Freeze Dried Drug Nanosuspensions

Abstract

The present invention relates to a freeze-dried (also called lyophilized) drug nanosuspension. The present freeze-dried drug nanosuspension composition has an acceptable stability of the particle size distribution during storage, including long term storage.

1 . A freeze-dried nanosuspension comprising a drug and a steric stabilizer which is a solid at room temperature. 
     
     
         2 . A freeze-dried nanosuspension as claimed in  claim 1  wherein the steric stabilizer is a crystalline solid at room temperature. 
     
     
         3 . A freeze-dried nanosuspension as claimed in  claim 1  wherein the steric stabilizer is an amorphous solid at room temperature. 
     
     
         4 . A freeze-dried nanosuspension as claimed in  claim 1  wherein the steric stabilizer is selected from a polymer or a surfactant. 
     
     
         5 . A freeze-dried nanosuspension as claimed in  claim 4  wherein the steric stabilizer is a surfactant. 
     
     
         6 . A freeze-dried nanosuspension as claimed in  claim 5  wherein the surfactant is a poloxamer. 
     
     
         7 . A freeze-dried nanosuspension as claimed in  claim 6  wherein the poloxamer is poloxamer 338. 
     
     
         8 . A freeze-dried nanosuspension as claimed in  claim 1  further comprising a cryoprotectant. 
     
     
         9 . A freeze-dried nanosuspension as claimed in  claim 8  wherein the cryoprotectant is selected from polyvinyl pyrrolidone, sucrose, trehalose. 
     
     
         10 . A freeze-dried nanosuspension as claimed in  claim 9  wherein the cryoprotectant is polyvinyl pyrrolidone. 
     
     
         11 . A freeze-dried nanosuspension as claimed in  claim 1  wherein the drug is a slightly soluble, very slightly soluble or practically insoluble drug. 
     
     
         12 . A freeze-dried nanosuspension as claimed in  claim 11  wherein the drug is 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A freeze-dried nanosuspension as claimed in  claim 12  wherein the drug is 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile base. 
     
     
         14 . A freeze-dried nanosuspension as claimed in  claim 12  wherein the drug is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile. 
     
     
         15 . An aqueous nanosuspension obtained by reconstituting a freeze-dried nanosuspension as claimed in  claim 1  with an aqueous dispersion medium. 
     
     
         16 . An aqueous nanosuspension obtained by reconstituting a freeze-dried nanosuspension according to  claim 1  with an aqueous dispersion medium, wherein the reconstituted nanosuspension comprises by weight based on the total volume of the composition:
 (a) from 3% to 50% (w/v), or from 10% to 40% (w/v), or from 10% to 30% (w/v), or 10% (w/v), or 20% (w/v), or 30% (w/v) of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, in particular of rilpivirine; 
 (b) from 0.5% to 10%, or from 0.5% to 2% (w/v), or 3% (w/v), or 5% (w/v) of a steric stabilizer according to the present invention, e.g. a poloxamer, e.g. poloxamer 338; 
 (c) from 0 to 20% (w/v), or from 0 to 10% (w/v), or 5% (w/v) of a cryoprotectant or lyoprotectant, e.g. PVP; 
 (d) from 0% to 10%, or from 0% to 5%, or from 0% to 2%, or from 0% to 1% of one or more buffering agents; 
 (e) from 0% to 10%, or from 0% to 6% (w/v) of an isotonizing agent 
 (f) from 0% to 2% (w/v) preservatives; and 
 (g) water for injection q.s. ad 100%. 
 
     
     
         17 . The aqueous nanosuspension as claimed in  claim 16  comprising rilpivirine. 
     
     
         18 . A process for preparing an aqueous nanosuspension characterized by reconstituting the freeze-dried nanosuspension according to  claim 1  with an aqueous dispersion medium. 
     
     
         19 . A pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, in the form of a reconstituted nanosuspension of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; in a pharmaceutically acceptable aqueous carrier; wherein the nanosuspension is reconstituted from a freeze-dried nanosuspension comprising:
 (a) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]-amino]benzonitrile or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; and   (b) a steric stabilizer which is a solid at room temperature; and   (c) optionally a cryoprotectant or lyoprotectant.   
     
     
         20 . The pharmaceutical composition as claimed in  claim 19  comprising rilpivirine. 
     
     
         21 . The pharmaceutical composition as claimed in  claim 20  comprising poloxamer 338.