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 μm, and a 90% cumulative particle diameter of 100 to 200 μm.

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 μm and a 90% cumulative particle diameter of 100 to 200 μm,   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 μm, and the 90% cumulative particle diameter of the (c) low substituted hydroxypropylcellulose is 150 to 200 μm. 
     
     
         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.