Pharmaceutical compositions comprising nebivolol or a nebivolol analogue

Abstract

The disclosed pharmaceutical compositions for oral administration comprising as the active medicinal ingredient nebivolol, a nebivolol analogue or a pharmaceutically acceptable acid addition salt thereof and a wetting agent. The ratio of the wetting agent to the active ingredient is less than 0.025. The application also relates to methods of preparing these compositions and using said compositions for treating coronary vascular disorders in humans.

1 . A pharmaceutical composition for oral administration comprising an active ingredient and a wetting agent, wherein the active ingredient is nebivolol, a nebivolol analogue or a pharmaceutically acceptable salt thereof, the wetting agent is not colloidal silicon dioxide and the ratio (w/w) of wetting agent to active ingredient is less than 0.025. 
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable salt of nebivolol is the hydrochloride salt. 
   
   
       3 . The pharmaceutical composition of  claim 2 , wherein the active ingredient is unmicronized. 
   
   
       4 . The pharmaceutical composition of  claim 1 , wherein the wetting agent consists of a polysorbate. 
   
   
       5 . The pharmaceutical composition of  claim 4 , wherein the polysorbate is polysorbate 80. 
   
   
       6 . The pharmaceutical composition of  claim 1 , which additionally comprises a filler, a binder, a disintegrant, a lubricant, a glidant or a mixture thereof. 
   
   
       7 . The pharmaceutical composition of  claim 6 , which comprises nebivolol hydrochloride and wherein the wetting agent is polysorbate 80, the filler is a spray dried mixture of microcrystalline cellulose and lactose and/or lactose monohydrate, the binder is hydroxypropylmethylcellulose, the disintegrant is corn starch and/or croscarmellose sodium, the lubricant is magnesium stearate and the glidant is colloidal silicon dioxide. 
   
   
       8 . The pharmaceutical composition of  claim 6  comprising, on a weight percentage basis, from about 0.5% to about 10% of nebivolol or a pharmaceutically acceptable salt thereof, from about 0.01% to about 0.04% of a wetting agent, from about 20% to about 80% of a filler, from about 1% to about 4% of a binder, from about 2% to about 30% of a disintegrant, from about 0.25% to about 2% of a lubricant and from about 0.1% to about 2% of a glidant. 
   
   
       9 . The pharmaceutical composition of  claim 7  comprising, on a weight percentage basis, from about 0.5% to about 10% of nebivolol hydrochloride, from about 0.01% to about 0.04% of polysorbate 80, from about 20% to about 80% of a spray dried mixture of microcrystalline cellulose and lactose and/or lactose monohydrate, from about 1% to about 4% of hydroxypropylmethylcellulose, from about 2% to about 30% of corn starch and/or croscarmellose sodium, from about 0.25% to about 2% of magnesium stearate and from about 0.1% to about 2% of colloidal silicon dioxide. 
   
   
       10 . The pharmaceutical composition of  claim 7  comprising, on a weight percentage basis, about 2.37% of nebivolol hydrochloride, about 0.03% of polysorbate 80, about 26.36% of a spray dried mixture of microcrystalline cellulose and lactose, about 43.48% of lactose monohydrate, about 2% of hydroxypropylmethylcellulose, about 20% of corn starch, about 5% of croscarmellose sodium, about 0.5% of magnesium stearate and about 0.26% of colloidal silicon dioxide. 
   
   
       11 . The pharmaceutical composition of  claim 1  in the form of a tablet. 
   
   
       12 . The pharmaceutical composition of  claim 11 , wherein the tablet exhibits a dissolution of at least 75% after 45 minutes. 
   
   
       13 . A process for the preparation of a pharmaceutical composition of  claim 1  which comprises:
 (a) combining the active ingredient in intimate admixture with one or more pharmaceutically acceptable carriers; and   (b) optionally compressing the mixture from step (a) to form a tablet.   
   
   
       14 . The process of  claim 13 , wherein step a) comprises wet granulation. 
   
   
       15 . A method for treating coronary vascular disorders in a human which comprises the step of administering the pharmaceutical composition of  claim 1  to said human. 
   
   
       16 . The method according to  claim 15 , wherein the coronary vascular disorder is hypertension. 
   
   
       17 . The method according to  claim 16 , wherein the hypertension is moderate to mild essential hypertension. 
   
   
       18 . The pharmaceutical composition of  claim 1  consisting essentially of nebivolol or a pharmaceutically acceptable salt thereof, a wetting agent consisting of a polysorbate, a filler, a binder, a disintegrant, a lubricant, and a glidant. 
   
   
       19 . The pharmaceutical composition of  claim 18  wherein the nebivolol or the pharmaceutically acceptable salt thereof is unmicronized. 
   
   
       20 . The pharmaceutical composition of  claim 6  consisting essentially of nebivolol hydrochloride, polysorbate 80, a spray dried mixture of microcrystalline cellulose and lactose and/or lactose monohydrate, hydroxypropylmethylcellulose, corn starch and/or croscarmellose sodium, magnesium stearate and colloidal silicon dioxide.