric polymer agent is a methacrylate copolymer.

45. The fine granules of any one of claims 32 to 44, wherein the sustained-release agent is a methacrylate copolymer.

46. The fine granules of claim 43 or 44, wherein the sustained-release agent is contained in an amount of to 15 weight % relative to 100 weight % of the aqueous enteric polymer agent.

47. The fine granules of any one of claims 32 to 46, wherein the enteric coating layer is contained in an amount of 50 to 70 weight % relative to 100 weight % of the fine granules.

48. The fine granules of any one of claims 32 to 47, wherein the composition also comprises at least one member selected from the group consisting of water-soluble polymers; binders; lubricants; and excipients.

49. A tablet, granule, fine granule, capsule or suspension preparation which comprises the fine granules of any one of claims 32 to 48.

50. An orally disintegrable tablet which comprises:

(i) fine granules having an average particle diameter of 300 to 400 µm and a maximum particle diameter of 425 µm, wherein the fine granules are made of a composition coated by an enteric coating layer comprising a first component which is an enteric coating agent and a second component which is a sustained-release agent; and wherein the composition comprises (a) 10 to 50 weight % (based on the composition) of an acid-labile physiologically active substance and, (b) a basic inorganic salt in an amount of 0.3 to 200 weight % based on the acid-labile physiologically active substance and (c) may further comprises at least one other ingredient selected from the group consisting of water-soluble polymers, binders, lubricants and excipients; and (ii) an additive which comprises a water-soluble sugar alcohol and which may further comprise at least one other member selected from the group consisting of crystalline cellulose, hydroxypropyl cellulose, binders, acids, artificial sweeteners, flavorants, lubricants, colorants, stabilizers, excipients and disintegrants, wherein the tablet disintegrates within 1 minute or less in a healthy adult buccal saliva.

51. The orally disintegrable tablet according to claim 50, wherein the acid-labile physiologically active substance is a benzimidazole compound having an antiulcer activity of the formula:

(wherein:

ring A may have at least one substituent selected from the group consisting of halogen, C1-10o alkyl, C3-7 cycloalkyl, C2-16 alkenyl, C1-10 alkoxy, cyano, carboxyl, C1-7 alkoxycarbonyl, C1-4 alkoxycarbonyl-C1-4 alkyl, carbamoyl, carbamoyl-C1-4 alkyl, hydroxyl, hydroxy-C1-7 alkyl, C1-6 acyl, carbamoyloxy, nitro, C2-6 acyloxy, C6-12 aryl, C6-12 aryloxy, C1-6 alkylthio and C1-6 alkylsulfinyl, where the C1-10 alkyl, C3-7 cycloalkyl and C2-6 alkenyl groups may be further substituted by halogen, nitro, amidino, guanidino, carbamoyl or amino which may still further be substituted by one or two of C1-4 alkyl or C1-4 acyl;

R1, R3 and R4 are each independently hydrogen, C1-10 alkyl or C1-10 alkoxy;

R2 is C1-4 alkyl which may be substituted by at least one substituent selected from the group consisting of halogen, hydroxyl and C1-4 alkoxy; and n is 0 or 1) ;

or a pharmaceutically acceptable salt thereof.

52. The orally disintegrable tablet according to claim 50 or 51, wherein the composition is produced by coating a core comprising crystalline cellulose and lactose with (a) the acid-labile physiologically active substance, (b) the basic inorganic salt and optionally (c) the other ingredient.

53. An orally disintegrable tablet of lansoprazole, which comprises:

(i) fine granules having an average particle diameter of 400 µm or less, which fine granules comprise a composition coated by an enteric coating layer comprising a first component which is an enteric coating agent and a second component which is a sustained-release agent, the composition having 10 weight % or more of lansoprazole; and (ii) an additive comprising a water-soluble sugar alcohol.

54. The orally disintegrable tablet of claim 53, wherein the average particle diameter of the fine granules is 300 to 400 µm.

55. The orally disintegrable tablet of claim 53 or 54, wherein the fine granules further comprise a basic inorganic salt.

56. The orally disintegrable tablet of claim 55, wherein the basic inorganic salt is at least one of a magnesium salt and a calcium salt.

57. The orally disintegrable tablet of any one of claims 53 to 56, wherein the water-soluble sugar alcohol is at least one member selected from the group consisting of sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose and erythritol.

58. The orally disintegrable tablet of claim 57, wherein the additive further comprises at least one of (i) crystalline cellulose and (ii) low-substituted hydroxypropy-cellulose.

59. The orally disintegrable tablet of any one of claims 53 to 58, wherein the composition coated by an enteric coating layer is further coated by a coating layer which comprises a water-soluble sugar alcohol.

60. The orally disintegrable tablet of any one of claims 53 to 59, wherein 5 weight % or less of the fine granules have a particle diameter of more than 425 µm.

61. The orally disintegrable tablet of claim 55, wherein the composition comprises a core comprising crystalline cellulose and lactose and being coated by the basic inorganic salt and lansoprazole.

62. The orally disintegrable tablet of claim 61, wherein the core comprises 50 weight % or more of lactose.

63. Fine granules having an average particle diameter of 400 µm or less, which comprise a composition coated by an enteric coating layer, wherein the composition comprises (i) 25 weight % or more of lansoprazole and (ii) a basic inorganic salt; and the entreric coating layer comprises a first component which is an enteric coating agent and a second component which is a sustained-release agent.

64. The fine granules of claim 63, wherein the average particle diameter of the fine granules is 300 to 400 µm.

65. The fine granules of claim 63 or 64, wherein weight % or less of the fine granules have a particle diameter of more than 425 µm.

66. The fine granules of claim 63 or 64, wherein weight % or less of the fine granules have a particle diameter of more than 400 µm.

67. The fine granules of any one of claims 63 to 66, wherein the basic inorganic salt is at least one of a magnesium salt and a calcium salt.

68. The fine granules of any one of claims 63 to 67, wherein the composition comprises a core comprising crystalline cellulose and lactose and being coated by lansoprazole and the basic inorganic salt.

69. The fine granules of claim 68, wherein the core comprises 50 weight % or more of lactose.

70. The fine granule of any one of claims 63 to 69, wherein the composition comprises 25 to 40 weight % of lansoprazole.

71. The fine granules of any one of claims 63 to 70, which are produced by fluidized-bed granulation method.

72. The fine granules of any one of claims 63 to 71, wherein the enteric coating layer comprises an aqueous enteric polymer agent.

73. The fine granules of claim 72, wherein the aqueous enteric polymer agent is a methacrylate copolymer.

74. The fine granules of any one of claims 63 to 73, wherein the sustained-release agent is a methacrylate copolymer.

75. The fine granules of claim 72 or 73, wherein the sustained-release agent is contained in an amount of 5 to 15 weight % relative to 100 weight % of the aqueous enteric polymer agent.

76. The fine granules of any one of claims 63 to 75, wherein the enteric coating layer is contained in an amount of 50 to 70 weight % relative to 100 weight % of the fine granules.

77. The fine granules of any one of claims 63 to 76, wherein the composition also comprises at least one member selected from the group consisting of water-soluble polymers; binders; lubricants; and excipients.

78. A tablet, granule, fine granule, capsule or suspension preparation which comprises the fine granules of any one of claims 63 to 77.

79. An orally disintegrable tablet of lansoprazole, which comprises:

(i) fine granules having an average particle diameter of 300 to 400 µm and a maximum particle diameter of 425 µm, wherein the fine granules are made of a composition coated by an enteric coating layer comprising a first component which is an enteric coating agent and a second component which is a sustained-release agent; and wherein the composition comprises (a) 10 to 50 weight % (based on the composition) of lansoprazole and, (b) a basic inorganic salt in an amount of 0.3 to 200 weight % based on lansoprazole and (c) may further comprises at least one other ingredient selected from the group consisting of water-soluble polymers, binders, lubricants and excipients; and (ii) an additive which comprises a water-soluble sugar alcohol and which may further comprise at least one other member selected from the group consisting of crystalline cellulose, hydroxypropyl cellulose, binders, acids, artificial sweeteners, flavorants, lubricants, colorants, stabilizers, excipients and disintegrants, wherein the tablet disintegrates within 1 minute or less in a healthy adult buccal saliva.

80. The orally disintegrable tablet according to claim 79, wherein the composition is produced by coating a core comprising crystalline cellulose and lactose with a coating material which comprises (a) lansoprazole and (b) the basic inorganic salt and which may also comprise (c) the other ingredient.

81. The orally disintegrable tablet according to any one of claims 1 to 21, any one of claims 23 to 26 or any one of claims 50 to 52, which has a hardness strength of 2 to 15 kg.

82. The orally disintegrable tablet according to any one of claims 1 to 21, any one of claims 23 to 26 or any one of claims 50 to 52, which has a hardness strength of 3 to 8 kg.

83. An orally disintegrable tablet which is produced by tabletting:

(i) the fine granules as defined in any one of claims 32 to 48, and (ii) an additive which comprises a water-soluble sugar alcohol and which may further comprise at least one other member selected from the group consisting of crystalline cellulose, hydroxypropyl cellulose, binders, acids, artificial sweeteners, flavorants, lubricants, colorants, stabilizers, excipients and disintegrants.

84. An orally disintegrable tablet which is produced by tabletting:

(i) the fine granules as defined in any one of claims 63 to 77, and (ii) an additive which comprises a water-soluble sugar alcohol and which may further comprise at least one other member selected from the group consisting of crystalline cellulose, hydroxypropyl cellulose, binders, acids, artificial sweeteners, flavorants, lubricants, colorants, stabilizers, excipients and disintegrants.

85. A use of the fine granules as defined in any one of claims 32 to 48 or any one of claims 63 to 77 for manufacturing a tablet.

86. A method for producing a tablet, which comprises tabletting:

(i) the fine granules as defined in any one of claims 32 to 48 or any one of claims 63 to 77, and (ii) an additive which comprises a water-soluble sugar alcohol and which may further comprise at least one other member selected from the group consisting of crystalline cellulose, hydroxypropyl cellulose, binders, acids, artificial sweeteners, flavorants, lubricants, colorants, stabilizers, excipients and disintegrants.

87. The orally disintegrable tablet of any one of claims 1 to 31, any one of claims 50 to 62 or claim 79 or 80, wherein the enteric coating agent is at least one member selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylate copolymer, carboxymethyl cellulose and shellac.

88. A use of the orally disintegrable tablet of claim 11 or 51, any one of claims 53 to 62 or claim 79 or 80, for treatment or prevention of digestive ulcer, gastritis or reflux esophagitis; eradication of H. pylori; suppression of gastrointestinal bleeding caused by digestive ulcer, acute stress ulcer or hemorrhagic gastritis; suppression of gastrointestinal bleeding caused by invasive stress; treatment or prevention of ulcer caused by non-steroidal anti-inflammatory agent; or treatment or prevention of gastric hyperacidity or ulcer caused by postoperative stress.

89. An orally disintegrable tablet of lansoprazole, which comprises:

(i) fine granules which have an average particle diameter of 400 µm or less and comprise a composition coated by an undercoating layer and an enteric coating layer, the enteric coating layer comprising an aqueous enteric polymer agent, a methacrylate copolymer sustained-release agent and a plasticizer, wherein the composition comprises a core having an average particle diameter of 100 to 250 µm and being coated with a coating layer which comprises (a) 10 to 50 weight % (based on the composition) of lansoprazole, (b) a basic inorganic salt in an amount of 1 to 100 weight %
relative to lansoprazole and (c) which may further comprise at least one other ingredient selected from the group consisting of water-soluble polymers, binders, lubricants and excipients; and (ii) an additive which comprises a water-soluble sugar alcohol and which may further comprise at least one other member selected from the group consisting of crystalline cellulose, hydroxypropyl cellulose, binders, acids, artificial sweeteners, flavorants, lubricants, colorants, stabilizers, excipients and disintegrants.

90. The orally disintegrable tablet of claim 89, wherein the undercoating layer comprises a water-soluble polymer.

91. The orally disintegrable tablet of claim 90, wherein the water-soluble polymer in the undercoating layer is hydroxypropylmethyl cellulose; the basic inorganic salt is magnesium carbonate; the aqueous enteric polymer agent is a methacrylate copolymer; and the plasticizer is polyethylene glycol.

92. An orally disintegrable tablet of lansoprazole, which comprises:

(i) fine granules which have an average particle diameter of 400 µm or less and comprise a composition coated by an enteric coating layer, wherein the composition contains 25 weight % or more of lansoprazole and a basic inorganic salt; and (ii) an additive comprising a water-soluble sugar alcohol, wherein the tablet is free of a foaming agent.

93. The orally disintegrable tablet of claim 92, wherein the average particle diameter of the fine granules is 300 to 400 µm.

94. The orally disintegrable tablet of claim 92 or 93, wherein the fine granules further comprise a basic inorganic salt.

95. The orally disintegrable tablet of any one of claims 92 to 94, wherein the water-soluble sugar alcohol is at least one member selected from the group consisting of sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose and erythritol.

96. The orally disintegrable tablet of claim 95, wherein the additive further comprises at least one of (i) crystalline cellulose and (ii) low-substituted hydroxypropyl cellulose.

97. The orally disintegrable tablet of claim 94, wherein the composition comprises a core comprising crystalline cellulose and lactose and being coated by the basic inorganic salt and lansoprazole.

98. The orally disintegrable tablet of any one of claims 92 to 97, wherein the enteric coating layer comprises an aqueous enteric polymer agent and a sustained-release agent.

99. An orally disintegrable tablet, which comprises:
(i) fine granules which have an average particle diameter of 300 to 400 µm and comprise a composition coated by an enteric coating layer, wherein the composition has weight % or more of an acid-labile physiologically active substance, and (ii) an additive comprising a water-soluble sugar alcohol, wherein the tablet is free of a foaming agent.