Benzonatate modified release solid tablets and capsules

Abstract

A modified release benzonatate solid tablet or capsule is described which comprises a benzonatate adsorbate in a matrix with a sufficient amount of one or more pharmaceutically acceptable modified release pH-independent, substances to provide a modified release profile to the benzonatate, wherein there is substantially no benzonatate release from the tablet or capsule in the buccal cavity and no more than about 25% release of the benzonatate within 1 hour as determined in an in vitro dissolution assay.

1 . A modified release solid oral composition comprising:
 a matrix comprising (a) an adsorbate powder comprising benzonatate adsorbed to a silicon dioxide, and (b) at least one hydrophilic matrix forming material,   the composition provides benzonatate having a pharmacokinetic profile characterized by one or more of: an arithmetic mean Cmax of about 52 ng/mL, an arithmetic mean Cmax of about 60 ng/mL, a geometric mean AUCinf of about 137 ng.h/mL or an arithmetic mean AUCinf of about 160 ng.h/mL.   
     
     
         2 . The modified release solid oral composition according to  claim 1 ,wherein the composition comprises mini-tabs loaded into a capsule. 
     
     
         3 . The modified release solid oral composition according to  claim 1 , wherein the weight ratio of benzonatate to the amorphous adsorbent is in the range of about 5:1 to about 1:10. 
     
     
         4 . The modified release solid oral composition according to  claim 1 , which comprises about 5% w/w to about 35% w/w, or about 5% w/w to about 30% w/w of the at least one hydrophilic polymer, based on the weight of the homogenous solid dispersion. 
     
     
         5 . The modified release solid oral composition according to  claim 4 , wherein the matrix-forming substance comprises a low viscosity, hydrophilic polymer which is a hydroxypropyl methylcellulose having a viscosity of about 4000 mPa-s to about 100,000 mPa-s, or a blend of polymers containing said hydroxypropyl methycellulose. 
     
     
         6 . The modified release solid oral composition according to  claim 1 , wherein said reverse enteric coating comprises (a) a pH-dependent methyl methacrylate and diethylaminoethyl methacrylate copolymer or (b) a pH-dependent cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate. 
     
     
         7 . The modified release solid oral composition according to  claim 6 , wherein said reverse enteric coating comprises a pH-dependent cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate. 
     
     
         8 . The modified release solid oral composition according to  claim 6 , wherein said reverse enteric coating comprises about 5% to about 40% weight of said composition. 
     
     
         9 . The modified release solid oral composition according to  claim 6  which is a compressed tablet. 
     
     
         10 . The modified release solid oral composition according to  claim 9 , wherein the tablet further comprises at least one excipient selected from one or more of bulking agents, binders, and lubricants. 
     
     
         11 . The modified release solid oral composition according to  claim 1 , wherein said tablet further comprises at least one or more additional pharmaceutically active components. 
     
     
         12 . The modified release solid oral composition according to  claim 1 , wherein said at least one or more additional active components is selected from an anti-pyretic, an analgesic, an anti-histamine, an expectorant and a decongestant. 
     
     
         13 . The modified release solid oral composition according to  claim 12 , wherein said at least one or more additional active components are independently in immediate release form, in modified release form, or both. 
     
     
         14 . The modified release solid oral composition according  claim 1 , wherein said at least one or more additional active components-is the expectorant guaifenesin. 
     
     
         15 . The modified release solid oral composition according to  claim 14 , wherein at least one of the one or more additional active components is in the matrix. 
     
     
         16 . The modified release solid oral composition according to  claim 1 , wherein the adsorbate powder of (a)(i) comprises particles having an average size of about 50 μm to about 200 μm. 
     
     
         17 . The modified release solid oral composition according to  claim 1 , wherein the adsorbate powder of (a)(i) comprises at least about 55% w/w to about 60% w/w benzonatate. 
     
     
         18 . The modified release benzonatate solid composition according to  claim 1 , wherein said reverse enteric coat comprises a butylated methacrylate copolymer. 
     
     
         19 . The modified release benzonatate solid composition according to  claim 1 , wherein said solid dispersion further comprises one or more of microcrystalline cellulose, copovidone, hypromellose and magnesium stearate. 
     
     
         20 . A modified release solid oral composition comprising: (a) an adsorbate powder comprising benzonatate adsorbed to one or more of a silicon dioxide, and (b) a hydrophobic or hydrophilic matrix forming material, the composition provides benzonatate having a pharmacokinetic profile characterized by one or more of: a geometric mean maximum plasma concentration which has an area under the curve (AUC)inf of about 150 ng-h/mL and/or a Cmax of about 30 ng/mL.