Formulations of viloxazine

Abstract

Modified release formulations of viloxazine and methods of administering the same are disclosed. High-drug load formulations of viloxazine are further disclosed.

1 . A pharmaceutical formulation, comprising
 (a) an immediate release (IR) component comprising viloxazine and, optionally, a pharmaceutically acceptable excipient,   (b) a delayed release (DR) component comprising (i) viloxazine or a salt thereof, (ii) an extended release (XR) matrix having at least one release rate controlling compound, (iii) a layer comprising an enteric compound surrounding the matrix.   
     
     
         2 . The formulation of  claim 1 , wherein the XR matrix component comprises from about 30% (w/w) to about 60% (w/w) of viloxazine. 
     
     
         3 . The formulation of  claim 1 , wherein the XR matrix component is in the form of a plurality of particles. 
     
     
         4 . The formulation of  claim 1 , wherein the release rate controlling compound is present in an amount of 5% (w/w) to 65% (w/w) of the XR matrix component. 
     
     
         5 . The formulation of  claim 1 , wherein the release rate controlling compound in the XR matrix component is selected from the group consisting of ethylcellulose; cellulose acetate; cellulose acetate butyrate; waxes; hydrogenated vegetable oils; glyceryl behenate; glyceryl palmitostearate; PEG glyceryl esters; poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer; poly (ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride); polyvinyl acetate; cellulose acetate propionate, and combinations thereof. 
     
     
         6 . The formulation of  claim 1 , wherein the enteric compound is selected from the group consisting of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylic acid-co-methyl methacrylate), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, shellac, zein, and combinations thereof. 
     
     
         7 . The formulation of  claim 1  for once-a-day administration. 
     
     
         8 . The formulation of  claim 1  for twice-a-day administration. 
     
     
         9 . The formulation of  claim 1 , comprising from 10 mg to 800 mg of viloxazine. 
     
     
         10 . The formulation of  claim 1 , wherein the viloxazine salt comprises viloxazine hydrochloride. 
     
     
         11 . The formulation of  claim 1 , wherein the formulation provides for a maximum steady state plasma concentration (C max ) of viloxazine which is higher than the minimal therapeutically effective concentration and which is in the range of 80% to 125% relative to the maximum plasma concentration produced by administration of viloxazine as an IR formulation TID or BID. 
     
     
         12 . The formulation of  claim 1 , wherein the formulation provides for relative steady state area under the viloxazine plasma concentration time profiles for a 24 hour dosing interval (AUC tau ) in the range of 80% to 125% as compared to viloxazine administered as an immediate release formulation TID or BID. 
     
     
         13 . The formulation of  claim 1  in a dosage form selected from tablets, capsules, beads, granules, powders, caplets, troches, sachets, cachets, pouches, and sprinkles. 
     
     
         14 . A pharmaceutical formulation, comprising:
 (a) an immediate release (IR) component comprising an inert core and a layer comprising viloxazine and, optionally, a pharmaceutically acceptable excipient, surrounding the core,   (b) a delayed release (DR) component comprising: (i) an inert core, (ii) a first layer comprising viloxazine or a salt thereof and, optionally, a pharmaceutically acceptable excipient, surrounding the core, and (iii) a second layer comprising at least one release rate controlling compound surrounding the first layer, and (iv) a third layer comprising an enteric compound surrounding the second layer.   
     
     
         15 . The formulation of  claim 14 , wherein the DR component comprises from about 25% (w/w) to about 75% (w/w) of viloxazine. 
     
     
         16 . The formulation of  claim 14 , wherein the DR component is in the form of a plurality of particles. 
     
     
         17 . The formulation of  claim 14 , wherein the at least one release rate controlling compound is present in an amount of 5% (w/w) to 65% (w/w) of the DR component. 
     
     
         18 . The formulation of  claim 14 , wherein the at least one release rate controlling compound is selected from the group consisting of ethylcellulose; cellulose acetate; cellulose acetate butyrate; waxes; hydrogenated vegetable oils; glyceryl behenate; glyceryl palmitostearate; PEG glyceryl esters; poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer; poly (ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride); polyvinyl acetate; cellulose acetate propionate, and combinations thereof. 
     
     
         19 . The formulation of  claim 14 , wherein the second layer of the DR component further comprises at least one pore former. 
     
     
         20 . The formulation of  claim 19 , wherein the weight ratio of release rate controlling compound to pore former is 19:1 to 8.5:1.5. 
     
     
         21 . The formulation of  claim 20 , wherein the pore former is selected from the group consisting of povidone, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, and organic acids. 
     
     
         22 . The formulation of  claim 14 , wherein the enteric compound is selected from the group consisting of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), poly(methacrylic acid-co-methyl methacrylate), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, shellac, zein, and combinations thereof. 
     
     
         23 . The formulation of  claim 14  for once-a-day administration. 
     
     
         24 . The formulation of  claim 14  for twice-a-day administration. 
     
     
         25 . The formulation of  claim 14 , comprising from 10 mg to 800 mg of viloxazine. 
     
     
         26 . The formulation of  claim 14 , wherein the viloxazine salt comprises viloxazine hydrochloride. 
     
     
         27 . The formulation of  claim 14 , wherein the formulation provides for a maximum steady state plasma concentration (C max ) of viloxazine which is higher than the minimal therapeutically effective concentration and which is in the range of 80% to 125% relative to the maximum plasma concentration produced by administration of viloxazine as an IR formulation TID or BID. 
     
     
         28 . The formulation of  claim 14 , wherein the formulation provides for relative steady state area under the viloxazine plasma concentration time profiles for a 24 hour dosing interval (AUC tau ) in the range of 80% to 125% as compared to viloxazine administered as an immediate release formulation TID or BID. 
     
     
         29 . The formulation of  claim 14  in a dosage form selected from tablets, capsules, beads, granules, powders, caplets, troches, sachets, cachets, pouches, and sprinkles.