Compositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents

Abstract

The present invention provides compositions comprising a poorly water soluble pharmaceutical agent, a carrier protein, and an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. The amount of the antimicrobial agent in the composition may be below the level that induces a toxicological effect or at a level where a potential side effect can be controlled or tolerated. Also provided are compositions comprising a poorly water soluble pharmaceutical agent, a carrier protein, a sugar, and optionally an antimicrobial agent. Methods of using the compositions are also provided.

1 . A composition comprising a poorly water soluble pharmaceutical agent, a carrier protein, and an antimicrobial agent other than deferoxamine, wherein significant microbial growth is inhibited in the composition. 
     
     
         2 . The composition of  claim 1 , wherein the carrier protein is albumin. 
     
     
         3 . The composition of  claim 2 , wherein the weight ratio of albumin to the poorly water soluble pharmaceutical agent in the composition is about 18:1 or less. 
     
     
         4 . The composition of  claim 1 , wherein the composition comprises nanoparticles of the poorly water soluble pharmaceutical agents coated with the carrier protein. 
     
     
         5 . The composition of  claim 4 , wherein the nanoparticles in the composition have an average diameter of no greater than about 200 nm. 
     
     
         6 . The composition of  claim 1 , wherein the antimicrobial agent is a chelating agent. 
     
     
         7 . The composition of  claim 6 , wherein the chelating agent is selected from the group consisting of edetate, citrate, pentetate, tromethamine, derivatives thereof, and mixtures thereof. 
     
     
         8 . The composition of  claim 7 , wherein the chelating agent is edetate. 
     
     
         9 . The composition of  claim 8 , wherein the edetate is EDTA. 
     
     
         10 . The composition of  claim 1 , wherein the antimicrobial agent is a non-chelating agent. 
     
     
         11 . The composition of  claim 10 , wherein the non-chelating agent is selected from the group consisting of sulfites, benzoic acid, benzyl alcohol, chlorobutanol, paraben, derivatives thereof, and mixtures thereof. 
     
     
         12 . The composition of  claim 1 , wherein the poorly water soluble pharmaceutical agent is selected from the group consisting of paclitaxel, docetaxel, ortataxel or other taxane, geldanamycin, 17-allyl amino geldanamycin, thiocolchicine dimer, rapamycin, cyclosporine, epothilone, radicicol, and combretastatin. 
     
     
         13 . The composition of  claim 1 , wherein the poorly water soluble pharmaceutical agent is a taxane or a derivative thereof. 
     
     
         14 . The composition of  claim 13 , wherein the poorly water soluble pharmaceutical agent is paclitaxel. 
     
     
         15 . A method of treating cancer in an individual comprising administering to the subject an effective amount of a composition according to  claim 1 , wherein the poorly water soluble pharmaceutical agent is an antineoplastic agent. 
     
     
         16 . A method of preserving a composition comprising a poorly water soluble pharmaceutical agent and a carrier protein against significant microbial growth comprising adding to the composition an antimicrobial agent other than deferoxamine in an amount that is effective to inhibit significant microbial growth in the composition. 
     
     
         17 . A dry composition comprising a poorly water soluble pharmaceutical agent, a carrier protein, and a sugar, wherein the composition can be reconstituted to a stable aqueous suspension of the poorly water soluble pharmaceutical agent, and wherein the time of reconstitution of the composition is less than that for the composition absent the sugar, wherein the concentration of sugar in the reconstituted suspension is greater than about 50 mg/ml. 
     
     
         18 . The composition of  claim 17 , further comprising an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. 
     
     
         19 . The composition of  claim 18 , wherein the sugar is sucrose or mannitol. 
     
     
         20 . The composition of  claim 17 , wherein the poorly water soluble pharmaceutical agent is paclitaxel. 
     
     
         21 . The composition of  claim 17 , wherein the carrier protein is albumin.