Pharmaceutical composition containing tacrolimus and preparation methods thereof

Abstract

Disclosed are a pharmaceutical composition comprising tacrolimus and a preparation method thereof.

1 . A tacrolimus pharmaceutical composition, which comprises the active pharmaceutical ingredient tacrolimus and pharmaceutically acceptable fillers, adhesives, disintegrants, lubricants, wherein the pharmaceutical composition further comprises a crystallization inhibitor, wherein the mass ratio of tacrolimus to the crystallization inhibitor is 1:0.5 to 1:2.5. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the crystallization inhibitor is polyvinyl pyrrolidone or hydroxypropyl methylcellulose. 
     
     
         3 . The pharmaceutical composition according to  claim 2 , wherein the crystallization inhibitor is hydroxypropyl methylcellulose. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the filler is selected from the group consisting of sucrose, mannitol, lactose, starch and microcrystalline cellulose. 
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein the filler is lactose. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the disintegrant is selected from the group consisting of cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethylcellulose and low substituted hydroxypropyl cellulose. 
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein the disintegrant is cross-linked sodium carboxymethylcellulose. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein lubricant is selected from the group consisting of stearic acid, magnesium stearate, polyethylene glycol 6000 and castor oil hydrogenated. 
     
     
         9 . The pharmaceutical composition according to  claim 8 , wherein the lubricant is magnesium stearate. 
     
     
         10 . A method of preparing the pharmaceutical composition according to  claim 1 , comprising:
 (1) preparing a solution: dissolving the tacrolimus in ethanol and obtaining a clear solution,   (2) preparing premixed excipients: mixing the crystallization inhibitor, the disintegrant and the filler homogeneously using a wet granulating machine and obtaining premixed excipients,   (3) preparing soft materials: mixing the solution obtained in procedure (1) and the premixed excipients obtained in procedure (2) using a wet granulating machine and obtaining soft materials by wet granulation,   (4) drying the soft materials in a vacuum oven at 50° C. and granulating by forcing the soft materials through a 40-mesh sieve using a granulating machine, and   (5) adding the filler and lubricant into the granulated mass, mixing homogeneously, and filling in hard capsule shells.   
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the crystallization inhibitor is polyvinyl pyrrolidone or hydroxypropyl methylcellulose; the filler is selected from the group consisting of sucrose, mannitol, lactose, starch and microcrystalline cellulose; the disintegrant is selected from the group consisting of cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethylcellulose and low substituted hydroxypropyl cellulose; and the lubricant is selected from the group consisting of stearic acid, magnesium stearate, polyethylene glycol 6000 and castor oil hydrogenated. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the crystallization inhibitor is hydroxypropyl methylcellulose; the filler is lactose; the disintegrant is cross-linked sodium carboxymethylcellulose; and the lubricant is magnesium stearate. 
     
     
         13 . A method of preparing the pharmaceutical composition according to  claim 12 , comprising:
 (1) preparing a solution: dissolving the tacrolimus in ethanol and obtaining a clear solution,   (2) preparing premixed excipients: mixing hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose and lactose homogeneously using a wet granulating machine and obtaining premixed excipients,   (3) preparing soft materials: mixing the solution obtained in procedure (1) and the premixed excipients obtained in procedure (2) using a wet granulating machine and obtaining soft materials by wet granulation,   (4) drying the soft materials in a vacuum oven at 50° C. and granulating by forcing the soft materials through a 40-mesh sieve using a granulating machine, and   (5) adding lactose and magnesium stearate into the granulated mass, mixing homogeneously, and filling in hard capsule shells.