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 rapamycin, 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 rapamycin in the composition is about 18:1 or less. 
     
     
         4 : The composition of  claim 1 , wherein the composition comprises nanoparticles of the rapamycin coated with the carrier protein. 
     
     
         5 : The composition of  claim 4 , wherein the carrier protein is albumin. 
     
     
         6 : The composition of  claim 5 , wherein the weight ratio of albumin to the rapamycin in the composition is about 18:1 or less. 
     
     
         7 : The composition of  claim 4 , wherein the nanoparticles in the composition have an average diameter of no greater than about 200 nm. 
     
     
         8 : The composition of  claim 7 , wherein the composition is sterile filterable. 
     
     
         9 : The composition of  claim 1 , wherein the composition is an aqueous suspension of the rapamycin at a concentration of about 0.1 to about 20 mg/ml. 
     
     
         10 - 13 . (canceled) 
     
     
         14 : The composition of  claim 1 , wherein the antimicrobial agent is a chelating agent. 
     
     
         15 : The composition of  claim 14 , wherein the chelating agent is selected from the group consisting of edetate, citrate, pentetate, tromethamine, derivatives thereof, and mixtures thereof. 
     
     
         16 : The composition of  claim 15 , wherein the chelating agent comprises citrate and edentate. 
     
     
         17 : The composition of  claim 16 , wherein the chelating agent comprises 200 mM citrate and EDTA. 
     
     
         18 : The composition of  claim 1 , wherein the antimicrobial agent is a non-chelating agent. 
     
     
         19 : The composition of  claim 18 , wherein the non-chelating agent is selected from the group consisting of sulfites, benzoic acid, benzyl alcohol, chlorobutanol, paraben, derivatives thereof, and mixtures thereof. 
     
     
         20 - 25 . (canceled) 
     
     
         26 : A method of preserving a composition comprising rapamycin 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. 
     
     
         27 : A dry composition comprising rapamycin, a carrier protein, and a sugar, wherein the composition can be reconstituted to a stable aqueous suspension of the rapamycin, 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. 
     
     
         28 : The composition of  claim 27 , further comprising an antimicrobial agent, wherein significant microbial growth is inhibited in the composition. 
     
     
         29 : The composition of  claim 27 , wherein the sugar is sucrose or mannitol. 
     
     
         30 . (canceled) 
     
     
         31 : The composition of  claim 27 , wherein the carrier protein is albumin. 
     
     
         32 : A composition comprising rapamycin, an albumin, and a sugar, wherein the weight ratio of the albumin to the rapamycin is about 9:1 or less, and wherein the sugar in the composition or a reconstituted suspension resulting from the composition is greater than about 50 mg/ml. 
     
     
         33 : The composition of  claim 32 , wherein the composition comprises nanoparticles comprising albumin and rapamycin. 
     
     
         34 : The composition of  claim 32 , wherein the sugar is sucrose or mannitol.