Orally disintegrable tablets

Abstract

An orally disintegrable tablet, of the present invention, 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, 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.

Claims

1. An orally disintegrable tablet, which comprises: (i) fine granules comprising a composition coated with an enteric coating layer, said composition comprising: 10 weight % or more of lansoprazole or a salt thereof relative to the composition; and a basic inorganic salt selected from the group consisting of a salt of magnesium and a salt of calcium; and (ii) an additive comprising crospovidone and a water-soluble sugar alcohol, wherein the water-soluble sugar alcohol is comprised in the tablet separately from the fine granules, the enteric coating layer is about 30-70 weight % relative to the fine granule, the enteric coating layer comprises a methacrylic acid copolymer as an aqueous enteric polymer agent, the orally disintegrable tablet is administerable without water, an oral disintegration time of the orally disintegrable tablet is one minute or less, the orally disintegrable tablet is not an effervescent, and the composition does not comprise alkaline metal carbonate.

2. The orally disintegrable tablet of claim 1, wherein the composition coated by an enteric coating layer is further coated by a coating layer which comprises a water-soluble sugar alcohol.

3. The orally disintegrable tablet of claim 1, wherein the additive further comprises at least one material selected from the group consisting of (i) crystalline cellulose and (ii) low-substituted hydroxypropyl cellulose.

4. The orally disintegrable tablet of claim 1, wherein a particle diameter of the fine granules is practically 425 ?m or less.

5. The orally disintegrable tablet of claim 1, wherein a particle diameter of the fine granules is practically 400 ?m or less.

6. The orally disintegrable tablet of claim 1, wherein the composition comprises a core being coated with the lansoprazole or the salt thereof and the basic inorganic salt, said core comprising crystalline cellulose and lactose.

7. The orally disintegrable tablet of claim 6, wherein the core comprises lactose in an amount of 50 weight % or more.

8. The orally disintegrable tablet of claim 6, wherein the core comprises crystalline cellulose in an amount from 40 to 50 weight % and the lactose in an amount from 50 to 60 weight %.

9. The orally disintegrable tablet of claim 1, wherein the composition comprises the lansoprazole or the salt thereof in an amount of 20 weight % or more.

10. The orally disintegrable tablet of claim 1, wherein the composition comprises the lansoprazole or the salt thereof in an amount from 20 to 50 weight %.

11. The orally disintegrable tablet of claim 1, wherein the fine granules are produced by fluidized-bed granulation method.

12. The orally disintegrable tablet of claim 1, wherein the enteric coating layer further comprises a sustained-release agent.

13. The orally disintegrable tablet of claim 12, wherein the sustained-release agent is a methacrylate copolymer.

14. The orally disintegrable tablet of claim 12, wherein the sustained-release agent is contained in an amount from 5 to 15 weight % relative to 100 weight % of the aqueous enteric polymer agent.

15. The orally disintegrable tablet of claim 1, wherein the water-soluble sugar alcohol is erythritol.

16. The orally disintegrable tablet of claim 1, wherein the water-soluble sugar alcohol is mannitol.

17. The orally disintegrable tablet of claim 12, wherein the water-soluble sugar alcohol is contained in an amount from 5 to 97 weight % relative to 100 weight % of the orally disintegrable tablet apart from the fine granules.

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

19. The orally disintegrable tablet of claim 1, wherein the tablet comprises no lubricant inside the tablet.

20. The orally disintegrable tablet of claim 1, wherein the enteric coating layer has a thickness from 20 to 70 ?m.

21. The orally disintegrable tablet of claim 1, wherein the oral disintegration time of the tablet is about 40 seconds or less.

22. The orally disintegrable tablet of claim 1, wherein the orally disintegrable tablet has a tablet hardness in a range from about 1 kg to about 20 kg.

Description

BEST MODE FOR CARRYING OUT THE INVENTION

(1) The following Examples and Reference Examples are further illustrative but by no means limitative of the present invention.

(2) Unless otherwise specifically indicated, the following % means weight %.

(3) Also, the content of the hydroxypropoxyl group is measured in accordance with the methods described in Japanese Pharmacopoeia (13th edition).

(4) The physical properties of the tablets and granules prepared in Examples were determined by the following test methods.

(5) (1) Hardness Test

(6) Determination was carried out with a tablet hardness tester [manufactured by Toyama Sangyo, Co. Ltd. (Japan)]. The test was performed in 10 ?ms and mean values were shown.

(7) (2) Oral Disintegration Time

(8) Time for complete disintegration only by saliva in the oral cavity was determined.

(9) (3) Remaining Ratio

(10) 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, the enteric fine granule was collected by means of the sieve.

(11) 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 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)
(4) Acid-resistance: Dissolution Using 0.1N HCl

(12) 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 HCl.

(13) (5) Average Particle Diameter: Volume Based Distribution Median Diameter (Median Diameter: 50% Particle Diameter from Cumulative Distribution)

(14) Determination was carried out with Raser Diffraction Analyzer, type: HEROS RODOS [trade name, manufactured by Sympatec (Germany)].

EXAMPLES

Example 1

(15) (1) Production of Granules having a Core

(16) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] is charged with 300 g of Nonpareil 105 (70-140) (particle diameter of 100 to 200 ?m). With the inlet air temperature and the temperature of the loading being controlled at 85? C. and about 28? C. respectively, the Nonpareil is coated by spraying a bulk liquid of the following composition prepared in advance in accordance with the tangential spray method at a spray rate of 20 g/min. The spraying operation 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 ?m) and a #100 circular sieve (150 ?m) to provide 750 g of granules having a core.

(17) Bulk Liquid:

(18) TABLE-US-00001 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

(19) 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.

(20) Undercoating Liquid:

(21) TABLE-US-00002 HPMC 32 g (Type 2910, viscosity: 3 centistokes) Talc 8 g Water 760 g
(3) Production of Enteric Coated Granules having a Core

(22) 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 ?m) to provide 950 g of enteric coated granules having a core.

(23) Enteric Film Coating Liquid:

(24) TABLE-US-00003 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

(25) TABLE-US-00004 Sieve weight ratio #18 (850 ?m) on 0% #30 (500 ?m) on 0% #200 (75 ?m) on 100% #200 (75 ?m) pass 0%
(4) Production of Granulated Powders

(26) A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1] is charged with 1321.2 g of erythritol [manufactured by Nikken Chemical Co., Ltd. (Japan)], 360.0 g 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 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.

(27) (5) Production of Orally Disintegrable Tablets

(28) Hereinafter, the above enteric coated granules having a core is referred to as enteric coated powders.

(29) 200.0 g of the above enteric coated powders and 300.0 g of the above mixed powders are 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/cm.sup.2 to provide tablets each weighing 500 mg.

Reference Example 1

(30) An alkaline cellulose comprising 24.1% of NaOH, 1.7% of Na.sub.2CO.sub.3, 42.9% of cellulose, 31.8% of H.sub.2O 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.

(31) On the other side, a kneader was charged with 2.5 weight parts of hot water at 65? C. and 0.13 weight parts of glacial acetic acid (about 40 weight % against equivalent for 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.

(32) 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

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

Example 2

(34) (1) Production of Granules having a Core

(35) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 300 g of Nonpareil 105 [(trade name) particle diameter: 100 to 200 ?m]. 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 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 ?m) to provide 2186 g of powders (150 to 300 ?m) having a core.

(36) Spray liquid:

(37) TABLE-US-00005 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 ?m) Hydroxypropyl cellulose (Type SSL) 309 g Purified water 3955 g
(2) Production of Film-Undercoated Granules having a Core

(38) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 2040 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 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.

(39) Undercoating Liquid:

(40) TABLE-US-00006 Hydroxypropylmethylcellulose 264 g (Type 2910, viscosity: 3 centistokes) Purified water 5016 g
(3) Production of Enteric Coated Granules having a Core

(41) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 1710 g of the above film-undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 70? C. and about 40? C., respectively, an enteric film 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 ?m) to provide 2393 g of enteric coated powders (177 to 355 ?m) having a core.

(42) Enteric Film Coating Liquid:

(43) TABLE-US-00007 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

(44) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 600 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.

(45) The average particle diameter of the obtained granules was 334.1 ?m.

(46) Film Coating Liquid:

(47) TABLE-US-00008 Mannitol 33 g Purified water 297 g
(5) Production of Mannitol-Granulated Powders

(48) 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.

(49) (6) Production of Mixed Powders

(50) 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 name), 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.

(51) (7) Production of Orally Disintegrable Tablets

(52) 250.0 g of the above mixed powders were tabletted using Autograph (trade name; compressing force measurement apparatus) with a punch (15R), 11 mm in diameter, at a tabletting pressure of 1.5 ton/cm.sup.2, to provide tablets each weighing 500 mg.

(53) The hardness and oral disintegration time of each tablet thus obtained were 5.9 kg and 30 seconds, respectively.

Example 3

(54) (1) Production of Granules having a Core

(55) 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 29? 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 ?m) and a #100 circular sieve (150 ?m) to provide 2424 g of granules having a core.

(56) Bulk Liquid:

(57) TABLE-US-00009 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

(58) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 2337.5 g of the above granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 80? C. and about 41? C., respectively, an undercoating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 18 g/min. The spraying operation was stopped when the specified amount 6050 g of the undercoating liquid had been sprayed, and then drying was carried out in the granulator for 10 minutes to provide 2551 g of film-undercoated granules having a core.

(59) Undercoating Liquid:

(60) TABLE-US-00010 Hydroxypropyl methylcellulose 332.5 g (Type 2910, viscosity: 3 centistokes) Low-substituted hydroxypropyl cellulose LH-32 17.5 g (hydroxypropoxyl group contents: 8.8 weight %) (average particle diameter: 17.57 ?m) Purified water 6650 g
(3) Production of Enteric Coated Granules having a Core

(61) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 570 g of the above film-undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 75? C. and about 40? C., respectively, an enteric film coating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 18 g/min. The spraying operation was stopped when the specified amount 2646 g of the enteric film coating liquid had been sprayed, and then drying was carried out in the granulator for 8 minutes. The coated powders were sieved through a #42 circular sieve (355 ?m) and a #70 circular sieve (212 ?m) to provide 1116 g of enteric coated granules having a core.

(62) The average particle diameter of the obtained granules was 326.9 ?m.

(63) Enteric film coating liquid:

(64) TABLE-US-00011 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

(65) 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 hydroxypropyl cellulose LH-23 (hydroxypropoxyl group contents: 5.8 weight %, average particle diameter: 17.8 ?m), 60.0 g of crystalline cellulose [CEOLUS KG-801 (trade name), manufactured by Asahi Chemical Co., Ltd. (Japan)], 15.0 g of crospovidone, 2.8 g of citric acid anhydrous and 25 g of magnesium stearate, which was admixed in a bag to give mixed powders.

(66) (5) Production of Orally Disintegrable Tablets

(67) 250.0 g of the above mixed powders were tabletted using Autograph (trade name; compressing force measurement apparatus) with a punch (15R), 11 mm in diameter, at a tabletting pressure of 1.5 ton/cm.sup.2, to provide tablets each weighing 500 mg.

(68) The hardness and oral disintegration time of each tablet thus obtained were 4.2 kg and 24 seconds, respectively.

Example 4

(69) (1) Production of Granules having a Core

(70) 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).

(71) 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.

(72) Bulk Liquid:

(73) TABLE-US-00012 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

(74) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 1020 g of the above granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 85? C. and about 40? C., respectively, an undercoating liquid of the following composition prepared in advance was sprayed in accordance with the tangential spray method at a spray rate of 15 g/min. The spraying operation was stopped when the specified amount 1980 g of the undercoating liquid 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.

(75) Undercoating Liquid:

(76) TABLE-US-00013 Hydroxypropylmethylcellulose 120 g (Type 2910, viscosity: 3 centistokes) Titanium oxide (TiO.sub.2) 240 g Sterilized Talc (trade name) 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

(77) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 460 g of the above film-undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 80? C. and about 41? C., respectively, an enteric film 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.

(78) Enteric Film Coating Liquid:

(79) TABLE-US-00014 Eudragit L30D-55 2290 g Eudragit NE30D 253 g Triethyl citrate 153 g Glyceryl monostearate 20 g Polysorbate 80 8 g Titanium oxide (TiO.sub.2) 53 g Sterilized Talc H (trade name) 53 g [produced by Matsumura Sangyo Co. Ltd. (Japan)] Purified water 2420 g
(4) Production of Enteric Coated and Mannitol Coated Granules having a Core

(80) 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 accordance with the tangential spray method at a spray rate of 16 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 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 pin) and a #60 circular sieve (250 ?m) to provide 806 g of enteric coated and mannitol coated granules having a core.

(81) The average particle diameter of the obtained granules was 326.6 pun.

(82) Film Coating Liquid:

(83) TABLE-US-00015 Mannitol 320 g Purified water 2880 g
(5) Production of Mixed Powders

(84) 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 name), manufactured by Asahi Chemical Co., Ltd. (Japan)], 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.

(85) (6) Production of Orally Disintegrable Tablets

(86) 250.0 g of the above mixed powders were tabletted using Autograph (trade name; compressing force measurement apparatus) with a punch (15R), 11 mm in diameter, at a tabletting pressure of 1.5 ton/cm.sup.2, to provide tablets each weighing 500 mg.

(87) The hardness and oral disintegration time of each tablet thus obtained were 3.9 kg and 20.5 seconds, respectively.

(88) The remaining ratio of the obtained tablet after acid-resistance test was 97%.

Example 5

(89) (1) Production of Granules having a Core

(90) 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 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 5661 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 2074 g of granules having a core.

(91) Bulk Liquid:

(92) TABLE-US-00016 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 4680 g
(2) Production of Film-Undercoated Granules having a Core

(93) 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 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 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 sieve (150 ?m) to provide 2555 g of film-undercoated granules having a core.

(94) Undercoating Liquid:

(95) TABLE-US-00017 Hydroxypropylmethylcellulose 252 g (Type 2910, viscosity: 3 centistokes) Titanium oxide (TiO.sub.2) 108 g Sterilized Talc (trade name) 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
(3) Production of Enteric Coated Granules having a Core

(96) 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 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 g of the enteric film coating liquid had been sprayed.

(97) Enteric Film Coating Liquid (A):

(98) TABLE-US-00018 Eudragit 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

(99) 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 composition 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.

(100) Enteric Film Coating Liquid (B):

(101) TABLE-US-00019 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

(102) 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.

(103) (4) Production of Enteric Coated and Mannitol Coated Granules having a Core

(104) 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.

(105) The average particle diameter of the obtained granules was 333.7 ?m.

(106) Film Coating Liquid:

(107) TABLE-US-00020 Mannitol 180 g Purified water 1080 g
(5) Production of Mixed Powders

(108) 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 name), 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 name), manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed in a bag to give mixed powders.

(109) (6) Production of Orally Disintegrable Tablets

(110) 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/cm.sup.2, to provide tablets each weighing 570 mg.

(111) The hardness and oral disintegration time of each tablet thus obtained were 2.6 kg and 20 seconds, respectively.

(112) The acid-resistance of the obtained tablet was 3.5%.

Example 6

(113) (1) Production of Granules Having a Core

(114) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 750 g of Nonpareil 105 (trade name) (particle diameter of 100 to 200 ?m). With the 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 ?l and a #100 circular sieve (150 ?m) to provide 1811 g of granules having a core.

(115) Bulk Liquid:

(116) TABLE-US-00021 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

(117) A centrifugal 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 ?m) and a #100 circular sieve (150 ?m) to provide 2628 g of film-undercoated granules having a core.

(118) Undercoating Liquid:

(119) TABLE-US-00022 Hydroxypropylmethylcellulose 378 g (Type 2910, viscosity: 3 centistokes) Titanium oxide (TiO.sub.2) 162 g Sterilized Talc (trade name) 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 Granules having a Core

(120) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 1560 g of the above film-undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 70? C. and about 40? C., respectively, an enteric film coating liquid (A) of the following composition prepared in advance was sprayed in accordance with the 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.

(121) Enteric Film Coating Liquid (A):

(122) TABLE-US-00023 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

(123) 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.

(124) Enteric Film Coating Liquid (B):

(125) TABLE-US-00024 Eudragit L30D-55 609.6 g Eudragit NE30D 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 (yellow) 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

(126) 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 prepared in 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)]. 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 17 minutes. The resulting granules were sieved through a #35 circular sieve (420 pun) and a #60 circular sieve (250 ?m) to provide 2825 g of enteric coated and mannitol coated granules having a core.

(127) The average particle diameter of the obtained granules was 330.5 ?m.

(128) Film Coating Liquid:

(129) TABLE-US-00025 Mannitol 180 g Purified water 1080 g
(5) Production of Mixed Powders

(130) 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 name), 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 name), manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed in a bag to give mixed powders.

(131) (6) Production of Orally Disintegrable Tablets

(132) 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/cm.sup.2, to provide tablets each weighing 570 mg.

(133) The hardness and oral disintegration time of each tablet thus obtained were 3.1 kg and 22 seconds, respectively.

(134) The acid-resistance of the obtained tablet was 2.5%.

Example 7

(135) (1) Production of Granules having a Core

(136) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 750 g of Nonpareil 105 (trade name) (particle diameter of 100 to 200 ?m). With the 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 tangential 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.

(137) Bulk Liquid:

(138) TABLE-US-00026 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

(139) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 1842 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.

(140) Undercoating Liquid:

(141) TABLE-US-00027 Hydroxypropylmethylcellulose 378 g (Type 2910, viscosity: 3 centistokes) Titanium oxide (TiO.sub.2) 162 g Sterilized Talc (trade name) 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 Granules having a Core

(142) 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 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 5040 g of the enteric film coating liquid had been sprayed, and then drying was carried out in the granulator for 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.

(143) Enteric Film Coating Liquid (A):

(144) TABLE-US-00028 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

(145) 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.

(146) Enteric Film Coating Liquid (B):

(147) TABLE-US-00029 Eudragit L30D-55 610.4 g Eudragit NE30D 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 (yellow) 0.12 g Citric acid anhydrous 0.24 g Purified water 845.12 g
(4) Production of Enteric Coated and Mannitol Coated Granules having a Core

(148) 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 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 (Type 2)]. 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 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.

(149) The average particle diameter of the obtained granules was 307.1 ?m.

(150) Film Coating Liquid:

(151) TABLE-US-00030 Mannitol 120 g Purified water 720 g
(5) Production of Mixed Powders

(152) 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 name), 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 name), manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed in a bag to give mixed powders.

(153) (6) Production of Orally Disintegrable Tablets

(154) 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/cm.sup.2, to provide tablets each weighing 570 mg.

(155) The hardness and oral disintegration time of each tablet thus obtained were 3.2 kg and 24 seconds, respectively.

Example 8

(156) (1) Production of Granules Having a Core

(157) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 900 g of Nonpareil 105T (trade name) (particle diameter of 100 to 200 ?m). 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 #100 circular sieve (150 ?m) to provide 1723 g of granules having a core.

(158) Bulk Liquid:

(159) TABLE-US-00031 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 4680 g
(2) Production of Film-Undercoated Granules having a Core

(160) 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 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 ?m) and a #100 circular sieve (150 ?m) to provide 1958 g of film-undercoated granules having a core.

(161) Undercoating Liquid:

(162) TABLE-US-00032 Hydroxypropylmethylcellulose 252 g (Type 2910, viscosity: 3 centistokes) Titanium oxide (TiO.sub.2) 108 g Sterilized Talc (trade name) 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
(3) Production of Enteric Coated Granules having a Core

(163) A centrifugal fluidized coating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type 2)] was charged with 1100 g of the above film-undercoated granules having a core. With the inlet air temperature and the temperature of the loading being controlled at 80? C. and about 41? C., respectively, an enteric film 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.

(164) Enteric Film Coating Liquid (A):

(165) TABLE-US-00033 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

(166) 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.

(167) Enteric Film Coating Liquid (B):

(168) TABLE-US-00034 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

(169) 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.

(170) (4) Production of Enteric Coated and Mannitol Coated Granules having a Core

(171) 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 (Type 2)]. 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.

(172) The average particle diameter of the obtained granules was 392.7 ?m.

(173) Film Coating Liquid:

(174) TABLE-US-00035 Mannitol 100 g Purified water 600 g
(5) Production of Mixed Powders

(175) 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 name), 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 name), manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed in a bag to give mixed powders.

(176) (6) Production of Orally Disintegrable Tablets

(177) 570 g of the above mixed powders were tabletted using Autograph (trade name; compressing force measurement apparatus) with a punch having a beveled edge, 12 mm in diameter, at a tabletting pressure of 1.5 ton/cm.sup.2, to provide tablets each weighing 570 mg.

(178) The hardness and oral disintegration time of each tablet thus obtained were 3.7 kg and 35 seconds, respectively.

(179) The acid-resistance of the obtained tablet was 3.4%.

Example 9

(180) (1) Production of Granules having a Core

(181) A centrifugal fluidized 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 following composition prepared in advance in accordance with the tangential spray method at a spray rate of 20 g/min. The spraying operation was stopped when the specified amount of the bulk liquid had been sprayed, and then drying was carried out in the granulator for 7 minutes. The resulting granules were sieved through a #48 circular sieve (300 ?m) and a #100 circular sieve (150 ?m) to provide 757 g of granules having a core.

(182) Bulk Liquid:

(183) TABLE-US-00036 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

(184) 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.

(185) Undercoating Liquid:

(186) TABLE-US-00037 HPMC 32 g (Type 2910, viscosity: 3 centistokes) Talc 8 g Water 760 g
(3) Production of Enteric Coated Granules having a Core

(187) 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 ?m) and a #80 circular sieve (177 ?m) to provide 950 g of enteric coated granules having a core.

(188) The average particle diameter of the obtained granules was 285.4 ?m.

(189) Enteric Film Coating Liquid:

(190) TABLE-US-00038 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

(191) TABLE-US-00039 Sieve weight ratio #18 (850 ?m) on 0% #30 (500 ?m) on 0% #200 (75 ?m) on 100% #200 (75 ?m) pass 0%
(4) Production of Granulated Powders

(192) A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1] was charged with 1321.2 g of erythritol [manufactured by Nikken Chemical Co., Ltd. (Japan)], 360.0 g 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.

(193) (5) Production of Orally Disintegrable Tablets

(194) 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/cm.sup.2, to provide tablets each weighing 500 mg.

(195) 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

(196) The orally disintegrable tablet of the present invention has superior disintegrability or dissolution so that it can be used for treatment or prevention of various diseases, as an orally disintegrable tablet capable of being administered to the aged or children and easily administered without water. Also, because the orally disintegrable tablet of the present invention contains fine granules having the average particle diameter and an enteric coating layer such that it will not impart roughness in mouth, it can be administered easily without discomfort at the administration and has superior acid-resistance.

(197) 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.

(198) 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 by 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.