Patent Publication Number: US-2023135963-A1

Title: Anti-arrhythmic pharmaceutical composition and preparation method therefor

Description:
TECHNICAL FIELD 
     The present application belongs to the field of pharmaceutical preparations, and particularly relates to an anti-arrhythmic pharmaceutical composition and a preparation method thereof. 
     BACKGROUND 
     Sudden cardiac death (SCD) is one of the main causes of death from cardiovascular diseases. SCD will be caused if regular heart rhythm disappears due to the instability of cardiac electrophysiology. The most serious ones are persistent ventricular tachycardia and ventricular fibrillation. 
     Patent ZL200710181295.7 discloses 1-(3-methanesulfonamido benzyl)-6-methoxy, 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline (hereinafter referred to as compound A) or a salt thereof. The compound A is known to be a class III anti-arrhythmic drug, can prolong action potential duration, and is effective to ventricular tachycardia and ventricular fibrillation. 
     SUMMARY 
     An objective of the present application is to provide an anti-arrhythmic pharmaceutical composition with high stability and rapid dissolution, and a preparation method thereof. Specifically, the pharmaceutical composition provided by the present application includes: 
     an active ingredient, including 1-(3-methanesulfonamido benzyl)-6-methoxy, 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof; and 
     auxiliary materials, including lactose, microcrystalline cellulose and a pre-gelatinized starch, which account for 30% to 80% of the total weight of the composition. 
     Further, the lactose, the microcrystalline cellulose and the pre-gelatinized starch account for 40% to 60% of a total weight of the composition. 
     Preferably, a weight ratio of the lactose to the microcrystalline cellulose to the pre-gelatinized starch is 1:(1.8-2.2):(0.9-1.1). Preferably, the weight ratio is 1:(1.9-2.1):(0.9-1.1). More preferably, the weight ratio is 1:2:1. 
     Further, the pharmaceutical composition further includes a disintegrating agent, wherein the disintegrating agent is selected from at least one of carboxymethyl starch sodium, croscarmellose sodium, low-substituted hydroxypropyl cellulose and crospovidone. 
     Further, the disintegrating agent content is 1%-30% of the total weight of the composition, preferably, 2%-20%, more preferably, 2.5%-4%. 
     Further, the pharmaceutical composition further includes a lubricant, wherein 
     the lubricant is selected from at least one of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, superfine silica powder, talcum powder and colloidal silicon dioxide, preferably, at least one of magnesium stearate and colloidal silicon dioxide. 
     Specifically, the lubricant content is 0.5%-5% of the total weight of the composition, preferably, 0.7%. 
     Specifically, the pharmaceutical composition may be a granule, tablet or capsule obtained after the active ingredient and the auxiliary materials are subjected to mixing granulation and drying processes. 
     Further, the active ingredient content is 5%-70% of the total weight of the composition, preferably, 10%-50%, more preferably, 20%-45%. When the pharmaceutical composition is a tablet, the specific weight of the active ingredient content per tablet is 0.1-1000 mg, preferably, 10-500 mg, more preferably, 50-300 mg, further preferably, 100 mg. 
     Further, the pharmaceutically acceptable salt may be hydrochloride or phosphate. 
     Further, the pharmaceutical composition further includes an adhesive, wherein 
     the adhesive is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone and methylcellulose; and the adhesive content is 0.5%-10% of the total weight of the composition, preferably, 0.9%. 
     More preferably, the prescription weight ratio of the pharmaceutical composition is as follows: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Ingredients 
                 Dosage 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Compound B 
                 43.6 
               
               
                   
                 Lactose 
                 13.2 
               
               
                   
                 Microcrystalline cellulose 
                 26.4 
               
               
                   
                 Pre-gelatinized starch 
                 13.2 
               
               
                   
                 Croscarmellose sodium 
                 2.9 
               
               
                   
                   
               
            
           
         
       
     
     The compound B is phosphate of the compound A. 
     The present application further provides an application of the pharmaceutical composition as described in any one of the above to anti-arrhythmic therapy. 
     The present application further provides a method for preparing the pharmaceutical composition as described above. The method includes: 
     a) mixing and sieving an active ingredient, lactose, microcrystalline cellulose and a pre-gelatinized starch; 
     b) performing wet granulation; 
     c) drying; and 
     d) performing granulation arrangement and total mixing. 
     Specifically, the drying adopts static drying or fluidized drying. 
     Specifically, the granulation method adopts a high-speed shearing granulation method or a fluidized bed spray granulation method. 
     Further, when the pharmaceutical composition is selected from a tablet, the method further includes: 
     weighing 43.6 parts by weight of 1-(3-methanesulfonamido benzyl)-6-methoxy, 7-benzyloxy-1,2,3,4-tetrahydroisoquinoline phosphate, 13.2 parts by weight of lactose, 26.4 parts by weight of microcrystalline cellulose and 13.2 parts by weight of pre-gelatinized starch, mixing the materials uniformly and screening the materials with an 80-mesh sieve; 
     adding a 75% ethanol solution with 3% hydroxypropyl methylcellulose to prepare a soft material, and screening the material with a 20-mesh sieve for granulation; 
     performing air-blowing drying at 50° C. by using a hot air circulation oven; 
     performing granule arrangement by using a 20-mesh sieve; 
     adding 2.9 parts of croscarmellose sodium and 0.7 part of magnesium stearate into dry granules after granule arrangement; and 
     tableting. 
     According to the present application, the pharmaceutical composition with the characteristics of rapid dissolution and high stability is finally obtained by screening the types and the dosage ratio of the auxiliary materials. Under the condition of 0.01 mol/L hydrochloric acid medium, the dissolution rate (%) of the active ingredient in the pharmaceutical composition reaches 80% or higher in 30 minutes. Furthermore, the pharmaceutical composition is simple in preparation process and is more suitable for industrialized mass production. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    is a dissolution curve of a pharmaceutical composition according to the present application taking water as a dissolution medium; 
         FIG.  2    is a dissolution curve of a pharmaceutical composition according to the present application taking 0.01 mol/L Hydrochloric acid as a dissolution medium; 
         FIG.  3    is a dissolution curve of a pharmaceutical composition according to the present application taking acetic acid buffer salt with the pH of 4.0 as a dissolution medium; and 
         FIG.  4    is a dissolution curve of a pharmaceutical composition according to the present application taking phosphoric acid buffer salt with the pH of 6.8 as a dissolution medium. 
     
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
     The study found that when a pharmaceutical composition was prepared from a compound A and a salt thereof, a drug was decomposed under the condition of moisture and heat, and the pharmaceutical composition absorbs moisture to reduce the dissolution rate of the drug, thereby bringing difficulties to the industrialized mass production of preparations. Accordingly, the present application provides an anti-arrhythmic pharmaceutical composition with high stability and rapid dissolution, and a preparation method thereof. 
     The present application is further described below by the following embodiments and test examples. The embodiments and test examples are only used to illustrate the objective, but not to limit the scope of the present application. 
     1. Selecting the Types of Filling Agents 
     Phosphate of a compound A (hereinafter referred to as compound B), lactose, microcrystalline cellulose and pregelatinized starch were subjected to wet granulation according to a ratio in Table 1, granulation and drying were performed by taking a 3% hydroxypropyl methylcellulose (50 cp) in 60% ethanol solution as an adhesive, then dry granules (the moisture content is less than 3%) were subjected to granule arrangement, the prescription amount of croscarmellose sodium and magnesium stearate were added for mixing, and tableting was performed after uniform mixing according to the standard that each tablet contains 100 mg of compound B. The dissolution rate was measured by using 1000 ml of 0.01 mol/L hydrochloric acid solution according to the second method (slurry method) for determining the dissolution rate in Appendix 0931, Volume IV, Chinese Pharmacopoeia, 2015 (the same below). 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Investigating the types of filling agents 
               
            
           
           
               
            
               
                 Names of 
               
            
           
           
               
               
            
               
                 Raw and 
                 Types of Filling Agents (g) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Auxiliary 
                 Prescrip- 
                 Prescrip- 
                 Prescrip- 
                 Prescrip- 
                 Prescrip- 
                 Prescrip- 
                 Prescrip- 
                 Prescrip- 
                 Prescrip- 
               
               
                 Materials 
                 tion 1 
                 tion 2 
                 tion 3 
                 tion 4 
                 tion 5 
                 tion 6 
                 tion 7 
                 tion 8 
                 tion 9 
               
               
                   
               
               
                 Compound 
                 6.1 
                 6.1 
                 6.1 
                 6.1 
                 6.1 
                 6.1 
                 6.1 
                 6.1 
                 6.1 
               
               
                 B 
               
               
                 Lactose 
                 3.7 
                 2.5 
                 4.9 
                 3.7 
                 2.5 
                 4.9 
                 — 
                 — 
                 — 
               
               
                 Microcrystalline 
                 3.7 
                 4.9 
                 2.5 
                 — 
                 — 
                 — 
                 3.7 
                 2.5 
                 4.9 
               
               
                 cellulose 
               
               
                 Pregelatinized 
                 — 
                 — 
                 — 
                 3.7 
                 4.9 
                 2.5 
                 3.7 
                 4.9 
                 2.5 
               
               
                 starch 
               
               
                 60% 
                 5.5 
                 5.2 
                 5.5 
                 5.5 
                 5.7 
                 5.4 
                 5.8 
                 6.0 
                 6.0 
               
               
                 ethanol 
               
               
                 solution 
               
               
                 with 3% 
               
               
                 hydroxypropyl 
               
               
                 methylcellulose 
               
               
                 (ml) 
               
               
                 Croscarmellose 
                 0.4 
                 0.4 
                 0.4 
                 0.4 
                 0.4 
                 0.4 
                 0.4 
                 0.4 
                 0.4 
               
               
                 sodium 
               
               
                 Magnesium 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 stearate 
               
            
           
           
               
            
               
                 Measuring items 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Granule 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
                 White 
               
               
                 character 
                 granule, 
                 granule, 
                 granule, 
                 granule, 
                 granule, 
                 granule, 
                 granule, 
                 granule, 
                 granule, 
               
               
                   
                 uniform 
                 uniform 
                 uniform 
                 uniform 
                 uniform 
                 uniform 
                 more 
                 more 
                 more 
               
               
                   
                 granular- 
                 granular- 
                 granular- 
                 granular- 
                 granular- 
                 granular- 
                 fine 
                 fine 
                 fine 
               
               
                   
                 ity, hard 
                 ity, hard 
                 ity, hard 
                 ity, hard 
                 ity, hard 
                 ity, hard 
                 powder 
                 powder 
                 powder 
               
               
                   
                 granule 
                 granule 
                 granule 
                 granule 
                 granule 
                 granule 
               
               
                 Sticking or 
                 Yes 
                 Yes 
                 Yes 
                 Yes 
                 Yes 
                 Yes 
                 No 
                 No 
                 No 
               
               
                 not 
               
               
                 Appearance 
                 Coarse 
                 Coarse 
                 Coarse 
                 Coarse 
                 Coarse 
                 Coarse 
                 Bright 
                 Bright 
                 Bright 
               
               
                   
                 surface 
                 surface 
                 surface 
                 surface 
                 surface 
                 surface 
                 and 
                 and 
                 and 
               
               
                   
                   
                   
                   
                   
                   
                   
                 clean 
                 clean 
                 clean 
               
               
                   
                   
                   
                   
                   
                   
                   
                 surface 
                 surface 
                 surface 
               
               
                 Dissolution 
                 Dispersed 
                 Dispersed 
                 Dispersed 
                 Dispersed 
                 Dispersed 
                 Dispersed 
                 Dispersed 
                 Dispersed 
                 Dispersed 
               
               
                 phenomenon 
                 in 5-10 
                 in 4-10 
                 in 5 
                 in 15 
                 in 15 
                 in 15 
                 in 4-6 
                 in 5 
                 in 3-5 
               
               
                   
                 minutes 
                 minutes 
                 minutes 
                 minutes 
                 minutes 
                 minutes 
                 minutes 
                 minutes 
                 minutes 
               
               
                 Dissolution 
                 92.09 
                 94.13 
                 92.34 
                 86.12 
                 83.13 
                 90.33 
                 95.40 
                 96.49 
                 96.28 
               
               
                 rate (%) 
               
               
                   
               
            
           
         
       
     
     Conclusion: in the prescriptions 1-6, the lactose-microcrystalline granules and the lactose-pre-gelatinized starch granules are excessively hard, and the amount of fine powder in the granules is less, so the appearance of the tablet is affected; the lactose-microcrystalline granules are disintegrated rapidly and have good dissolution rate, but are sticking; and the lactose-pre-gelatinized starch granules are disintegrated slowly, increase the dissolution rate with the increasing of the dosage of the lactose, but are sticking. In the prescriptions 7-9, the microcrystalline-pre-gelatinized starch is disintegrated rapidly and is not sticking, but the amount of fine powder is more. Therefore, the influence of the lactose, the microcrystalline cellulose and the pre-gelatinized starch with different proportions on the formability and dissolution rate of the tablet will be investigated. 
     2. Selecting the Proportions of Filling Agents 
     A compound B, lactose, microcrystalline cellulose and pre-gelatinized starch were subjected to wet granulation according to a ratio in Table 2, granulation and drying were performed by taking a 60% ethanol solution with 3% hydroxypropyl methylcellulose (50 cp) as an adhesive, then dry granules (the moisture content is less than 3%) were subjected to granule arrangement, the prescription amount of croscarmellose sodium and magnesium stearate were added for mixing, and tableting was performed after uniform mixing according to the standard that each tablet contains 100 mg of compound A. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Investigating the filling agents with different proportions 
               
            
           
           
               
               
            
               
                 Names of Raw and 
                 The proportions of the filling agents 
               
            
           
           
               
               
               
               
               
            
               
                 Auxiliary Materials 
                 Prescription 10 
                 Prescription 11 
                 Prescription 12 
                 Prescription 13 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Compound B (g) 
                 6.1 
                 6.1 
                 6.1 
                 6.1 
               
               
                 Lactose (g) 
                 2.5 
                 3.7 
                 1.85 
                 1.85 
               
               
                 Microcrystalline cellulose (g) 
                 2.5 
                 1.85 
                 3.7 
                 1.85 
               
               
                 Pre-gelatinized starch(g) 
                 2.5 
                 1.85 
                 1.85 
                 3.7 
               
               
                 60% ethanol solution containing 
                 6.0 
                 5.7 
                 5.8 
                 6.3 
               
               
                 3% hydroxypropyl methylcellulose 
               
               
                 (50 cp) (ml) 
               
               
                 Croscarmellose sodium (g) 
                 0.4 
                 0.4 
                 0.4 
                 0.4 
               
               
                 Magnesium stearate (g) 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
            
           
           
               
            
               
                 Measuring items 
               
            
           
           
               
               
               
               
               
            
               
                 Granule character 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                 granule, 
                 granule, 
                 granule, 
                 granule, 
               
               
                   
                 uniform 
                 uniform 
                 uniform 
                 uniform 
               
               
                   
                 granularity, 
                 granularity, 
                 granularity 
                 granularity 
               
               
                   
                 hard granules 
                 hard granules 
               
               
                 Sticking or not 
                 No 
                 No 
                 No 
                 No 
               
               
                 Appearance 
                 Coarse 
                 Coarse 
                 Flat 
                 Flat 
               
               
                   
                 surface 
                 surface 
                 surface 
                 surface 
               
               
                 Dissolution phenomenon 
                 — 
                 — 
                 Dispersed 
                 Dispersed 
               
               
                   
                   
                   
                 in 7 minutes 
                 in 12 minutes 
               
               
                   
               
            
           
         
       
     
     Conclusion: in the prescriptions 10 and 11, the lactose content is high, and the prepared granules are hard and have coarse surfaces; in the prescriptions 12 and 13, the granules are uniform and have flat and smooth surfaces; and in the prescription 12, the dissolution rate is high, the large proportion of the pre-gelatinized starch affects the disintegration and dissolution, so the prescription 12 is preferred. 
     3. Investigating the Types of Disintegrating Agents 
     A compound B, lactose, microcrystalline cellulose and pre-gelatinized starch were subjected to wet granulation according to a ratio in Table 3, granulation and drying were performed by taking a 75% ethanol solution with 3% hydroxypropyl methylcellulose (50 cp) as an adhesive, then dry granules (the moisture content is less than 3%) were subjected to granule arrangement, croscarmellose sodium/carboxymethyl starch sodium/crospovidone and magnesium stearate in Table 3 were added for mixing, and tableting was performed after uniform mixing according to the standard that each tablet contains 100 mg of compound A. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Investigating the disintegrating agents 
               
            
           
           
               
               
            
               
                 Names of Raw and 
                 Disintegrating agents 
               
            
           
           
               
               
               
               
            
               
                 Auxiliary Materials 
                 Prescription 14 
                 Prescription 15 
                 Prescription 16 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Compound B (g) 
                 6.1 
                 6.1 
                 6.1 
               
               
                 Lactose (g) 
                 1.85 
                 1.85 
                 1.85 
               
               
                 Microcrystalline cellulose (g) 
                 3.7 
                 3.7 
                 3.7 
               
               
                 Pre-gelatinized starch (g) 
                 1.85 
                 1.85 
                 1.85 
               
               
                 Magnesium stearate (g) 
                 0.1 
                 0.1 
                 0.1 
               
               
                 75% ethanol solution containing 
                 6.0 
                 6.0 
                 6.0 
               
               
                 3% hydroxypropyl methylcellulose 
               
               
                 (50 cp) 
               
               
                 Croscarmellose sodium (g) 
                 0.4 
                 — 
                 — 
               
               
                 Carboxymethyl starch sodium (g) 
                 — 
                 0.4 
                 — 
               
               
                 Crospovidone (g) 
                 — 
                 — 
                 0.4 
               
            
           
           
               
            
               
                 Measuring items 
               
            
           
           
               
               
               
               
            
               
                 Granule character 
                 White 
                 White 
                 White 
               
               
                   
                 granule, 
                 granule, 
                 granule, 
               
               
                   
                 uniform 
                 uniform 
                 uniform 
               
               
                   
                 granularity 
                 granularity 
                 granularity 
               
               
                 Sticking or not 
                 No 
                 No 
                 No 
               
               
                 Appearance 
                 Flat and 
                 Flat and 
                 Flat and 
               
               
                   
                 smooth 
                 smooth 
                 smooth 
               
               
                   
                 surface 
                 surface 
                 surface 
               
               
                 Dissolution phenomenon 
                 All dispersed 
                 All dispersed 
                 All dispersed 
               
               
                   
                 in 5 
                 in 12 
                 in 7 
               
               
                 Dissolution rate (%) 
                 95.79 
                 90.81 
                 94.15 
               
               
                   
               
            
           
         
       
     
     Conclusion: according to the granule character, the dissolution phenomenon and the dissolution rate results, the prescription 14 is preferred. The dosage of the filling agents is further screened on the basis of determining the disintegrating agent. 
     4. Selecting the Dosage of the Filling Agents 
     A compound B, lactose, microcrystalline cellulose and pre-gelatinized starch were subjected to wet granulation according to a ratio in Table 4, granulation and drying were performed by taking a 75% ethanol solution with 3% hydroxypropyl methylcellulose (50 cp) as an adhesive, then dry granules (the moisture content is less than 3%) were subjected to granule arrangement, croscarmellose sodium and magnesium stearate were added for mixing, and tableting was performed after uniform mixing according to the standard that each tablet contains 100 mg of compound A. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Selecting the dosage of the filling agents 
               
            
           
           
               
               
            
               
                 Names of Raw and 
                 Filling agents 
               
            
           
           
               
               
               
               
               
            
               
                 Auxiliary Materials 
                 Prescription 17 
                 Prescription 18 
                 Prescription 19 
                 Prescription 20 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Compound B (g) 
                 6.1 
                 6.1 
                 6.1 
                 6.1 
               
               
                 Lactose (g) 
                 1.85 
                 1.85 
                 2.05 
                 1.15 
               
               
                 Microcrystalline cellulose (g) 
                 3.0 
                 4.4 
                 3.3 
                 4.4 
               
               
                 Pre-gelatinized starch(g) 
                 2.55 
                 1.15 
                 2.05 
                 1.85 
               
               
                 Croscarmellose sodium (g) 
                 0.4 
                 0.4 
                 0.4 
                 0.4 
               
               
                 Magnesium stearate (g) 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 75% ethanol solution containing 
                 6.3 
                 6.0 
                 6.0 
                 6.0 
               
               
                 3% hydroxypropyl methylcellulose 
               
               
                 (50 cp) 
               
            
           
           
               
            
               
                 Measuring items 
               
            
           
           
               
               
               
               
               
            
               
                 Granule character 
                 White 
                 White 
                 White 
                 White 
               
               
                   
                 granule, 
                 granule, 
                 granule, 
                 granule, 
               
               
                   
                 uniform 
                 uniform 
                 uniform 
                 uniform 
               
               
                   
                 granularity 
                 granularity 
                 granularity 
                 granularity 
               
               
                 Sticking or not 
                 No 
                 No 
                 No 
                 No 
               
               
                 Appearance 
                 Flat and 
                 The surface is 
                 Flat and 
                 The surface is 
               
               
                   
                 smooth 
                 uneven and 
                 smooth 
                 uneven and 
               
               
                   
                 surface 
                 easy to crack 
                 surface 
                 easy to crack 
               
               
                 Dissolution phenomenon 
                 All dispersed 
                 / 
                 All dispersed 
                 / 
               
               
                   
                 in 7 minutes 
                   
                 in 5 minutes 
               
               
                 Dissolution rate (%) 
                 89.4 
                 / 
                 93.22 
                 / 
               
               
                   
               
            
           
         
       
     
     Result: according to the granule character, the dissolution phenomenon and the dissolution rate results, the prescription 14 is preferred. 
     Two batches of samples (500 tablets in each batch) were prepared respectively according to the prescriptions 14 and 19, and were placed for 30 days under the conditions of high temperature (60° C.), high humidity (75% RH) and illumination (4500 Lx). The result of the influence factor test shows that the dissolution rate, related materials and content in the prescriptions 14 and 19 have no obvious changes under the conditions of high temperature and illumination, but under the condition of high humidity, the appearance of the tablet in the prescription 19 is slightly swelled and the dissolution rate in the prescription 19 is obviously reduced compared with the tablet in the prescription 14. 
     Conclusion: by the above prescription screening and influence factor test, the prescription 14 has good granule fluidity, tablet appearance, dissolution phenomenon, dissolution rate and stability, so the prescription 14 is determined as the preferred prescription. 
     According to the preliminarily determined prescription 14, three batches compound B tablets were prepared, with batch number: batch A, batch B and batch C, 3000 tablets in each batch. The quality was studied. After study on the quality of the preparation was completed, three batches of compound B tablets were prepared, with batch number: batch 1, batch 2 and batch 3, 10000 tablets in each batch. The stability was studied. 
     5. Prescription and Preparation Process 
     Prescription: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Ingredients 
                 Dosage 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Compound B 
                 43.6 
               
               
                   
                 Lactose 
                 13.2 
               
               
                   
                 Microcrystalline cellulose 
                 26.4 
               
               
                   
                 Pre-gelatinized starch 
                 13.2 
               
               
                   
                 Croscarmellose sodium 
                 2.9 
               
               
                   
                 Hydroxypropyl methylcellulose 
                 — 
               
               
                   
                 Magnesium stearate 
                 0.7 
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
               
                   
                 Unit: mass % 
               
            
           
         
       
     
     Preparation Process: 
     {circle around (1)} Pretreatment 
     A compound B, lactose, microcrystalline cellulose and pre-gelatinized starch were mixed uniformly, and the mixture was sieved with a 80-mesh sieve for future use. 
     {circle around (2)} Granulation 
     A 75% ethanol solution with 3% hydroxypropyl methylcellulose (50 cp) was added into the pretreated raw and auxiliary materials to prepare a soft material, and the soft material was sieved with a 20-mesh sieve for granulation. 
     {circle around (3)} Drying 
     Air-blowing drying was performed at 50° C. by using a hot air circulation oven, and the granules were turned every half hour. The moisture content was measured by a fast moisture determination instrument, drying was finished when the moisture was 2.0%-3.0%, and materials were collected. 
     {circle around (4)} Granule Arrangement 
     Granule arrangement was performed by a 20-mesh sieve. 
     {circle around (5)} Total Mixing 
     Croscarmellose sodium and magnesium stearate were added into dry granules after granule arrangement, and the croscarmellose sodium, the magnesium stearate and the dry granules were mixed in a material bag for 5 minutes. 
     {circle around (6)} Tableting 
     A 13 mm×6.5 mm elliptic mold tablet press was adopted, tablet weight control: the weight difference should be controlled to be ±5.0%, and the friability should be less than 0.7%. 
     {circle around (7)} Coating 
     The weight gain of the coating was about 3%. 
     {circle around (8)} Packaging with a white plastic bottle 
     Sealing was performed by an electromagnetic induction aluminum foil sealing machine, with tight aluminum seal and neat appearance. 
     6. Quality Inspection Data 
     Three batches of pilot-scale samples (10000 tablets in each batch) were prepared according to the above process. See Table 5 for the test result of the main items. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 The test result of the main items of the compound B 
               
            
           
           
               
               
               
               
            
               
                 Inspection items 
                 Batch 1 
                 Batch 2 
                 Batch 3 
               
               
                   
               
               
                 [Character] 
                 This product is a film-coated 
                 This product is a film-coated 
                 This product is a film-coated 
               
               
                   
                 tablet, which appears white 
                 tablet, which appears white 
                 tablet, which appears white 
               
               
                   
                 after the coating is removed. 
                 after the coating is removed. 
                 after the coating is removed. 
               
               
                 [Authentication] 
                 Consistent with the relative 
                 Consistent with the relative 
                 Consistent with the relative 
               
               
                   
                 retention time of the 
                 retention time of the 
                 retention time of the 
               
               
                   
                 reference solution 
                 reference solution 
                 reference solution 
               
            
           
           
               
            
               
                 [Inspection] 
               
               
                 Related substances 
               
            
           
           
               
               
               
               
            
               
                 1-OX 
                 0.03% 
                 0.03% 
                 0.03% 
               
               
                 Compound 14 
                 0.06% 
                 0.06% 
                 0.06% 
               
               
                 Other largest single impurity 
                 0.08% 
                 0.08% 
                 0.08% 
               
               
                 Total impurity 
                 0.20% 
                 0.20% 
                 0.20% 
               
               
                 Dissolution rate 
                 101.7% 
                 101.5% 
                 102.1% 
               
               
                 Weight difference 
                 Conform to 
                 Conform to 
                 Conform to 
               
               
                   
                 specification 
                 specification 
                 specification 
               
               
                 [Content measurement] 
                 103.3% 
                 101.0% 
                 102.4% 
               
               
                   
               
            
           
         
       
     
     According to the test results of the main items of the three batches of samples, the process of this product is stable. 
     7. Related Characteristics of the Preparation 
     (1) Dissolution Curve 
     The dissolution rate was measured according to the second method (slurry method) for determining the dissolution rate in Appendix 0931, Volume IV, Chinese Pharmacopoeia, 2015, 1000 ml of 0.01 mol/L hydrochloric acid solution, acetic acid buffer salt with the pH 4.0, phosphoric acid buffer salt with the pH 6.8 and water were taken as dissolution mediums, and dissolution test was performed at 37.0±0.5° C. and at the propeller speed of 50 rpm. The dissolution curves of four batches of preparation in different dissolution mediums were compared. 
     The dissolution curve graphs of the four dissolution mediums are attached. By taking the 0.01 mol/L hydrochloric acid solution, acetic acid buffer salt with the pH 4.0, phosphoric acid buffer salt with the pH 6.8 as the dissolution mediums, the dissolution rate of this product is over 85% in 15 minutes; and by taking the water as the dissolution medium, the dissolution rate is close to 85% in 15 minutes. 
     (2) Related Substances 
     The test results of three batches of related substances are shown in Table 6. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 The measured results of three batches of compounds B 
               
            
           
           
               
               
            
               
                   
                 Batch number 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Related substances (%) 
                 Batch 1 
                 Batch 2 
                 Batch 3 
               
               
                   
                   
               
               
                   
                 1-OX 
                 0.03% 
                 0.03% 
                 0.03% 
               
               
                   
                 Largest single impurity 
                 0.06% 
                 0.06% 
                 0.06% 
               
               
                   
                 Other largest single impurity 
                 0.08% 
                 0.08% 
                 0.08% 
               
               
                   
                 Total impurity 
                 0.20% 
                 0.20% 
                 0.20% 
               
               
                   
                   
               
            
           
         
       
     
     The properties of the raw materials of this product are stable, the raw and auxiliary materials in the preparation are good in compatibility, single impurity does not exceed 0.1%, and the related substances of three batches of preparations all conform to the specification. 
     (3) Stability 
     {circle around (1)} Influence Factor Test 
     Batch number: batch 1; batch: 10000 tablets; specification: 0.1 g; package: high-density polyethylene bottle for oral solid drugs 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 The investigation results of the influence factors 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Other 
                   
                   
                   
               
               
                   
                   
                   
                   
                 Largest 
                 largest 
               
               
                   
                   
                   
                   
                 single 
                 single 
                 Total 
                 Dissolu- 
               
               
                 Investigation 
                 Time 
                   
                 1-OX 
                 impurity 
                 impurity 
                 impurity 
                 tion rate 
                 Content 
               
               
                 target 
                 (day) 
                 Character 
                 (%) 
                 (%) 
                 (%) 
                 (%) 
                 (%) 
                 (%) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Quality 
                   
                 After the coating 
                 ≤0.2% 
                 ≤0.2% 
                 ≤0.2% 
                 ≤1.5% 
                 ≥80.0% 
                 It should 
               
               
                 standard 
                   
                 was removed, it 
                   
                   
                   
                   
                   
                 be 
               
               
                   
                   
                 should be white 
                   
                   
                   
                   
                   
                 90.0%- 
               
               
                   
                   
                 or off-white 
                   
                   
                   
                   
                   
                 110.0% 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 of the 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 labeled 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 amount 
               
               
                 60° C. 
                 0 
                 Conformity 
                 0.03 
                 0.06 
                 0.08 
                 0.20 
                 101.7 
                 103.3 
               
               
                 high-temper- 
                 5 
                 Conformity 
                 0.03 
                 0.08 
                 0.09 
                 0.22 
                 98.8 
                 102.8 
               
               
                 ature test 
                 10 
                 Conformity 
                 0.03 
                 0.07 
                 0.10 
                 0.22 
                 102.0 
                 102.6 
               
               
                   
                 30 
                 Conformity 
                 0.02 
                 0.07 
                 0.11 
                 0.24 
                 94.0 
                 103.1 
               
               
                 4500 Lx 
                 0 
                 Conformity 
                 0.03 
                 0.06 
                 0.08 
                 0.20 
                 101.7 
                 103.3 
               
               
                 strong 
                 5 
                 Conformity 
                 0.02 
                 0.07 
                 0.09 
                 0.21 
                 99.7 
                 103.2 
               
               
                 illumina- 
                 10 
                 Conformity 
                 0.03 
                 0.07 
                 0.09 
                 0.22 
                 102.7 
                 103.3 
               
               
                 tion test 
                 30 
                 Conformity 
                 0.02 
                 0.07 
                 0.10 
                 0.22 
                 96.4 
                 102.7 
               
               
                 90% RH 
                 0 
                 Conformity 
                 0.03 
                 0.06 
                 0.08 
                 0.20 
                 101.7 
                 103.3 
               
               
                 high-humid- 
                 5 
                 Conformity 
                 0.03 
                 0.08 
                 0.09 
                 0.23 
                 99.9 
                 103.5 
               
               
                 ity test 
                 10 
                 Conformity 
                 0.03 
                 0.07 
                 0.10 
                 0.22 
                 101.9 
                 102.4 
               
               
                   
                 30 
                 Conformity 
                 0.03 
                 0.07 
                 0.10 
                 0.23 
                 95.3 
                 102.9 
               
               
                   
               
            
           
         
       
     
     Conclusion: the test results of the compound B tablets under the conditions of high temperature, high humidity and illumination for 0, 5, 10 and 30 days: the sample character, the related substances, the dissolution rate and the content have no significant changes compared with those in 0 day. 
     {circle around (2)} Acceleration Test 
     Batch number: batch 1; batch: 10000 tablets; specification: 0.1 g; package: high-density polyethylene bottle for oral solid drugs; and investigation conditions: 40° C.±2° C. and RH75%±5%. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Acceleration stability investigation-batch 1 
               
            
           
           
               
               
            
               
                 Investigation 
                 Time (month) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 items 
                 Limit requirement 
                 0 
                 1 
                 2 
                 3 
                 6 
               
               
                   
               
               
                 Character 
                 After the coating was 
                 After the 
                 After the 
                 After the 
                 After the 
                 After the 
               
               
                   
                 removed, it should be 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
               
               
                   
                 white or off-white 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
               
               
                   
                   
                 should be 
                 should be 
                 should be 
                 should be 
                 should be 
               
               
                   
                   
                 white 
                 white 
                 white 
                 white 
                 white 
               
               
                 Related 
                 The debenzylated 
                 Not 
                 Not 
                 Not 
                 Not 
                 Not 
               
               
                 substances 
                 impurity should be 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
               
               
                 (%) 
                 less than or equal to 
               
               
                   
                 0.2% 
               
               
                   
                 1-OX should be less 
                 0.03 
                 0.03 
                 0.03 
                 0.03 
                 0.03 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 The compound 14 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.05 
               
               
                   
                 should be less than or 
               
               
                   
                 equal to 0.2% 
               
               
                   
                 Other largest single 
                 0.08 
                 0.09 
                 0.09 
                 0.09 
                 0.06 
               
               
                   
                 impurity should be 
               
               
                   
                 less than or equal to 
               
               
                   
                 0.2% 
               
               
                   
                 Total impurity should 
                 0.20 
                 0.21 
                 0.20 
                 0.22 
                 0.15 
               
               
                   
                 be less than or equal to 
               
               
                   
                 1.0% 
               
               
                 Dissolution 
                 should be greater than 
                 101.7 
                 103.5 
                 101.2 
                 101.8 
                 100.1 
               
               
                 rate (%) 
                 or equal to 80% 
               
               
                 Content (%) 
                 It should be 
                 103.3 
                 102.3 
                 102.2 
                 101.8 
                 102.1 
               
               
                   
                 90.0%-110.0% of the 
               
               
                   
                 labeled amount 
               
               
                   
               
            
           
         
       
     
     Batch number: batch 2; batch: 10000 tablets; specification: 0.1 g; package: high-density polyethylene bottle for oral solid drugs; and investigation conditions: 40° C.±2° C. and RH75%±5% 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Acceleration stability investigation-batch 2 
               
            
           
           
               
               
            
               
                 Investigation 
                 Time (month) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 items 
                 Limit requirement 
                 0 
                 1 
                 2 
                 3 
                 6 
               
               
                   
               
               
                 Character 
                 After the coating was 
                 After the 
                 After the 
                 After the 
                 After the 
                 After the 
               
               
                   
                 removed, it should be 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
               
               
                   
                 white or off-white 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
               
               
                   
                   
                 should be 
                 should be 
                 should be 
                 should be 
                 should be 
               
               
                   
                   
                 white 
                 white 
                 white 
                 white 
                 white 
               
               
                 Related 
                 The debenzylated 
                 Not 
                 Not 
                 Not 
                 Not 
                 Not 
               
               
                 substances 
                 impurity should be less 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
               
               
                 (%) 
                 than or equal to 0.2% 
               
               
                   
                 1-OX should be less 
                 0.03 
                 0.03 
                 0.03 
                 0.03 
                 0.03 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 The largest single 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Other largest single 
                 0.08 
                 0.08 
                 0.08 
                 0.10 
                 0.08 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Total impurity should 
                 0.20 
                 0.20 
                 0.20 
                 0.22 
                 0.17 
               
               
                   
                 be less than or equal to 
               
               
                   
                 1.0% 
               
               
                 Dissolution 
                 should be greater than 
                 101.5 
                 102.2 
                 98.0 
                 102.2 
                 100.1 
               
               
                 rate (%) 
                 or equal to 80% 
               
               
                 Content (%) 
                 It should be 
                 101.0 
                 100.4 
                 100.0 
                 100.3 
                 100.6 
               
               
                   
                 90.0%-110.0% of the 
               
               
                   
                 labeled amount 
               
               
                   
               
            
           
         
       
     
     Batch number: batch 3; batch: 10000 tablets; specification: 0.1 g; package: high-density polyethylene bottle for oral solid drugs; and investigation conditions: 40° C.±2° C. and RH75%±5% 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Acceleration stability investigation-batch 3 
               
            
           
           
               
               
            
               
                 Investigation 
                 Time (month) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 items 
                 Limit requirement 
                 0 
                 1 
                 2 
                 3 
                 6 
               
               
                   
               
               
                 Character 
                 After the coating was 
                 After the 
                 After the 
                 After the 
                 After the 
                 After the 
               
               
                   
                 removed, it should be 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
               
               
                   
                 white or off-white 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
               
               
                   
                   
                 should be 
                 should be 
                 should be 
                 should be 
                 should be 
               
               
                   
                   
                 white 
                 white 
                 white 
                 white 
                 white 
               
               
                 Related 
                 The debenzylated 
                 Not 
                 Not 
                 Not 
                 Not 
                 Not 
               
               
                 substances 
                 impurity should be less 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
               
               
                 (%) 
                 than or equal to 0.2% 
               
               
                   
                 1-OX should be less 
                 0.03 
                 0.03 
                 0.03 
                 0.03 
                 0.03 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 The largest single 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Other largest single 
                 0.08 
                 0.09 
                 0.09 
                 0.09 
                 0.08 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Total impurity should 
                 0.20 
                 0.20 
                 0.21 
                 0.21 
                 0.17 
               
               
                   
                 be less than or equal to 
               
               
                   
                 1.0% 
               
               
                 Dissolution 
                 should be greater than 
                 102.1 
                 102.7 
                 100.1 
                 103.9 
                 99.6 
               
               
                 rate (%) 
                 or equal to 80% 
               
               
                 Content (%) 
                 It should be 
                 102.4 
                 101.6 
                 101.4 
                 101.2 
                 101.8 
               
               
                   
                 90.0%-110.0% of the 
               
               
                   
                 labeled amount 
               
               
                   
               
            
           
         
       
     
     Conclusion: the results of the accelerated stability test of three batches of samples of the compound B tablets for 6 months show that: compared with those in 0 month, the character, related substances, dissolution rate and content of this product have not significant changes in each test indexes, indicating that the accelerated stability test results of this product are good. 
     {circle around (3)} Long-Term Test 
     Batch number: batch 1; batch: 10000 tablets; specification: 0.1 g; package: high-density polyethylene bottle for oral solid drugs; and investigation conditions: 30° C.±2° C. and RH65%±5% 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Long-term stability investigation-batch 1 
               
            
           
           
               
               
            
               
                 Investigation 
                 Time (month) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 items 
                 Limit requirement 
                 0 
                 3 
                 6 
                 9 
                 12 
               
               
                   
               
               
                 Character 
                 After the coating was 
                 After the 
                 After the 
                 After the 
                 After the 
                 After the 
               
               
                   
                 removed, it should be 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
               
               
                   
                 white or off-white 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
               
               
                   
                   
                 should be 
                 should be 
                 should be 
                 should be 
                 should be 
               
               
                   
                   
                 white 
                 white 
                 white 
                 white 
                 white 
               
               
                 Related 
                 The debenzylated 
                 Not 
                 Not 
                 Not 
                 Not 
                 Not 
               
               
                 substances 
                 impurity should be less 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
               
               
                 (%) 
                 than or equal to 0.2% 
               
               
                   
                 1-OX should be less 
                 0.03 
                 0.04 
                 0.03 
                 0.02 
                 0.04 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 The largest single 
                 0.06 
                 0.06 
                 0.07 
                 0.06 
                 0.06 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Other largest single 
                 0.08 
                 0.10 
                 0.09 
                 0.07 
                 0.09 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Total impurity should 
                 0.20 
                 0.23 
                 0.20 
                 0.16 
                 0.20 
               
               
                   
                 be less than or equal to 
               
               
                   
                 1.0% 
               
               
                 Dissolution 
                 should be greater than 
                 101.7 
                 100.2 
                 100.2 
                 101.7 
                 98.1 
               
               
                 rate (%) 
                 or equal to 80% 
               
               
                 Content (%) 
                 It should be 
                 103.3 
                 101.8 
                 102.1 
                 101.6 
                 101.4 
               
               
                   
                 90.0%-110.0% of the 
               
               
                   
                 labeled amount 
               
               
                   
               
            
           
         
       
     
     Batch number: batch 2; batch: 10000 tablets; specification: 0.1 g; package: high-density polyethylene bottle for oral solid drugs; and investigation conditions: 30° C.±2° C. and RH65%±5% 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Long-term stability investigation-batch 2 
               
            
           
           
               
               
            
               
                 Investigation 
                 Time (month) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 items 
                 Limit requirement 
                 0 
                 3 
                 6 
                 9 
                 12 
               
               
                   
               
               
                 Character 
                 After the coating was 
                 After the 
                 After the 
                 After the 
                 After the 
                 After the 
               
               
                   
                 removed, it should be 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
               
               
                   
                 white or off-white 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
               
               
                   
                   
                 should be 
                 should be 
                 should be 
                 should be 
                 should be 
               
               
                   
                   
                 white 
                 white 
                 white 
                 white 
                 white 
               
               
                 Related 
                 The debenzylated 
                 Not 
                 Not 
                 Not 
                 Not 
                 Not 
               
               
                 substances 
                 impurity should be less 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
               
               
                 (%) 
                 than or equal to 0.2% 
               
               
                   
                 1-OX should be less 
                 0.03 
                 0.03 
                 0.04 
                 0.03 
                 0.04 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 The largest single 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.09 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Other largest single 
                 0.08 
                 0.09 
                 0.08 
                 0.06 
                 0.09 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Total impurity should 
                 0.20 
                 0.22 
                 0.18 
                 0.16 
                 0.32 
               
               
                   
                 be less than or equal to 
               
               
                   
                 1.0% 
               
               
                 Dissolution 
                 should be greater than 
                 101.5 
                 101.7 
                 100.1 
                 101.9 
                 101.7 
               
               
                 rate (%) 
                 or equal to 80% 
               
               
                 Content (%) 
                 It should be 
                 101.0 
                 100.2 
                 100.5 
                 100.1 
                 100.1 
               
               
                   
                 90.0%-110.0% of the 
               
               
                   
                 labeled amount 
               
               
                   
               
            
           
         
       
     
     Batch number: batch 3; batch: 10000 tablets; specification: 0.1 g; package: high-density polyethylene bottle for oral solid drugs; and investigation conditions: 30° C.±2° C. and RH65%±5% 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Long-term stability investigation-batch 3 
               
            
           
           
               
               
            
               
                 Investigation 
                 Time (month) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 items 
                 Limit requirement 
                 0 
                 3 
                 6 
                 9 
                 12 
               
               
                   
               
               
                 Character 
                 After the coating was 
                 After the 
                 After the 
                 After the 
                 After the 
                 After the 
               
               
                   
                 removed, it should be 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
                 coating was 
               
               
                   
                 white or off-white 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
                 removed, it 
               
               
                   
                   
                 should be 
                 should be 
                 should be 
                 should be 
                 should be 
               
               
                   
                   
                 white 
                 white 
                 white 
                 white 
                 white 
               
               
                 Related 
                 The debenzylated 
                 Not 
                 Not 
                 Not 
                 Not 
                 Not 
               
               
                 substances 
                 impurity should be less 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
                 Detected 
               
               
                 (%) 
                 than or equal to 0.2% 
               
               
                   
                 1-OX should be less 
                 0.03 
                 0.03 
                 0.04 
                 0.03 
                 0.04 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 The largest single 
                 0.06 
                 0.06 
                 0.07 
                 0.05 
                 0.07 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Other largest single 
                 0.08 
                 0.09 
                 0.08 
                 0.06 
                 0.08 
               
               
                   
                 impurity should be less 
               
               
                   
                 than or equal to 0.2% 
               
               
                   
                 Total impurity should 
                 0.20 
                 0.21 
                 0.19 
                 0.15 
                 0.20 
               
               
                   
                 be less than or equal to 
               
               
                   
                 1.0% 
               
               
                 Dissolution 
                 should be greater than 
                 102.1 
                 101.3 
                 99.8 
                 101.1 
                 102.1 
               
               
                 rate (%) 
                 or equal to 80% 
               
               
                 Content (%) 
                 It should be 
                 102.4 
                 101.6 
                 101.3 
                 101.3 
                 101.5 
               
               
                   
                 90.0%-110.0% of the 
               
               
                   
                 labeled amount 
               
               
                   
               
            
           
         
       
     
     Conclusion: the results of the long-term stability test of three batches of samples of the compound B tablets for 12 months show that: compared with those in 0 month, the character, related substances, dissolution rate and content of this product have not significant changes in each test indexes, indicating that the long-term stability test results of this product are good. 
     Conclusion: the accelerated 6-month and long-term 12-month stability tests of three batches of samples of the compound B tablets of the present application show that: this product is sealed and stored under the proposed packaging conditions (high-density polyethylene bottle for oral solid drugs), which can ensure the good stability of the samples. 
     It should be noted that those skilled in the art may learn from the contents of the specification to appropriately improve process parameters, and all the similar substitutions and modifications are obvious to those skilled in the art and should be considered to be included in the present application.