PHARMACEUTICAL SOLID PREPARATION COMPRISING BENZAZEPINES AND PRODUCTION METHOD THEREOF

Abstract

The subject invention provides a novel pharmaceutical solid preparation that has superior disintegration properties and excellent solubility, leading to sufficient absorbability of active ingredients through the gastrointestinal tract. The pharmaceutical solid preparation of the present invention comprises: (a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and/or salt thereof; (b) hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater; and (c) at least one member selected from the group consisting of carmellose, sodium carboxy methyl starch, crospovidone, and low substituted hydroxypropylcellulose with an average particle diameter of 30 to 70 m, and a 90% cumulative particle diameter of 100 to 200 m.

Claims

1. A dosing regimen for administering a benzoazepine compound to a patient in need of a vasopressin antagonist, the dosing regimen comprising: (1) administering to the patient a first loading dose of about 45 mg of the benzoazepine compound formulated in a solid dosage form on a first day of treatment; (2) administering to the patient a second loading dose of about 15 mg of the benzoazepine compound formulated in the solid dosage form on the first day of treatment, for a total loading dose of about 60 mg on the first day of treatment; (3) administering to the patient a first titration dose of about 60 mg of the benzoazepine compound formulated in the solid dosage form on a second day of treatment that is after the first day of treatment; (4) administering to the patient a second titration dose of about 30 mg of the benzoazepine compound formulated in the solid dosage form on the second day of treatment, for a total titration dose of about 90 mg on the second day of treatment; (5) administering to the patient a first target dose of about 90 mg of the benzoazepine compound formulated in the solid dosage form on a third day of treatment that is after the second day of treatment; and (6) administering to the patient a second target dose of about 30 mg of the benzoazepine compound formulated in the solid dosage form on the third day of treatment, for a total target dose of about 120 mg on the third day of treatment, wherein the benzoazepine compound is selected from the group consisting of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and a salt thereof.

2. The dosing regimen according to claim 1, wherein the second loading dose is administered about 8 hours after the first loading dose.

3. The dosing regimen according to claim 1, wherein the second titration dose is administered about 8 hours after the first titration dose.

4. The dosing regimen according to claim 1, wherein the second target dose is administered about 8 hours after the first target dose.

5. The dosing regimen according to claim 1, wherein the second day of treatment begins at least a week after the first day of treatment.

6. The dosing regimen according to claim 1, wherein the third day of treatment begins at least a week after the second day of treatment.

7. The dosing regimen according to claim 1, wherein the first loading dose and the second loading dose are repeated daily until the second day of treatment.

8. The dosing regimen according to claim 1, wherein the first titration dose and the second titration dose are repeated daily until the second day of treatment.

9. The dosing regimen according to claim 1, wherein the solid dosage form comprises: (a) the benzoazepine compound; (b) hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater; and (c) low substituted hydroxypropylcellulose having an average particle diameter of 30 to 70 m and a 90% cumulative particle diameter of 100 to 200 m, wherein the solid dosage form contains the (a) benzoazepine compound in an amount of 15 to 90 mg.

10. The dosing regimen according to claim 9, wherein the solid dosage form contains a plurality of amorphous composites consisting of the (a) benzoazepine compound and the (b) hydroxypropylcellulose.

11. The dosing regimen according to claim 10, further comprising (i) crystalline cellulose, and (ii) corn starch and/or lactose monohydrate.

12. The dosing regimen according to claim 9, wherein the (c) low substituted hydroxypropylcellulose is cellulose containing a hydroxy propoxyl group in an amount of 10 to 13%.

13. The dosing regimen according to claim 9, wherein the average particle diameter of the (c) low substituted hydroxypropylcellulose is 45 to 65 m, and the 90% cumulative particle diameter of the (c) low substituted hydroxypropylcellulose is 150 to 200 m.

14. The dosing regimen according to claim 9, wherein the (c) low substituted hydroxypropylcellulose directly contacts at least some of the plurality of amorphous composites.

15. The dosing regimen according to claim 9, wherein a content of the (c) low substituted hydroxypropylcellulose is 1 to 15 wt % of the solid dosage form.

16. The dosing regimen according to claim 9, wherein the solid dosage form is a tablet.

17. The dosing regimen according to claim 9, wherein the solid dosage form is not coated with an enteric film or a sustained-release film configured to modify a release of the benzoazepine compound in the gastrointestinal tract.

18. The dosing regimen according to claim 9, wherein the benzoazepine compound is 0.01 to 95 wt % of the solid dosage form.

19. The dosing regimen according to claim 9, wherein a content of (b) the hydroxypropylcellulose is 0.01 to 2 times that of the content of the (a) benzoazepine compound.

20. The dosing regimen according to claim 9, wherein a content of the (c) low substituted hydroxypropylcellulose is 3 to 12 wt % of the solid preparation.

21. The dosing regimen according to claim 9, further comprising crystalline cellulose, microcrystalline cellulose, corn starch, lactose monohydrate, and magnesium stearate.

22. The dosing regimen according to claim 9, wherein the solid dosage form is obtained by a method comprising: Step 1 of producing amorphous composites consisting of the (a) benzoazepine compound and the (b) hydroxypropylcellulose; Step 2 of processing a mixture of (i) the amorphous composites obtained in Step 1, (ii) crystalline cellulose, and (iii) corn starch and/or lactose into granules using a granulation method; Step 3 of mixing the granules obtained in Step 2 with the (c) low substituted hydroxypropylcellulose to obtain a mixture, wherein the (c) low substituted hydroxypropylcellulose directly contacts at least some of the amorphous composites; and Step 4 of processing the mixture obtained in Step 3 into the solid dosage form.

23. A dosing regimen for administering a benzoazepine compound to a patient in need of a vasopressin antagonist, the dosing regimen comprising: (1) administering to the patient a total loading dose of about 60 mg of the benzoazepine compound on a first day of treatment; (2) administering to the patient a total titration dose of about 90 mg of the benzoazepine compound on a second day of treatment that is after the first day of treatment; and (3) administering to the patient a total target dose of about 120 mg of the benzoazepine compound formulated in the solid dosage form on a third day of treatment that is after the second day of treatment, wherein the benzoazepine compound is selected from the group consisting of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and a salt thereof.

24. A dosing regimen for administering a benzoazepine compound to a patient in need of a vasopressin antagonist, the dosing regimen comprising: (1) administering to the patient a plurality of initial doses of the benzoazepine compound for a total loading dose of about 60 mg of the benzoazepine compound per day; (2) administering to the patient a plurality of titration doses of the benzoazepine compound for a total titration dose of about 90 mg of the benzoazepine compound per day; and (3) administering to the patient a plurality of target doses of the benzoazepine compound for a total target dose of about 120 mg of the benzoazepine compound per day, wherein the benzoazepine compound is selected from the group consisting of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and a salt thereof.

Description

BEST MODE FOR CARRYING OUT THE INVENTION

[0170] The present invention is more specifically described below in reference to the Reference Examples, Examples, Comparative Examples and Experiment Examples; however, the present invention is not limited to those examples.

Reference Example 1 (Preparation of Amorphous Powder)

[0171] 100 g of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine (main ingredient, hereinafter) and 50 g of hydroxypropylcellulose (HPC-SL; Nippon Soda Co. Ltd.) containing 53 to 78 wt. % of hydroxy propoxyl group was dissolved in a mixed solution of 1,390 g of dichloromethane and 350 g of ethanol. The solution was treated with an ODT-8 spray drier (Ohkawara Kakohki Co., Ltd.), and then immediately dried with an LCV-232 vacuum dryer (Tabai Espec Corporation), to prepare an amorphous powder.

Reference Example 2 (Preparation of Granulation Substance)

[0172] 135 g of the amorphous powder, 222 g of lactose monohydrate, 60 g of corn starch, and 60 g of crystalline cellulose were mixed, and the mixture was placed in a Multiplex MP-01 stirring fluidized-bed granulation drier (Powrex Corporation). Fluidizing-bed granulation was carried out with 240 g of a 5 w/v % aqueous solution of hydroxypropylcellulose containing a hydroxy propoxyl group in an amount of 53 to 78 wt. % (HPC-L; Nippon Soda Co., Ltd.), followed by drying. A granulation substance was thus obtained.

[0173] In the Examples and Comparative Examples below, the following products were used as Component (c).

Component (c)

[0174] Low substituted hydroxypropylcellulose (an average particle diameter of 45 to 65 m, and a 90% cumulative particle diameter of 150 to 200 m; content of hydroxy propoxyl group=10.0 to 12.9 wt. %) (LH-11; Shin-Etsu Chemical Co., Ltd.) [0175] Low substituted hydroxypropylcellulose (an average particle diameter of 35 to 55 m, and a 90% cumulative particle diameter of 100 to 150 m; content of hydroxy propoxyl group=10.0 to 12.9 wt. %) (LH-21; Shin-Etsu Chemical Co. Ltd.) [0176] Low substituted hydroxypropylcellulose (an average particle diameter of 17 to 23 m, and a 90% cumulative particle diameter of 40 to 100 m; content of hydroxy propoxyl group=10.0 to 12.9 wt. %) (LH-31; Shin-Etsu Chemical Co. Ltd.) [0177] Low substituted hydroxypropylcellulose (an average particle diameter of 45 to 65 m, and a 90% cumulative particle diameter of 100 to 150 m; content of hydroxy propoxyl group=10.0 to 12.9 wt. %) (LH-B1; Shin-Etsu Chemical Co. Ltd.) [0178] Carmellose ((carboxymethylcellulose) NS-300; Nichirin Chemical Industries Ltd.) [0179] Sodium carboxy methyl starch (Primojel; DMV; After a screening with a 63 m sieve, 5% or less of the particles remain on the sieve) [0180] Partly pregelatinized starch (PCS PC-10; Asahi Kasei Chemicals; an average particle diameter of 70 m, not more than 3 wt. % water soluble content) [0181] Crospovidone (Polyplasdone XL; ISP; an average particle diameter of 75 m) [0182] Carmellose calcium ((carboxymethylcellulose calcium) ECG-505; Nichirin Chemical Industries, Ltd.)

[0183] Crosscarmellose sodium ((crosscarboxymethylcellulose sodium) Ac-Di-Sol; FMC International)

Example 1

[0184] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.3 g of LH-11, and 0.3 g of magnesium stearate were mixed. Using an Autograph AG-I Universal Testing Instruments (Shimadzu Corporation), a flat tablet (6 mm in diameter) about 84 mg in weight, containing 15 mg of the main ingredient, was produced under a compression speed of 6 kN, with a compression rate of 20 mm/min.

[0185] The content of LH-11 in the flat tablet was 1.2 wt. %.

Example 2

[0186] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 1.4 g of LH-11, and 0.3 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0187] The content of LH-11 in the flat tablet was 5.2 wt. %.

Example 3

[0188] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 2.9 g of LH-11, and 0.4 g of magnesium stearate were mixed. A flat tablet about 92 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0189] The content of LH-11 in the flat tablet was 10.3 wt. %.

Example 4

[0190] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 4.4 g of LH-11, and 0.3 g of magnesium stearate were mixed. A flat tablet about 97 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0191] The content of LH-11 in the flat tablet was 14.9 wt. %.

Example 5

[0192] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.5 g of LH-21, and 0.1 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0193] The content of LH-21 in the flat tablet was 5.2 wt. %.

Example 6

[0194] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.5 g of LH-B1, and 0.1 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner of Example 1.

[0195] The content of LH-B1 in the flat tablet was 5.2 wt. %.

Comparative Example 1

[0196] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, and 0.3 g of magnesium stearate were mixed. A flat tablet about 83 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

Comparative Example 2

[0197] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.1 g of LH-31, and 0.1 g of magnesium stearate were mixed. A flat tablet about 84 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0198] The content of LH-31 in the flat tablet was 1.2 wt. %.

Comparative Example 3

[0199] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.5 g of LH-31, and 0.1 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0200] The content of LH-31 in the flat tablet was 5.2 wt. %.

Comparative Example 4

[0201] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.3 g of Ac-Di-Sol, and 0.3 g of magnesium stearate were mixed. A flat tablet about 84 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0202] The content of Ac-Di-Sol in the flat tablet was 1.2 wt. %.

Comparative Example 5

[0203] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 1.3 g of Ac-Di-Sol, and 0.3 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0204] The content of Ac-Di-Sol in the flat tablet was 5.2 wt. %.

Comparative Example 6

[0205] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 2.9 g of Ac-Di-Sol, and 0.3 g of magnesium stearate were mixed. A flat tablet about 92 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0206] The content of Ac-Di-Sol in the flat tablet was 10.3 wt. %.

Comparative Example 7

[0207] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 4.4 g of Ac-Di-Sol, and 0.3 g of magnesium stearate were mixed. A flat tablet about 97 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0208] The content of Ac-Di-Sol in the flat tablet was 14.9 wt. %.

Comparative Example 8

[0209] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.3 g of ECG-505, and 0.3 g of magnesium stearate were mixed. A flat tablet about 84 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0210] The content of ECG-505 in the flat tablet was 1.2 wt. %.

Comparative Example 9

[0211] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 1.4 g of ECG-505, and 0.3 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0212] The content of ECG-505 in the flat tablet was 5.2 wt. %.

Comparative Example 10

[0213] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 2.9 g of ECG-505, and 0.3 g of magnesium stearate were mixed. A flat tablet about 92 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0214] The content of ECG-505 in the flat tablet was 10.3 wt. %.

Comparative Example 11

[0215] 24.5 g of the granulation substance prepared in the above-mentioned Reference Example 2, 4.4 g of ECG-505, and 0.3 g of magnesium stearate are mixed. A flat tablet about 97 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0216] The content of ECG-505 in the flat tablet was 14.9 wt. %.

Experiment Example 1

[0217] Using six tablets each, the respective tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 11 were examined for their disintegration properties according to a disintegration test method disclosed in Japanese Pharmacopoeia (test fluid: water, no disk).

[0218] Table 1 shows the results of the disintegration test for Examples 1 to 6 and Comparative Examples 1 to 11.

TABLE-US-00001 TABLE 1 Disintegration Time (Second, Average standard Flat Tablet Deviation) Example 1 70.8 5.8 (LH-11, 1.2%) Example 2 63.7 3.9 (LH-11, 5.2%) Example 3 52.8 2.4 (LH-11, 10.3%) Example 4 60.5 2.0 (LH-11, 14.9%) Example 5 79.8 10.7 (LH-21, 5.2%) Example 6 75.5 1.9 (LH-B1, 5.2%) Comparative Example 1 95.8 6.1 (No Disintegrating Agent) Comparative Example 2 104.7 6.2 (LH-31, 1.2%) Comparative Example 3 130.3 37.4 (LH-31, 5.2%) Comparative Example 4 92.3 3.0 (Ac-Di-Sol, 1.2%) Comparative Example 5 161.3 12.0 (Ac-Di-Sol, 5.2%) Comparative Example 6 163.8 3.5 (Ac-Di-Sol, 10.3%) Comparative Example 7 188.0 3.8 (Ac-Di-Sol, 14.9%) Comparative Example 8 85.5 3.9 (ECG-505, 1.2%) Comparative Example 9 100.5 5.1 (ECG-505, 5.2%) Comparative Example 10 130.3 4.5 (ECG-505, 10.3%) Comparative Example 11 170.0 5.1 (ECG-505, 14.9%)

[0219] Table 1 revealed the following.

[0220] For the tablets of Comparative Examples 2 and 3 that use LH-31 (low substituted hydroxypropylcellulose (an average particle diameter of 17 to 23 m, and a 90% cumulative particle diameter of 40 to 100 m), the disintegration time was longer than Comparative Example 1 not containing a disintegrating agent.

[0221] The disintegration time in the tablet of Comparative Example 4 containing 1.2 wt. % of Ac-Di-Sol (cross carmellose sodium) and in the tablet of Comparative Example 8 containing of 1.2 wt. % of ECG-505 (carmellose sodium) was slightly shorter than that in the tablet of Comparative Example 1 not containing any disintegrating agents. However, by increasing the proportions of Ac-Di-Sol and ECG-505 in the tablets to 5.2 wt. %, 10.3 wt. %, and 14.9 wt. % (Comparative Examples 5 to 7 and Comparative Examples 9 to 11), the disintegration time lengthened remarkably.

[0222] Although Ac-Di-Sol used in Comparative Examples 4 to 7 and ECG-505 used in Comparative Examples 8 to 11 are known as super disintegration agents, the tablets using these disintegration agents instead of the disintegration agents used for the present invention turned out to exhibit insufficient disintegration properties. Moreover, as its amount increased, the disintegration properties lowered significantly.

[0223] In contrast, as shown in Table 1, the disintegration time was significantly short in Examples 1 to 4 using LH-11 as a disintegrating agent, compared with Comparative Examples 1 to 11, and desirable disintegration properties were obtained.

[0224] Additionally, in the solid preparation of Example 5 which uses LH-21 as a disintegrating agent, the disintegration time was shorter than Comparative Example 1 not containing any disintegrating agent, and desirable disintegration properties were obtained.

[0225] Further, in the solid preparation of Example 6 which uses LH-B1 as disintegrating agent, the disintegration time was shorter than Comparative Example 1 not containing any disintegrating agents. Desirable disintegration properties were thus obtained.

Experiment Example 2

[0226] Table 2 shows the average value and variation in disintegration time among the six solid samples (No. 1 to 6) for each of Examples 2, 5, and 6 and Comparative Example 3, which were measured in the above-mentioned Experiment Example 1.

TABLE-US-00002 TABLE 2 Solid Exam- Exam- Exam- Com- Preparation ple ple ple parative No. 2 5 6 Example 3 Dis- 1 58 70 73 106 integration 2 60 72 74 107 Time 3 64 73 75 112 (Seconds) 4 66 80 76 121 5 66 86 77 132 6 68 98 78 204 Average Disintegration Time 63.7 79.8 75.5 130.3 (Seconds) Variation (Seconds) 3.9 10.7 1.9 37.4

[0227] As shown in Table 2, the variation in disintegration time in Example 2 using LH-11 as a disintegrating agent was 3.9 seconds; the variation in disintegration time in Example 5 using LH-21 was 10.7 seconds; and the variation in disintegration time in Example 6 using LH-B1 was 1.9 seconds. That is, the variation in disintegration time was small for the tablets of all Examples 2, 5, and 6; more specifically, the tablets of these Examples ensure a uniform pharmacologic effect.

[0228] Meanwhile, the variation in disintegration time in Comparative Example 3 using LH-31 was 37.4 seconds, which is very large.

Example 7

[0229] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.5 g of NS-300, and 0.1 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0230] The content of NS-300 in the flat tablet was 5.2 wt. %.

Example 8

[0231] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 1.0 g of NS-300, and 0.1 g of magnesium stearate were mixed. A flat tablet about 92 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0232] The content of NS-300 in the flat tablet was 10.3 wt. %.

Experiment Example 3

[0233] A disintegration test was conducted for each of the six solid samples in Examples 7 and 8, using a disintegration test method according to Japanese Pharmacopoeia (test fluid: water, no disk).

[0234] Table 3 shows the results of the disintegration test for Examples 7 and 8.

TABLE-US-00003 TABLE 3 Disintegration Time (Seconds, Average standard Deviation) Example 7 88.8 7.0 (NS-300, 5.2%) Example 8 55.2 15.1 (NS-300, 10.3%)

[0235] Table 3 revealed the following.

[0236] In the solid preparations of Examples 7 and 8, using NS-300 as a disintegrating agent, their disintegration times were shorter than that of Comparative Example 1 (shown in Table 1) not containing any disintegrating agents, and desirable disintegration properties were obtained.

[0237] Particularly, the disintegration time of Example 8 using 10.3 wt. % of NS-300 in each table was significantly shorter than that of Comparative Examples 1 to 11. The disintegration properties of Example 8 were thus excellent.

Example 9

[0238] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.1 g of Primojel, and 0.1 g of magnesium stearate were mixed. A flat tablet about 84 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0239] The content of Primojel in the flat tablet was 1.2 wt. %.

Example 10

[0240] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.5 g of Primojel, and 0.1 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0241] The content of Primojel in the flat tablet was 5.2 wt. %.

Example 11

[0242] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 1.0 g of Primojel, and 0.1 g of magnesium stearate were mixed. A flat tablet about 92 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0243] The content of Primojel in the flat tablet was 10.3 wt. %.

Example 12

[0244] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.5 g of PCS PC-10, and 0.1 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0245] The content of PCS PC-10 in the flat tablet was 5.2 wt. %.

Example 13

[0246] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 1.0 g of PCS PC-10, and 0.1 g of magnesium stearate were mixed. A flat tablet about 92 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0247] The content of PCS PC-10 in the flat tablet was 10.3 wt. %.

Experiment Example 4

[0248] A disintegration test was conducted for each of the six solid samples in Examples 9 to 13, using a disintegration test method according to Japanese Pharmacopeia (test fluid: water, no disk).

[0249] Table 4 shows the results of the disintegration test for Examples 9 to 13.

TABLE-US-00004 TABLE 4 Disintegration Time (Seconds, Average standard Deviation) Example 9 58.8 7.4 (Primojel, 1.2%) Example 10 65.2 4.2 (Primojel, 5.2%) Example 11 72.2 7.4 (Primojel, 10.3%) Example 12 87.2 5.3 (PCS PC-10, 5.2%) Example 13 92.5 2.9 (PCS PC-10, 10.3%)

[0250] Table 4 revealed the following.

[0251] In the solid preparations of Examples 9 to 11 using Primojel (sodium carboxy methyl starch) as a disintegrating agent, the disintegration time was shorter than that of Comparative Example 1 not containing any disintegrating agents, and desirable disintegration properties were obtained.

[0252] Particularly, the disintegration time was significantly short in Example 9 using 1.2 wt. % of Primojel as a disintegrating agent, compared with Comparative Examples 1 to 11. The disintegration properties of Example 9 were thus excellent.

[0253] Additionally, in the solid preparations of Examples 12 and using PCS PC-10 (partly pregelatinized starch) as a disintegrating agent, the disintegration time was shorter than Comparative Example 1 not containing a disintegrating agent, and desirable disintegration properties were obtained.

Example 14

[0254] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.1 g of Polyplasdone XL, and 0.1 g of magnesium stearate were mixed. A flat tablet about 84 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0255] The content of Polyplasdone XL in the flat tablet was 1.2 wt. %.

Example 15

[0256] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 0.5 g of Polyplasdone XL, and 0.1 g of magnesium stearate were mixed. A flat tablet about 87 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0257] The content of Polyplasdone XL in the flat tablet was 5.2 wt. %.

Example 16

[0258] 8.2 g of the granulation substance prepared in the above-mentioned Reference Example 2, 1.0 g of Polyplasdone XL, and 0.1 g of magnesium stearate were mixed. A flat tablet about 92 mg in weight, containing 15 mg of the main ingredient, was produced in the same manner as Example 1.

[0259] The content of Polyplasdone XL in the flat tablet was 10.3 wt. %.

Experiment Example 5

[0260] A disintegration test was conducted for each of the six solid samples in Examples 14 to 16, using a disintegration test method according to Japanese Pharmacopeia (test fluid: water, no disk).

[0261] Table 5 shows the results of the disintegration test for Examples 14 to 16.

TABLE-US-00005 TABLE 5 Disintegration Time (Seconds, Average standard Deviation) Example 14 80.5 19.9 (Polyplasdone XL, 1.2%) Example 15 73.5 6.6 (Polyplasdone XL, 5.2%) Example 16 53.8 3.4 (Polyplasdone XL, 10.3%)

[0262] Table 5 revealed the following.

[0263] In the solid preparations of Examples 14 to 16 using Polyplasdone XL (crospovidone) as a disintegrating agent, the disintegration time was shorter than that of Comparative Examples 1 to 11, and desirable disintegration properties were obtained.

[0264] Particularly, the disintegration time was significantly short in Example 16 using the solid preparation containing 10.3 wt. % of Polyplasdone XL. The disintegration properties of Example 16 were thus excellent.

Example 17

[0265] 270 g of the amorphous powder obtained in Reference Example 1, 50.5 g of lactose monohydrate, 60 g of corn starch, and 60 g of crystalline cellulose were mixed, and the mixture was placed in a Multiplex MP-01 stirring fluidized-bed granulation drier (Powrex Corporation). Fluidizing-bed granulation was carried out with 240 g of a 5 w/v % aqueous solution of hydroxypropylcellulose containing a hydroxy propoxyl group in an amount of 53 to 78 wt. %, followed by drying. A granulation substance was thus obtained in the same manner as Reference Example 2. The obtained granulation substance was mixed with 27 g of LH-11, 0.48 g of FDC blue No. 2 aluminum lake, and 6 g of magnesium stearate to prepare granules for tablets. With the obtained granules, flat tablets were produced with a Rotary Tabletting Machine 12HUK-AWC (product of Kikusui Seisakusho Ltd.), at 40 rpm and under a compression force at 900 kg. Each tablet was about 162 mg in weight, 8 mm in diameter, and contains 60 mg of a main ingredient. The content of LH-11 in each tablet was 5.6 wt. %.

Example 18

[0266] 112.5 g of the amorphous powder obtained in Reference Example 1, 184.6 g of lactose monohydrate, 50 g of corn starch, and 50 g of crystalline cellulose were mixed, and the mixture was placed in a Multiplex MP-01 stirring fluidized-bed granulation drier (Powrex Corporation). Fluidizing-bed granulation was carried out with 200 g of a 5 w/v % aqueous solution of hydroxypropylcellulose containing a hydroxy propoxyl group in an amount of 53 to 78 wt. %, followed by drying. A granulation substance was thus obtained in the same manner as Reference Example 2. The obtained granulation substance was mixed with 22.5 g of LH-11, 0.43 g of FDC blue No. 2 aluminum lake, and 5 g of magnesium stearate to prepare granules for tablets. With the obtained granules, flat tablets were produced with a Rotary-Tabletting Machine 12HUK-AWC (product of Kikusui Seisakusho Ltd.), at 40 rpm and under a compression force at 900 kg. Each tablet was about 174 mg in weight, 8 mm in diameter, and contains 30 mg of a main ingredient. The content of LH-11 in each tablet was 5.2 wt. %.

Example 19

[0267] With the granules obtained in Example 18, flat tablets were produced with a Rotary Tabletting Machine 12HUK-AWC (product of Kikusui Seisakusho Ltd.), at 40 rpm and under a compression force at 900 kg. Each tablet was about 87 mg in weight, 6 mm in diameter, and contains 15 mg of a main ingredient. The content of LH-11 in each tablet was 5.2 wt. %.

Example 20

[0268] 56.3 g of the amorphous powder obtained in Reference Example 1, 255.8 g of lactose monohydrate, 50 g of corn starch, and 50 g of crystalline cellulose were mixed, and the mixture was placed in a Multiplex MP-01 stirring fluidized-bed granulation drier (Powrex Corporation). Fluidizing-bed granulation was carried out with 200 g of a 5 w/v % aqueous solution of hydroxypropylcellulose containing a hydroxy propoxyl group in an amount of 53 to 78 wt. %, followed by drying. A granulation substance was thus obtained in the same manner as Reference Example 2. The obtained granulation substance was mixed with 22.5 g of LH-11, 0.45 g of FDC blue No. 2 aluminum lake, and 5 g of magnesium stearate to prepare granules for tablets. With the obtained granules, flat tablets were produced with a Rotary Tabletting Machine 12HUK-AWC (product of Kikusui Seisakusho Ltd.), at 50 rpm and under a compression force at 1000 kg. Each tablet was about 180 mg in weight, 8 mm in diameter, and contains 15 mg of a main ingredient. The content of LH-11 in each tablet was 5.0 wt. %.

Example 21

[0269] 33.75 g of the amorphous powder obtained in Reference Example 1, 350.25 g of lactose monohydrate, 60 g of corn starch, and 60 g of crystalline cellulose were mixed, and the mixture was placed in a Multiplex MP-01 stirring fluidized-bed granulation drier (Powrex Corporation). Fluidizing-bed granulation was carried out with 240 g of a 5 w/v % aqueous solution of hydroxypropylcellulose containing a hydroxy propoxyl group in an amount of 53 to 78 wt. %, followed by drying. A granulation substance was thus obtained in the same manner as Reference Example 2. The obtained granulation substance was mixed with 27 g of LH-11, and 6 g of magnesium stearate to prepare granules for tablets. With the obtained granules, flat tablets were produced with a Rotary Tabletting Machine 12HUK-AWC (product of Kikusui Seisakusho Ltd.), at 50 rpm and under a compression force at 1000 kg. Each tablet was about 183 mg in weight, 8 mm in diameter, and contains 7.5 mg of a main ingredient. The content of LH-11 in each tablet was 4.9 wt. %.

INDUSTRIAL APPLICABILITY

[0270] The pharmaceutical solid preparation of the present invention contains (a) benzoazepine compound, (b) hydroxypropylcellulose containing a hydroxy propoxyl group in an amount of 50% or greater, and a disintegrating agent, which is either (c-1) low substituted hydroxypropylcellulose, (c-2) carmellose, (c-3) sodium carboxy methyl starch or (c-4) crospovidone. With this composition, the pharmaceutical solid preparation of the present invention ensures superior disintegration properties and excellent solubility, leading to sufficient absorbability of the active ingredient through the gastrointestinal tract. The pharmaceutical solid preparation of the present invention therefore serves many uses in the medical field. The production method of the present invention provides the pharmaceutical solid preparation with such superior characteristics.