Excipients for use in adeno-associated virus pharmaceutical formulations and pharmaceutical formulations made therewith

Abstract

Stable pharmaceutical compositions comprising recombinant adeno-associated virus (AAV) virions are described. The compositions provide protection against loss of recombinant AAV vector genomes and transduceability under conditions such as exposure to cycles of freezing and thawing and storage in glass or polypropylene vials. The compositions comprise recombinant AAV virions in combination with one or more dihydric or polyhydric alcohols, and, optionally, a detergent, such as a sorbitan ester. Also described are methods of using the compositions.

1 . A pharmaceutical composition comprising recombinant adeno-associated virus (AAV) virions and at least one dihydric or polyhydric alcohol. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the dihydric or polyhydric alcohol is one or more alcohols selected from the group consisting of polyethylene glycol, propylene glycol and sorbitol. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the one or more alcohols is sorbitol and the sorbitol is present at a concentration of about 0.1 wt. % to about 10 wt. %. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein sorbitol is present at a concentration of about 1 wt. % to about 5 wt. %. 
     
     
         5 . The pharmaceutical composition of  claim 2 , wherein the one or more alcohols is polyethylene glycol and the polyethylene glycol is present at a concentration of about 2 wt. % to about 40 wt. %. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein polyethylene glycol is present at a concentration of about 10 wt. % to about 25 wt. %. 
     
     
         7 . The pharmaceutical composition of  claim 2 , wherein the one or more alcohols is propylene glycol and the propylene glycol is present at a concentration of about 2 wt. % to about 60 wt. %. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein propylene glycol is present at a concentration of about 5 wt. % to about 30 wt. %. 
     
     
         9 . The pharmaceutical composition of  claim 1 , further comprising a detergent. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the detergent is a nonionic detergent. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the detergent is a sorbitan ester. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the detergent is selected from the group consisting of polyoxyethylenesorbitan monolaurate (TWEEN-20), polyoxyethylenesorbitan monopalmitate (TWEEN-40), polyoxyethylenesorbitan monostearate (TWEEN-60), polyoxyethylenesorbitan tristearate (TWEEN-65), polyoxyethylenesorbitan monooleate (TWEEN-80) and polyoxyethylenesorbitan trioleate (TWEEN-85). 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the detergent is polyoxyethylenesorbitan monolaurate (TWEEN-20) present at a concentration of about 0.05 wt. % to about 5 wt. %. 
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein the detergent is polyoxyethylenesorbitan monooleate (TWEEN-80), present at a concentration of about 0.05 wt. % to about 5 wt. %. 
     
     
         15 . A pharmaceutical composition comprising recombinant AAV virions present in an amount sufficient to provide a therapeutic effect when given in one or more doses, sorbitol present at a concentration of about 1 wt. % to about 5 wt. % and a detergent present at a concentration of about 0.1 wt. % to about 1 wt. %, wherein the detergent is polyoxyethylenesorbitan monolaurate (TWEEN-20) or polyoxyethylenesorbitan monooleate (TWEEN-80). 
     
     
         16 - 25 . (canceled) 
     
     
         26 . A method for protecting a recombinant AAV virion from loss of activity resulting from storage of the virion in a glass vessel comprising admixing the virion with a virion-stabilizing composition comprising a dihydric or polyhydric alcohol. 
     
     
         27 . The method of  claim 26 , wherein the dihydric or polyhydric alcohol is one or more alcohols selected from the group consisting of polyethylene glycol, propylene glycol and sorbitol. 
     
     
         28 . The method of  claim 27 , wherein the one or more alcohols is sorbitol. 
     
     
         29 . The method of  claim 27 , wherein the one or more alcohols is polyethylene glycol. 
     
     
         30 . The method of  claim 27 , wherein the one or more alcohols is propylene glycol. 
     
     
         31 . The method of  claim 26 , wherein the virion-stabilizing composition further comprises a detergent. 
     
     
         32 . The method of  claim 31 , wherein the detergent is a sorbitan ester. 
     
     
         33 . The method of  claim 32 , wherein the sorbitan ester is selected from the group consisting of polyoxyethylenesorbitan monolaurate (TWEEN-20), polyoxyethylenesorbitan monopalmitate (TWEEN-40), polyoxyethylenesorbitan monostearate (TWEEN-60), polyoxyethylenesorbitan tristearate (TWEEN-65), polyoxyethylenesorbitan monooleate (TWEEN-80) and polyoxyethylenesorbitan trioleate (TWEEN-85). 
     
     
         34 . The method of  claim 26 , wherein the recombinant AAV virion is provided as a lyophilized preparation. 
     
     
         35 . A method for protecting a recombinant AAV virion from loss of activity resulting from storage of the virion in a glass vessel comprising admixing the virion with a virion-stabilizing composition comprising sorbitol and a sorbitan ester selected from the group consisting of polyoxyethylenesorbitan monolaurate (TWEEN-20) and polyoxyethylenesorbitan monooleate (TWEEN-80).