Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof

Abstract

The present invention provides novel compositions for the delivery of a hypnotic agent across the oral mucosa. In particular, the buffer system in the compositions of the present invention raises the pH of saliva to a pH greater than about 7.8, thereby facilitating the substantially complete conversion of the hypnotic agent from its ionized to its un-ionized form. As a result, the dose of hypnotic agent is rapidly and efficiently absorbed by the oral mucosa with surprisingly low inter-subject variability. Furthermore, delivery of the hypnotic agent across the oral mucosa advantageously bypasses hepatic first pass metabolism of the drug and avoids enzymatic degradation of the drug within the gastrointestinal tract. Methods for using the compositions of the present invention for treating sleep disorders such as insomnia are also provided.

What is claimed is: 
     
         1 . A solid composition for delivery of a hypnotic agent across the oral mucosa, said composition comprising:
 (a) a hypnotic agent selected from the group consisting of an imidazopyridine, a dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically acceptable salt thereof;   (b) a carrier that provides complete buccal or sublingual disintegration in about 5 minutes or less following administration to the mouth; and   (c) a binary buffer system comprising a carbonate salt and a bicarbonate salt,   
       wherein said binary buffer system raises the pH of saliva to a pH greater than about 7.8, irrespective of the starting pH of saliva. 
     
     
         2 . The composition of  claim 1 , wherein said binary buffer system raises the pH of saliva to a pH greater than about 8.5, irrespective of the starting pH of saliva. 
     
     
         3 . The composition of  claim 1 , wherein said binary buffer system raises the pH of saliva to a pH greater than about 9, irrespective of the starting pH of saliva. 
     
     
         4 . The composition of  claim 1 , wherein said carrier provides complete buccal or sublingual disintegration in about 2 minutes or less following administration. 
     
     
         5 . The composition of  claim 1 , wherein said carrier comprises at least one binder and at least one disintegrating agent in such relative proportion to provide a buccal or sublingual disintegration time of about 5 minutes or less following administration. 
     
     
         6 . The composition of  claim 5 , wherein the ratio of said binder to said disintegrating agent is from about 0.26 to about 0.79. 
     
     
         7 . The composition of  claim 5 , wherein said binder is selected from the group consisting of a sugar, a sugar alcohol, and combinations thereof. 
     
     
         8 . The composition of  claim 7 , wherein said sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, and combinations thereof. 
     
     
         9 . The composition of  claim 1 , wherein said imidazopyridine is selected from the group consisting of zolpidem and alpidem. 
     
     
         10 . The composition of  claim 1 , wherein said dihydropyrrolopyrazine is zopeclon. 
     
     
         11 . The composition of  claim 1 , wherein said mazolopyrimidine is selected from the group consisting of zaleplon and indiplon. 
     
     
         12 . The composition of  claim 1 , wherein said carbonate salt is selected from the group consisting of sodium carbonate and potassium carbonate. 
     
     
         13 . The composition of  claim 1 , wherein said bicarbonate salt is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. 
     
     
         14 . The composition of  claim 1 , wherein said binary buffer system comprises sodium carbonate and sodium bicarbonate. 
     
     
         15 . The composition of  claim 1 , wherein said composition further comprises a sweetening agent, a flavoring agent, a protecting agent, a plasticizer, a wax, an elastomeric solvent, a filler material, a preservative, a lubricating agent, a wetting agent, an emulsifying agent, a solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent, or combinations thereof. 
     
     
         16 . The composition of  claim 1 , wherein said composition is a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, and a dissolving tablet. 
     
     
         17 . The composition of  claim 1 , wherein said oral mucosa is selected from the group consisting of the sublingual mucosa, the buccal mucosa, and a combination thereof. 
     
     
         18 . The composition of  claim 1 , wherein said hypnotic agent is zolpidem and said binary buffer system comprises sodium carbonate and sodium bicarbonate. 
     
     
         19 . The composition of  claim 18 , wherein said zolpidem is selected from the group consisting of a pharmaceutically acceptable salt thereof, a free base thereof, and mixtures thereof. 
     
     
         20 . A solid composition for delivery of a hypnotic agent across the oral mucosa, said composition comprising:
 (a) a therapeutically effective amount of zolpidem;   (b) a carrier that provides complete buccal or sublingual disintegration in about 5 minutes or less following administration to the mouth; and   (c) a binary buffer system comprising a carbonate salt and a bicarbonate salt, wherein said binary buffer system raises the pH of saliva to a pH greater than about 7.8, irrespective of the starting pH of saliva