CA2587022A1

CA2587022A1 - Orally disintegrable tablets

Info

Publication number: CA2587022A1
Application number: CA002587022A
Authority: CA
Inventors: Toshihiro Shimizu; Shuji Morimoto; Tetsuro Tabata
Original assignee: Takeda Pharmaceutical Company Limited; Toshihiro Shimizu; Shuji Morimoto; Tetsuro Tabata; Takeda Chemical Industries, Ltd.
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 1998-05-18
Filing date: 1999-05-17
Publication date: 1999-11-25
Also published as: JP2000281564A; KR20010042940A; US20080292701A1; EP1736144A3; HK1096021A1; HK1036401A1; EP2263660B1; KR100554924B1; WO1999059544A2; US7875292B2; US9901546B2; PT1121103E; EP1121103A2; US20110081412A1; US6328994B1; US20020142034A1; EP1121103B1; DE69934505D1; PT2263660T; EP1736144A2

Abstract

An orally disintegrable tablet, of the present invention, 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, 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 ~tm, 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 m 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 m or less, preferably about 350 ~im.

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 jAm 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 m or less, when the coating is performed so that at least 20 um 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;

)5-1241 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 }im 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 r~o 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;

_205-1241 [22] an orally disintegrable tablet of the above [20], wherein the sustained-release agent is in an amount of 5 to 15 weight o relative to 100 weight % of the aqueous enteric polymer agent;

[23] an orally disintegrable tablet of the above [4], wherein the water-soluble sugar alcohol is erythritol;

[24] an orally disintegrable tablet of the above [4], wherein the water-soluble sugar alcohol is mannitol;

[25] an orally disintegrable tablet of the above [5],.
wherein the water-soluble sugar alcohol is in an amount of 5 to 97 weight % relative to 100 weight % of the orally disintegrable tablet apart from the fine granules;

[26] an orally disintegrable tablet.of the above [4], wherein the crystalline cellulose is in an amount of 3 to 50 weight % relative to 100 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 disintegrable tablet of the above .[6], wherein the content of hydroxypropoxyl group in the low-substituted hydroxypropyl cellulose is 5.0 to 7.0 weight t;

[29] an orally disintegrable tablet of the above [1], which further comprises crospovidone;

[30] an orally disintegrable tablet of the above [1], wherein the oral disintegration time is one minute or less;

[31] an orally disintegrable.tablet of the above [1], which comprises no lubricant inside the tablet;

[32] fine granules having an average particle diameter of 400 Eun or less, which comprise a composition coated by an enteric coating layer, the composition having (i) 25 weight % or more of an acid-labile physiologically active substance and (ii) a basic inorganic salt;

[331 fine granules of the above [32], wherein the average particle diameter. of the fine granules is 300 to 400 m;

[34] fine granules of the above [32], wherein the particle diameter of the fine granules is practically 425 um or less;
[35] fine granules of the above [32], wherein the particle diameter of the fine grariules is practically 400 ~im 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 o 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 o relative to 100 weight o of the aqueous enteric polymer agent;

[481 fine granules of the above [32], wherein the enteric coating layer is in an amount of 50 to 70 weight % relative to 100 weight t of the fine granules;
[49] a tablet, granule, fine granule, capsule, effervescent or suspension preparation which comprises the fine granules of the above [321, and so forth.

In the present specification, "coating" means also partial coating and adhesion or adsorption in addition to coating the whole surface 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 distribution), unless otherwise specified. It can be measured by, for example, a laser diffraction particle distribution measurement method.
20. Concretely exemplified is 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 granules having an average particle diameter of 400 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) anadditive.
In the present invention, "fine granules having an average particle diameter of 400 .m or less, which fine granules comprise a composition coated by an enteric coating layer, the composition having 10 weight o or more of an acid-labile physiologically active substance" have an average particle diameter of about 400 m 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 um.

Aside from the average particle diameter of the above "fine granules", regarding the maximum particle size, the 5 particle diameter is practically 425 m or less, and preferably practically 400 m or less. Preferably, the particle diameter is practically 300 to 425 ~im, more preferably 300 to 400 ~Lm.
"Practically" as used in "the particle diameter is practically 425 ~un 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
N '0' ) R4 H n 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, Cl_7 alkoxycarbonyl, Cl-4 alkoxycarbonyl-Cl-4 alkyl, carbamoyl, carbamoyl-C1-4 alkyl, hydroxy, hydroxy-Cl-7 alkyl, Cl-6 acyl, carbamoyloxy, nitro, C2-6 acyloxy, C6-12 aryl, C6-12 aryloxy, C1-6 alkylthio, Cl_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 C1-4 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 Cl-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 Cl-6 alkyl. More preferred is a straight-chain or branched Cl-3 alkyl.

The "alkoxy" for Rl, 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 Cl-3 alkoxy.
The "Cl-4 alkyl" of the "C1-4 alkyl which may be substituted by a substituent(s) selected from the group consisting of halogen, hydroxy and Cl_4 alkoxy" for R2 includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.
The "Cl - 4 alkoxy" of the above "C1 _ 4 alkyl which may be substituted by a Cl-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 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'CO3'4H20], aluminum magnesium hydroxide [2.5MgO'Al203'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 1 % 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 o 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 %. 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 Pharmacopoeia, hydroxypropylmethyl cellulose 2910 defined by Japanese Pharmacopoeia, and so forth. Hydroxypropyl 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 s, 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 10, substance in the composition containing the physiologically active substance and retain a high content of the physiologic:ally.active substance_.

The above "enteric.coating layer" which coats the "composition having 10 weight % or more of an acid-labile phvsiologically active substance" includes, for example, an aqueous enteric polymer agent such as cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate (hereinafter, referred to as HP-55), hydroxymethyl cellulose acetate succinate, methacrylate copolymer [e.g., Eudragit L30D-55 etc. (trade mark; manufactured by Rohm GmbH (Germany) ), KolllCoat MAE30DP (trade mark; manufactured by BASF
(Germany)), Polyquid PA-30 (trade mark; manufactured by SanyoKasei (Japan)), etc.], carboxymethyl cellulose, shellac, etc.; a sustained-release agent such as methacrylate 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, polyethylene 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 methacrylate 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 _205-1241(S) weight % 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 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, co'lorants, stabi.lizers, 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 abotit 30 -minutes at 20 0 C by strongly shaking every 5 minutes for 30 seconds.
The "water-soluble sugar'alcohol" includes, for example, sorbitol, mannitol, maltitol, reduced starch sac.charide, 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 .:205-124?

size of at most 50 mesh .is used. Such erythritol is available on the market, e.g. as manufactured by Nikken Chemical Co.
.Ltd. (Japan).
The "water-soluble sugar alcohol" is usually employed in an amount of about 5 to 97 weight %, preferably about 10 to 90 weight o relative to 100 weictht t of the orallv dis.intearable tablet apart from the fine aranules, in order to obtain sufficient strength of the preparation and sufficient disintegration or dissolution in the oral cavity.
For example, mannitol or erythritol is usually employed in an amount of about 5 to 90 weight %, preferably about 10 to 80 weight -W, 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 qranu]es.
The "crystalline cellulose" includes refined one having partially a-cellulose depolymerization. Such crystalline cellulose includes one called microcrystalline cellulose.
Examples of the "crystalline cellulose" include CEOLUS KG801, Avicel PH101, Avicel PH102,Avicel PH301, Avicel*PH302,Avicel RC=591(crystalline cellulose carmellose sodium), etc. Among these, preferably employed is CEOLUS KG801 which is also called crystalline cellulose of high compressibility. =Two or more of the crystalline cellulose can be used as a mixture in a given ratio. Such crystalline cellulose is available 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 o, preferably about 5 to 40 weight more preferably about 5 to 20 weight o relative to 100 wei.ght % of the orally disintegrable tablet apart from the fine granules.

The "low-substituted hydroxypropyl cellulose" means a loiv-substituted hydroxypropyl cellulose wherein the content of hydroxypropoxyl group 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, for 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 first, 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 %
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 o(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 o(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 %" to be used in the present invention is, for example, about 5 to 60 m,-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 Eun 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 m 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 %" or the "Iow-3 5 substituted hydroxypropyl cellulose wherein the content of HPC

24205-1241(S) group is 7 . 0 to 9. 9is usually employed in an amount of about 3 to 50 weight %, preferably about 5 to 40 weight %, relative to 100 weight o 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 f atty 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.

_4205-1241 The "disintegrants" include those conventionally used in the pharmaceutical field, such as (1) crospovidone, (2) super disintegrants such as croscarmellose sodium [FMC-Asahi Chemical Co., Ltd. (Japan)], carmellose calcium [Gotoku Chemical(Yakuhin), (Japan)], (3) carboxymethylstarch sodium [e.g., Matsutani Chemical.Co., Ltd. (Japan)], (4) low-substituted hydroxypropyl cellulose[e.g.,Shin-Etsu Chemical Co., Ltd. (Japan)'], (5) corn starch, etc. Among others, preferred is, for example, crospovidone.
. The "crospovidone" includes polyvinylpolypyrrolidone (PVPP), 1-vinyl-2-pyrrol.zdinone homopolymer, 1_-ethenyl-2-pyrrolidinone'homopolymer, etc, such as Kollidon*CL
[manufactured by BASF (Germany)], Polyplasdone*'XL
[manufactured by ISP Ltd. (Japan)], Polyplasdone XL-10 .15 [manufactured by ISP Ltd. (Japan)], Polyplasdone*INF-10 [manufactured b.yISP Ltd.(Japan)],etc. Usually crospovidone having a molecular weight of at least 1,000,000 is used.
Two or more,of these disintegrants cari be as a mixture in a given ratio. For example, (i) crospovidone solely, or (ii) crospovidone and another disintegrant(s) is preferably employed.
The "disintegrants" are used, for instance, in an amount of about 1 to 15 weight %, preferably about 1 to 10 weight o, more preferably about 3 to 7 weight A, relative to 100 weight % of the orally disintegrable tablet apart from the fine granules.
1n the pres.ent invention, the "fine granules" may contain, for example, titanium oxide as.a masking agent.
The diameter of the "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 the tablet.

The "orally disintegrable tabl. , et" of the present invention exhibits fast disintegrability 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 preferablv 3 tn 8 ;cg.
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 (i) 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 m or less. Preferably, the average particle diameter of the fine granules is 300 to 400 ~Lm. Aside from the averaqe particle diameter of the "fine granules", regarding the maximum particle size, the particle diameter is practically 425 m or less, and preferably practically 400~tm or less. Preferably, the particle diameter is practically 300 to 400 m 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 formulating 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-Marumerizer" 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 one *Trade-mark of a top spray method, a bottom spray method, a tan.gential spray method, and so forth. ''' Among others, a tangential spray method is pref erred .
The "compqsition" in the present invention.can be produced in accordance with, for example, a method which comprises coating 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 method), which comprises 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 polymer, etc. (hereinafter,. may be abbreviated to "coating layer"). For example, employed is a method which comprises coating a core with an acid-labile physiologically active substance-and a basic inorganic salt, and then further with binders, lubricants, excipients; a water-soluble polymer, etc.
The average particle diameter of the "cores" is about 250 m or less, preferably about 50 to 250 m, .more preferably about 100 to 250 m, 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 m) , particles where about 5 w/w % or less of the total remain on a#60 sieve (250 m), and particles where about 10 w/w % or less of the total pass through a #282 sieve (53 m) . The specific volume of the "core" is about 5 ml/g o.r less, preferably about 3 fnl/g or less.
Examples of the "core" include (1) a spherical granulated product comprising crystalline cellulose and lactose, (2) a spherical granulated product being about 150 to 250 pm and comprising crystalline cellulose (Avicel*SP, manufactured by Asahi Chemical Co. , Ltd. (Japan) ), (3) a stirrina granulated product being about 50 to 250 m and *Trade-mark .4205-1241 comprising lactose (9 parts) and a starch (1 part ), (4) a micro particle being about 250 m or less 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 granulation, (6) a processed procluct such as gelatin beads comprising oil component, (7) calcium silicate, (8) starch, (9) a porous particle such as chitin, cellulose, chitosan, etc, and (10) a bulk product such as granulated sugar, crystalline lactose or sodium chloride, and processed preparations 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 "spherical granulated product comprising crystalline cellulose and lactose" includes, for example (i) a spherical granulated product being 100 to 200 p.m and comprising crystalline cellulose (3 parts) and lactose (7 -parts) [e.g., Nonpareil*105(70-140) (particle diameter of 100 to 200 m), manufactured by Freund Industrial Co., Ltd.
(Japan)], (ii) a- spherical granulated product being about 150 to 250 m and comprising crystalline cellulose (3 parts) and lactose (7 parts) [e.g., Nonpareil! NP-7:3, manufactured by Freund Industrial Co., Ltd. (Japan)], (iii) a spherical granulated product being 100 to 200 m and comprising crystalline cellulose (4.5 parts) and lactose (5..5 parts) [e.g., Nonpareil 105T (70-140) (particle diameter of 100 to 200 m) , manufactured by Freund Industrial Co. ; Ltd. (Japan) (iv) a spherical granulated product being about 150 to 250 m and comprising crystalline cellulose (5 parts) and lactose (5 *
parts) [e.g., Nonpareil NP-5:5, manufactured by Freund Industrial Co., Ltd. (Japan)], and so forth.

In order to produce a pharmaceutical preparation which is superior in dissolution while retaining suitable strength, the "core" includes, for 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 % 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 ~tm 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 % of the water-soluble polymer. Further, in forming the inactive coat according to known methods, the coating layer may comprisesome 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 Ltm ). 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 ~un, preferably about 30 to 50 ~Lm 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 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-5-271054 and 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, failure 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 "o" 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 HCl (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 HCl for 1 hour)/(Content of the drug in the tablet) 35 (4) Acid-resistance: Dissolution using 0.1N HCI

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 HCl (75 rpm) for 1 hour. Then, test medium was collected and filtered by using a 0.45 m membrane filter. The absorbance was measured to calculate the dissolution of the drug into 0.1N HC1.
(5) Average particle diameter: Volume based distribution median diameter .(median diameter: 50% particle diameter from cumulative distribution) Determination was.carried out with Raser Diffraction Analyzer, type: HEROS RODOS [trade mark, manufactured by Sympatec (Germany)].

Examples Example 1 .
(1) Production of granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex'Corp. (Japan), MP-10 (Type 2) ] is charged with 300 g of Nonpareil 105 ( 70-140 )(parti.cle 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 blilk 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'is stopped when the specified amount of the bulk liquid has been sprayed, and then drying is carried out in the granulator for 7 minutes. The resulting granules are sieved through a #60 circular sieve (250 cn) and a #100 circular sieve (150 m) to provide 750 g of granules having a core.

Bulk liquid:

Lansoprazole 300 g Magnesium carbonate 100 g L-HPC 50 g *Trade-mark 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)] 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 m) and a #80 circular sieve (177 ~Lm) to provide 950 g of enteric coated granules having a core.

Enteric film coating liquid:

Eudragit L30D-55 1078.3 g Eudragit NE30D 138.5 g Triethyl citrate 46.0 g Glyceryl 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 m) on 0 ~

#30 (500 p.m) on 0 ~
#200 (75 pm) on 100 #200 (75 pm) pass 0 ~

(4) -Production of granulated powders A fluidized bed granulator [manufactured by Powrex Corp.
(Japan), LAB-i] is charged with 1321.2 g of erythritol [manufactured by Nikken Chemical Co., Ltd.( Japan )], 360. 0 g of low-suhqtituted 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 is carried out while spraying a solution which is prepared by dissolving 3.6 g of polyethylene glycol (PEG-6000) in 896.4 ml of purified water. The granules are dried to provide granulated powders.
To the granulated powders are added 90.0 g of crospovidone and 5.4 g of magnesium 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 referred to as "enteric coated powders".
200.0 g of the above enteric coated powders and 300.0 g of the above mixed powders are tabletted using Autograph (trade *Trade-mark mark; 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 . .

Reference Example 1 An alkaline cellulose comprising 24.1 % of NaOH, 1.7 0 of Na2CO3, 42.9 % of cellulose, 31.8 % of H20 was obtained by immersing a wood pulp in 49% aqueous solution of sodium hydroxide and then by pressing it. A reactor was charged with 100 weight parts of the alkaline cellulose. Then, nitrogen gas.replacement was carried out. After the replacement, 5 weight parts of propylene oxide was charged in the reactor and reacted with stirring at 40 C for 1 hour, at 50 C for 1 hour and at 70 C for 1 hour to obtain 103 weight parts of a reactant.
On the other side, a k:ieader 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 t against equivalent for neutralization, initial neutralized acid) and therein, 1 weight part of the above resulting alkaline cellulose was dispersed. Then, the temperature was set at 30 C to dissolve a part of the reactant, and 0. 20 weight -part of glacial acetic acid (the remainder of an equivalent for neutralization, complete neutralized acid) to obtain a processed fiber product containing a part of dissolution and a part of deposit.
The resulting product was washed with hot water at about 80 C, drained, 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-substituted hydroxypropyl cellulose LH-33 (the content of hydroxypropoxyl group: 5.8 weight %, the average particle diameter: 17.8 m).

Reference Example 2 Powders of low-substituted hydroxypropyl cellulose LH-23 ~205-1241 (hydroxypropoxyl group contents: 5.7 weight %, average particle diameter: 30.8 ~Lm) were obtained in the same manner as in Reference Example 1.

5 Example 2 (1) Production of granules- having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 300 g of Nonpareil 105 [(trade mark) particle diameter: 100 .to 200 10 rn]. With the inlet air temperature and the temperature of the loading being controlled at 70 C and about 30 C, respectively, the Nonpareil was coated by spraying a spray liquid of the following composition prepared in advance in accordance with the tangential spray method at a spray rate 15 of 22 g/min. , 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 E,un) to provide 2186 g of powders (150 to 300 m) having a core.
20 Spray liquid:
Lansoprazole 927 g Magnesium carbonate 309 g Low-substituted hydroxypropyl cellulose LH-32 154.5 g (hydroxypropoxyl group contents: 8.8 wt %) (average particle diameter: 17.57 Eun) Hydroxypropyl cellulose (Type SSL) 309 g Purified water 3955 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 2040 25 g of the above 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 undercoating liquid of the following composition prepared in 2z205-1241 advance was sprayed in accordance with the tangential spray method at a spray rate of 13 g/min. to provide 2145 g of film-undercoated granules having a core.

Undercoating liquid:
Hydroxypropylmethylcellulose 264 g (Type 2910, viscosity: 3 centistokes) Purified water 5016 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 1710 g of the above fi.lm-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 of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a-spray rate of 17 g/min. , and dried for 7 minutes, and then sieved through a #42 circular sieve (355 m) and a #80 circular sieve (177 tim) to provide 2393 g of enteric coated powders (177 to 355 pun) having a core.

Enteric film coating liquid:
Eudragit*L30D-55 5016.4 g Eudragit*NE30D 559.0 g Triethyl citrate 333.7 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 centrifugal fluidized coating granulator [manufactured by. Powrex Corp.( Japan ),'MP-10 (Type 2)] was charged with 600 *Trade-mark g of the above enteric 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 coating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 11 g/min ., and then dried for 7 minutes to provide 617 g of enteric coated and mannitol coated granules having a core.
The average particle diameter of the obtained granules was 334.1 m.

Film coatingliquid:
Mannitol 33 g Purified water 297 g (5) Production of mannitol-granulated powders A fluidized bed granulator [manufactured by Powrex Corp-.
(Japan), LAB-1] was charged with 800 g of mannitol [manufactured by Merck Japan Co., Ltd. ], and granulation was carried out while spraying 315 g of purified water. The granules were dried to provide 727.3 g of granulated 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 weight %, average particle diameter: 17.8 m), 22.5 g of crystalline cellulose [CEOLUS KG-801 (trade mark), manufactured by Asahi 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 to give mixed powders.

(7) Production of orally disintegrable tablets 250.0 g of the above mixed powders were tabletted using Autograph (trade mark; compressing force measurement apparatus) with a punch (15R), 11 mm in diameter, 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 seconds, respectively.
Example 3 (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 mark) (particle diameter of 100 to 200 pm). With the inlet air temperature and the temperature of the loading being co.ntrolled at 75 O C ana about 29 O 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 22 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 #60 circular sieve (250 pm) and a #100 circular sieve (150 m) to provide 2424 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 o) 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 byPowrex Corp.( Japan ), MP - 10 (Type 2)] was chargedwith 233 7. 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 o) (average particle diameter: 17.57 ~Lm) 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 um) and a #70 circular sieve (212 Um) to provide 1116 g of enteric coated granules having a core.
The average particle diameter of the obtained granules was 326.9 cn.

5 Enteric film coating liquid:
Eudragit*L30D-55 1911 g Eudragit*NE30D 212.9 g Triethyl citrate 127.1 g Glyceryl monostearate 40.6 g Polysorbate 80 13.3 g Red iron oxide 0.8 g Purified water 970.3 g .(4) Production of mixed powders To 200 g of the 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 t, average partiole diameter: 17 . 8pm) , 60.0 g of crystalline cellulose (CEOLUS KG-801 (trade mark), manufactured by Asahi Chemical Co. , Ltd. (Japan) ], 15'.0 g of crospovidone, 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 disintegrable tablets 250.0 g of the above mixed powders were tabletted using 20 Autograph (trade mark; compressing force measurement apparatus) with a punch (15R), 11 mm in diameter, 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 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 stoppedwhen the specified amount 1980 g of the undercoating liquid had been sprayed, and then drying was carried out in the granulator for 10 minutes to provide 1330.5 g of film-undercoated granules having a core.

Undercoating liquid:
Hydroxypropylmethylcellulose 120 g (Type 2910, viscosity: 3 centistokes) Titanium 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 enteric coated granules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan) , MP-10 (Type 2) ] was charged with 460 =10 g of the above fiim-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 coating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 13 g/min. The spraying operation was stopped when the specified amount 2205 g of the enteric film coating liquid had been sprayed.
Enteric film coating liquid:
Eudragit*L30D-55 2290 g Eudragit*NE30D 253 g Triethyl citrate 153 g Glyceryl monostearate . 20._g Polysorbate 80 8 g Titanium oxide (Ti02) 53 g Sterilized Talc H (trade mark) 53 g [produced by Matsumura Sangyo Co. Ltd. (Japan)]
Purified water . 2420 c *Trade-mark .205-1241 (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 80 C and about 35 C, respectively, an film coating liquid of the following composition prepared in advance was sprayed in accordanc~ with the tangeritial spray method at a spray rate of 16 g/min. using a centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan) , MP-10 (Type2)]. The spraying operation was stopped when the. specified amount 824 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 #42 circular sieve (355 pm) and a #60 circular=

sieve (250 rn) to provide 806 g of enteric coated and mannitol coated granules having a core.
The average particle diameter of the obtained granules was 326.6 pm..

Film coating liquid:
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 group 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 cellulose [CEOLUS KG-801 (trade mark), manufactured by Asahi Chemical Co., Ltd. (Japan) j , 6.5 g of crospovidone, 1. 3 g of citric acid anhydrous, 1. 3 g of aspartame and 0.65 g of magnesium stearate, which was admixed in a bag to give mixed powders.

24205-1241.

(6) Production of orally disintegrable tablets 250.0 g of the above mixed powders were tabletted using Autograph (trade mark; compressing force measurement apparatus)' with a punch (15R), 11 mm in diameter, 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 3.9 kg and 2Ø5 seconds, respectively.
The remaining ratio 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.( Japan ), MP-10,( Type 2)] was charged with 900.
g of Nonpareil 105 (trade mark) (particle diameter of 100 to 200 m). With the inlet air temperature and the temperature of the loading being controlled at 65 C and about 30 C
respectively, the Nonpareil*was.coated by spraying a bulk liquid of -the following composition prepared iri advance in accordance with the tangential'spray method at a spray rate of 22 g/min.=The spraying operation was stopped when the' specified amount 5661 g of the bulk liquid had been sprayed, and then drying was carried out in the granulator for 8 minutes.
The resul'ting granules were sieved through a#[42 circular sieve (350 pm) and a#[100 circular sieve (150 m) to provide 2074 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 %) *Trade-mark Hydroxypropyl cellulose -(Type SSL) 360 g Purified water 4680 g (2) Production of film-undercoated granules having a core A centrifugalfluidized coating granulator[manuf actured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged, with 2074 5 g of the above granules having a core.. With the inlet air temperature and the temperature of the loading being controlled at 78 C and about 40 C, respectively, an undercoating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray 10 method at a spray rate of 22 g%min. The spraying operation was stopped when the specified amount 1980 g of the undercoating liquid had been sprayed, and then drying was carried out in the granulator for 9 minutes. The resulting granules were sieved through a #42 circular sieve (350 m) and a #100 circular 15, sieve (150 cn) to provide 2555 g of film-undercoated granules having a core.

Undercoating liquid:
Hydroxypropylmethylcellulose 252 g (Type 2910, viscosity: 3 centistokes) Titanium oxide (TiOz) 108 g Sterilized Tald (trade mark) 108 g [produced by Matsumura Sangyo Co. Ltd. (Japan)]
Low-substituted hydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8 weight %) Mannitol 252 g Purified water . 3600 g 20 (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 1320 g of the above film-undercoated granules having a core. With_ the inlet air temperature and the temperature of the loading 4-i205-1241 being controlled at 80 C and about 42 C, respectively, an enteric film coating liquid (A) of the.following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 22 g/min. The specified amount 1638 a of the enteric film coating liquid had been sprayed.

Enteric film coating liquid (A):
EudragifF L30D-55 1219.2 g Eudragit*NE30D 134.4 g Polyethylene glycol 6000 40.8 g Glyceryl monostearate 24.0 g Polysorbate 80 7.2 g Ferric oxide 0.24 g Ferric oxide (yellow) 0.24 g Citric acid anhydrous 0.48 g.
Purified water 1693 g Following this, with_the inlet air temperature and the temperature of the loading being controlled at 76 C and about 42 C, respectively, an enteric film coating liquid (B) of the following compositi.on'prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 22 g/min. The specified amount 6552 g of the enteric film coating liquid had been sprayed.

Enteric film coating liquid (B):
Eudragit*L30D-55 4032 g g Eudragit*NE30D 447.8 Triethyl citrate 269.3 g Glyceryl monostearate 86.4 g Polysorbate 80 25.9 g Ferric oxide 0.86 g Ferric oxide (yellow) 0.86 g *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 mark), manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone, 3 g of cit ric acid anhydrous, 9 g of aspartame, 6 g of magnesium stearate and 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 orally disintegrable tablets 570 g of the above mixed powders were tabletted using Autograph (trade name; compressing force measurement apparatus) with a punch having a beveled edge, 13 mm in diameter, at a tabletting 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-resistance of theobtained tablet was 3.5 a.
Example 6 (1) Production of granules having a core A centrifugalfluidized 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 ~Lm) . With the inlet air temperature and the temperature of the loading being controlled at 65 C and about 30 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 22 g/min. The spraying operation was stopped when the specified amount 4717.5 g of the bulk liquid had been sprayed, and then drying was carried out in the granulator for 8 minutes.
The resulting granules were sieved through a #42 circular sieve (350 m) and a #100 circular sieve (150 m) to provide 1811 g of granules having a core.
Bulk liquid:
Lansoprazole 900 g Magnesium carbonate 300 g Low-substituted hyc.zoxypropyl cellulose LH-32= 150 g (hydroxypropoxyl group contents: 8.8 weight %) Hydroxypropyl cellulose (Type SSL) 300 g Purified water 3900 g (2) Production of film-undercoated'granules having a core A centri.fugal fluidized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 1811 .g of the above granules having a core. With the inlet air temperature and the temperature of the loading being 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 rate of 22 g/min. The spraying operation was stopped when the specified amount 5274 g of the undercoating liquid had been sprayed, and then drying was carried out in the granulator for 9 minutes. The resulting granules were sieved through a#42 circular sieve (350 p.m) and a #100 circular sieve (150 pun) to provide 2628 g of film-undercoated granules having a core.
Undercoating liquid:
Hydroxypropylmethylcellulose 378 g (Type 2910, viscosity: 3 centistokes) Titanium oxide (Ti02) 162 g Ster_ili_zed Talc (trade mark) 162 g [produced by Matsumura Sangyo Co. Ltd. (Japan)]
Low=substituted hydroxypropyl cellulose LH-32 270 g (hydroxypropoxyl group contents: 8.8 weight o) Mannitol 378 g Purified water 5400 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 1560 5 g of the above fi.lm-undcrcoated 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 in 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 film coating liquid (A):
Eudragit*L30D-55 4032 g Eudragit*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 (yellow) 0.86 g 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 72 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 19 g/min . The specified amount 819 g of the enteric film coating liquid had been sprayed.

Enteric film coating liquid (B):
Eudragit*L30D-55 609.6 g *Trade-mark Eudragit*NE30p 68.0 g Polyethylene glycol 6000 20.4 g Glyceryl monostearate 12.0 g Polysorbate 80 3.6 g Ferric oxide 0.12 g Ferric oxide (ye_low) 0.12 g Citric acid anhydrous 0.24 g Purified water 846.7 g (4) Production of enteric 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 C and about 38 C, respectively, an film coating liquid of the following composition preparedin advance was sprayed in accordance with the tangential spray method at a spray rate of 19 g/min. using .a centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10'(Type 2)]. Thespraying 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 17 minutes. The resulting granules were sieved through a #35 circular sieve (420 m) and a #60 circular sieve (250 N.m) to provide 2825 g of enteric coated and mannitol coated granules having a core.
The average particle diameter of the obtained granules was 330.5 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 *Trade-mark :205-12G1 (hydroxypropoxyl group contents: 5.8 weight o), 30 g of crystalline cellulose [CEOLUS KG-801 (trade mark), manufactured by Asahi Chernical. 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), manufactired by Nihon Filmenich Co., Ltd.
(Japan)which was admixed in a bag to give mixed pdwders.
(6) Production 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, 13 mm in diameter, at a tabletting 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 3.1 kg and 22 seconds, respectively.
The acid-resistance of the obtained tablet was 2.5 %.
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) (particle diameter of 100 to 200 pm ).. With the inlet 'air temperature 'and the temperature of the loading being controlled at 75 C and about 30 C
respectively, the Nonpareil was coated by spraying a bulk liquid of the following composition prepared in advance in accordance with the ta ngential spray method at a spray rate of 20 g/min. The spraying operation was stopped when the specified amount 4717.5 g of the bulk liquid had been sprayed, and then drying was carried 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 group contents: 8.8 weight %) Hydroxypropyl cellulose (Type SSL) 300 g Purified water .3900 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 18 4 2 5. g of the above granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 74 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 rate of 19 g/min. The spraying operation was stopped when the specified amount 5365 g of the undercoating liquid had been sprayed, and then drying was carried out in the granulator for 9 minutes.= The resulting granules were sieved through a #42 circular sieve (350 m) and a #100 circular sieve (150 m) to provide 2770.g of film-undercoated granules having a core.

Undercoating liquid:
Hydroxypropylmethylcellulose 378 g (Type 2910, viscosity: 3 centistokes) =
Titanium oxide (Ti02) 162 g Sterilized Talc (trade mark) 162 g [produced by Matsumura Sangyo Co. Ltd. (Japan)]
Low-substituted hydroxypropyl cellulose LH-32 270 g (hydroxypropoxyl group contents: 8.8 weight %) Mannitol 378 g Purified water 5400 g (3) Production of enteric coated grariules having a core A centrifugal fluidized coating granulator [manufactured by Powrex Corp. ( Japan ), MP-10 (Type 2)] was charged with 1300 g of the above film-undercoated granules having 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 wa: sprayed in accordance with the tangential spray method at a spray rate of 21 g/min. The spraying operation was stopped when the speci,fied amount 5040 g of the enteric film coating liquid had been sprayed, and then drying was carried out in the granulator f or 16 minutes . The resulting granules were sieved through a #35 circular sieve (420 m) and a #60 circular sieve (250 m) to provide 2453 g of enteric coated granules having a core.

Enteric film coating liquid (A):
Eudragit*L30D-55 4032 g Eudragit* 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 (yellow) 0.86 g Citric acid anhydrous 0.72 g Purified water 2624 g A centrifugal fluidized coating granulator [manufactured by Powrex Corp.( Japan ), MP-10 (Type 2)] was charged with 1000 g of the above enteric coated granules 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 following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 19 g/min.' The specified amount 273 g of the enteric film coating liquid had been sprayed.

*Trade-mark Enteric film coating liquid (B):
Eudragit*L30D-55 610.4 g Eudragit*NE30D 68.0 g Polyethylene glycol 6000 20.4 g Glyceryl monostea=ate 12.0 g Polysorbate 80 3.6 g Ferric oxide 0.12 g Ferric oxide (yellow) 0.12 g Citric acid anhydrous 0.24 g Purified water .845.12 g (4) Production of enteric coated and mannitol coated 5 granules having a core Following (3), while the inlet air temperature and the temperature of the loading being controlled 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 centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type2)]. The spraying operation was stopped when the specified amount 294 g of the film coating liquid had been sprayed, and then drying was carried out in 15 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 1061 g of enteric coated and mannitol coated granules having a core.
The average particle diameter of the obtained granules 20 was 307.1 rn.

Film coating liquid:
Mannitol 120 g Purified water 720 g (5). Production of mixed powders *Trade-mark -x205-1241 To 270 g of the above enteric coated and mannitol coated granules having a core 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 Lhemical 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=), manufactured by Nihon Filmenich Co., Ltd.
(.Japan)], which was admixed in a bag to give mixed powders.
(6) Production 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, 13 mm in diameter, at a tabletting pressure of 1.5 -ton/cm2, to provide tablets each weighing 570 mg.
The hardness and oral disintegration time of e ich tablet thus obtained were 3.2 kg and 24 seconds, respectively.
Example 8 (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 105T (trade mark) (particle diameter of 100 to 200 Wn) . With the inlet air temperature 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 tangential spray method at a spray rate of 21 g/min. The spraying operation was stopped when the specified amount 5550 g of the bulk liquid had been sprayed, and then drying was carried out in the granulator for 21 minutes. The resulting granules were sieved through a #42 circular sieve (350 m) and a#k100 circular sieve (150 rn) to .05-12a1 provide 1723 g of granules having a core.
Bulk liquid:
Lansoprazole 1080 g Magnesium carbonate 360 g Low-substituted hy6roxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8 weight Hydroxypropyl cellulose (Type SSL) 360 g Purified water 4680 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 2074 g of the above granules having a core. With the inlet air temperature and the temperature of the loading being 10. controlled at 77 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 21 g/min. The spraying operation was stopped when the specified amount 2787 g of the undercoating liquid had been sprayed, and then drying was carried out in the granulator for 13 minutes. The resulting granules were sieved through a #42 circular sieve (350 p.m) and a #100 circular sieve (150 m) to provide 1958 g of film-undercoated granules having a core.
Undercoatiiig liquid:
Hydroxypropylmethylcellulose 252 g (Type 2910, viscosity: 3 centistokes) Titanium oxide (Ti02) 108 g Sterilized Talc (trade mark.) 108 g [produced by Matsumura Sangyo Co. Ltd. (Japan)]
Low-substituted hydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8 weight o) Mannitol 252 g ?05-1241 Purified water 3600 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 1100 g of the above film-unde-,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 coating liquid (A) of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 22 g/min. The specified amount 1365 g of the enteric film coating liquid had been sprayed.

Enteric film coating'liquid (A):
Eudragit*L30D-55 1017.3 g Eudragit*NE30D 113.3 g Polyethylene glycol 6000 34.0 g Glyceryl monostearate 20.0 g=
Polysorbate 80 6.0 g Ferric oxide 0.2 g Ferric oxide (yellow) 0.2 g Citric acid anhydrous 0.4--g Purified water 1410.8 g Following this, with the inlet air temperature and the temperature of the loading being controlled at 76 C-and about 41 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/min. The specified amount 5040 g of the enteric film coating liquid had been sprayed.

Enteric film coating liquid (B):
*Trade-mark Eudragit*L30D-55 3360 g "Eudragit*NE30D 373.2 g Triethyl citrate 224.4 g Glyceryl monostearate 72.0 g Polysorbate 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 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 21 g/min . The specified amount 682 . 5 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 80 C and about 36 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 (Type2)]. The 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 .m) and a #60 circular sieve (250 m) to provide 2319.5 g of enteric coated and mannitol coated granules having a core.
The average particle diameter of the obtained granules was 392.7 m.

*Trade-mark Film coating liquid:
Mannitol 100 g Purified water 600 g (5) Production of mixel powders 5 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 hyciroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8 weight %), 30, g of crystalline cellulose [CEOLUS KG-801 (trade mark),.
10 manufactured by Asahi Chemical 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), manufactured by Nihon Filmenich Co., Ltd.
(Japan)], which was admixed in a bag to give mixed powders.
(b) Production 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:ing 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 3.7 kg and 35 seconds, respectively.
The acid-resistance of the obtained tablet was 3.4 %.
Example 9 (1) Production of granules having a core A centrifugal flui_dized coating granulator [manufactured by Powrex Corp. (Japan) , MP-10 (Type 2) ] was 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*was coated by spraying a bulk liquid of the *Trade-mark 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 ~im) and a #100 circular sieve (150 ~im) 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 controlled at 65 C and about 36 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 17 g/min . The coated powders were dried in vacuum at 40 C for 16 hours, and sieved through a #42 circular sieve (355 pun) and a #80 circular sieve (177 m) to provide 950 g of enteric coated granules having a core.
The"average particle diameter of the obtained granules was 285.4 m.

Enteric film coating liquid:
Eudragit*L30D-55 1078.3 g Eudragit*NE30D 138.5 g Triethyl citrate 46.0 g Glyceryl monostearate 16.5 g Talc 16.0 g Polysorbate 80 ~ 9.0 g Iron oxide 0.5 g Water 2038.5 g Sieve weight ratio #18 (850 m) on 0 ~

#30 (500 Eun) ori 0 ~
#200 (75 m) on 100 0 #200 (75 m) pass 0 ~

(4) Production of granulated powders A fluidized bed granulator [manufactured by Powrex Corp.
.(Japan), LAB-i] 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 disiiitegrable 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 or=ally 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

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, C1-10 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;

R 2 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 hydroxypropyl 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 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.