Method and composition for pharmaceutical product

Abstract

This invention is directed to a composition comprising dry granulated tenofovir DF and emtricitabine, and a method for making same. Dry granulation was unexpectedly found to be important in preparing a tenofovir DF containing composition suitable for inclusion in a combination dosage form containing emtricitabine, efavirenz and tenofovir DF.

1 . A composition comprising dry granulated emtricitabine and tenofovir DF.  
   
   
       2 . The composition of  claim 1  wherein the water content (Karl Fischer) is about from 0.1 to 10% by weight.  
   
   
       3 . The composition of  claim 1  wherein the bulk density of the granules is about from 0.1 to 1 g/mL.  
   
   
       4 . The composition of  claim 1  wherein the geometric mean diameter of the granules is about from 50 to 800 micrometers.  
   
   
       5 . The composition of  claim 1  further comprising a pharmaceutically acceptable disintegrant.  
   
   
       6 . The composition of  claim 5  wherein the disintegrant is croscarmellose sodium or crospovidone.  
   
   
       7 . The composition of  claim 1  further comprising a pharmaceutically acceptable filler.  
   
   
       8 . The composition of  claim 1  further comprising a pharmaceutically acceptable binder.  
   
   
       9 . The composition of  claim 1  further comprising a pharmaceutically acceptable lubricant.  
   
   
       10 . The composition of  claim 1  as a unitary dosage form.  
   
   
       11 . The composition of  claim 10  which is a tablet.  
   
   
       12 . The composition of  claim 1  wherein the amount of emtricitabine and tenofovir DF is greater than about 70% by weight of the granules.  
   
   
       13 . The composition of  claim 12  wherein the amount of emtricitabine and tenofovir DF is about 77% by weight of the granules.  
   
   
       14 . The composition of  claim 1  which further comprises at least one pharmaceutically acceptable excipient.  
   
   
       15 . The composition of  claim 1  comprising (by approximate weight percent) emtricitabine 30.6, tenofovir DF 46.0, microcrystalline cellulose 13.7, croscarmelose sodium 7.3 and magnesium stearate 2.2.  
   
   
       16 . The composition of  claim 1  wherein the LOD is about 10%.  
   
   
       17 . A method comprising granulating a composition comprising emtricitabine and tenofovir DF without contacting the composition with a destabilizing amount of liquid water.  
   
   
       18 . The method of  claim 17  wherein liquid water is not combined with the composition prior to or during granulation.  
   
   
       19 . The method of  claim 17  wherein the composition further comprises at least one pharmaceutically acceptable excipient.  
   
   
       20 . The method of  claim 17  wherein granulation comprises aggregating the composition and comminuting it to desired dimensions.  
   
   
       21 . The method of  claim 20  wherein the aggregation is accomplished by slugging or roller compaction.  
   
   
       22 . The method of  claim 20  wherein the composition is sieved to recover granules of the desired dimensions.  
   
   
       23 . The method of  claim 22  wherein the granules are retained by a 1.25 mm mesh.  
   
   
       24 . The method of  claim 19  wherein the excipient is a lubricant.  
   
   
       25 . The method of  claim 24  wherein the lubricant is an alkali metal salt of a C8-C18 fatty acid.  
   
   
       26 . A unitary dosage form made by a process comprising dry granulation of a composition comprising emtricitabine and tenofovir DF.  
   
   
       27 . A composition comprising greater than about 75% by weight emtricitabine and tenofovir DF.  
   
   
       28 . A composition comprising granules comprising tenofovir DF, emtricitabine and croscarmellose sodium in an extragranular matrix also comprising croscarmellose sodium.  
   
   
       29 . A method for antiviral therapy comprising administering an antivirally effective amount of the composition of  claim 1  to a patient in need of antiviral therapy.  
   
   
       30 . The method of  claim 29  wherein the antiviral therapy is anti-HIV therapy.