Pharmaceutical compositions for sleep apnea

Abstract

Pharmaceutical compositions are provided for the pharmacological treatment of breathing disorders and, more specifically, to compositions containing agents having serotonin receptor modulating activity for the alleviation of sleep apnea (central and obstructive) and other sleep-related breathing disorders wherein the active ingredients are released such as to extend effective blood plasma concentrations across the period of sleep.

1 . An orally administrable pharmaceutical composition for providing modified release of a serotonin receptor antagonist wherein the release of antagonist provides a therapeutically effective level of antagonist in the blood plasma of a subject over a continuous period in excess of 4 hours,
 wherein the composition further comprises an SNRI.   
     
     
         2 . A composition as claimed in  claim 1  wherein the period extends to between 6 and 14 hours from administration of the composition. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The composition as claimed in  claim 1  which provides a therapeutically effective level for a continuous period initiated at from 0 to 2 hours from administration of the composition and extending to between 6 and 14 hours from administration of the composition. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The composition as claimed in  claim 1  wherein the antagonist is ondansetron. 
     
     
         11 . A pharmaceutical formulation comprising a composition as claimed in  claim 1 , wherein the antagonist is released in two or more pulses, wherein a first pulse of antagonist is released within 30 minutes of oral administration and a second pulse is released between 1 hour and 4 hours of administration. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The composition according to  claim 1 , wherein the SNRI is a member selected from the group consisting of venlafaxine, duloxetine, and milnacipran. 
     
     
         19 . The composition according to  claim 1 , wherein the serotonin receptor antagonist is ondansetron and the SNRI is milnacipran. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . The formulation according to  claim 1  that provides ondansetron blood plasma levels that are characterized by C max  below approximately 1200 ng/ml. 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . The composition according to  claim 1  comprising an enteric coating. 
     
     
         30 . The composition according to  claim 1 , wherein the administrable ondansetron unit dose is from 1 to 100 mg. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . A kit comprising a composition as claimed in  claim 1  comprising different dosage units of antagonist to allow for dosage escalation. 
     
     
         34 . The kit as claimed in  claim 33  wherein the antagonist is ondansetron. 
     
     
         35 . The kit as claimed in  claim 33  comprising instruction on taking the formulation once daily before bedtime. 
     
     
         36 . A method of ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof a composition of  claim 1 . 
     
     
         37 . The method of  claim 36  wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring. 
     
     
         38 . An extended release formulation comprising ondansetron coated with one or more ammonio methacrylate copolymer. 
     
     
         39 . The composition of  claim 38  wherein the ammonio methacrylate copolymer is at least one of (a) a copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to remaining neutral (meth)acrylic ester groups of 1:20 and (b) a copolymer of acrylic and methacrylic esters having a molar ratio of ammonium groups to remaining neutral (meth)acrylic ester groups of 1:40. 
     
     
         40 . The composition of  claim 38  wherein the ammonio methacrylate copolymer is at least one of Eudragit L100 and Eudragit S100. 
     
     
         41 . The composition of  claim 40  wherein the ammonio methacrylate copolymer comprises Eudragit L100 and Eudragit S100.