Rapid reconstitution for lyophilized-pharmaceutical suspensions

Abstract

A method of preparing and reconstituting a sterile, lyophilized pharmaceutical active for rapid reconstitution by evacuating a lyophilized pharmaceutical active-containing container until the pressure within the container is less than about 300 Torr and hermetically sealing the evacuated container. The sterile, lyophilized pharmaceutical active can be prepared by flash freezing a pharmaceutical active-containing composition then lyophilizing the composition. The hermetically sealed lyophilized pharmaceutical active can be reconstituted by adding at least the total volume of liquid necessary for reconstitution of the sterile, lyophilized pharmaceutical active to the sterile, lyophilized pharmaceutical active, sealed under a pressure of less than about 300 Torr, in less than about 10 seconds to yield, within about 5 minutes, an administrable pharmaceutical active-containing composition. One aspect of the herein described sterile, lyophilized pharmaceutical active is a packaged sterile pharmaceutical active comprising an evacuated, hermetically sealed container having disposed therein a sterile, lyophilized pharmaceutical active, sealed under a pressure of less than about 300 Torr.

1 . A method of preparing a sterile, lyophilized pharmaceutical active for rapid reconstitution, comprising:
 evacuating a sterile, lyophilized pharmaceutical active-containing container until the pressure within the container is less than about 300 Torr (40 kPa); and   hermetically sealing the evacuated container.   
     
     
         2 . The method of  claim 1  further comprising:
 flash freezing a sterile pharmaceutical active-containing composition; 
 lyophilizing the flash frozen sterile pharmaceutical active-containing composition to yield the sterile, lyophilized pharmaceutical active; and thereby 
 preventing Ostwald ripening growth. 
 
     
     
         3 . The method of  claim 2 , wherein the lyophilizing of the flash frozen pharmaceutical active-containing composition comprises:
 storing a flash frozen pharmaceutical active-containing composition in a lyophilization chamber;   warming the flash frozen pharmaceutical active-containing composition disposed within the lyophilization chamber to a temperature of less than about −20° C.;   pulling a vacuum of less than about 1 Torr (133 Pa) on the lyophilization chamber;   warming the flash frozen pharmaceutical active-containing composition disposed within the lyophilization chamber to about −20° C.; and   maintaining the vacuum of less than about 1 Torr (133 Pa) on the lyophilization chamber for a period of time constituting a primary drying cycle that corresponds with a removal of a majority of a frozen solvent.   
     
     
         4 . The method of  claim 3  further comprising:
 after the end of the primary drying cycle, then warming the pharmaceutical active-containing composition to about 30° C. and maintaining the vacuum of less than about Ton (133 Pa) for a period of time constituting a secondary drying cycle. 
 
     
     
         5 . A method of reconstituting a sterile, lyophilized pharmaceutical active comprising:
 adding a volume of a sterile liquid to a sterile, lyophilized pharmaceutical active, sealed within an evacuated container wherein the pressure within the evacuated container is less than about 300 Torr (40 kPa), in less than about 10 seconds to yield, within about 5 minutes, an administrable pharmaceutical active-containing composition; wherein the volume of liquid added is at least the total volume of liquid necessary for reconstitution of the sterile, lyophilized pharmaceutical active.   
     
     
         6 . The method of  claim 5 , wherein the sterile, lyophilized pharmaceutical active is one having been lyophilized from a first volume of a liquid containing the pharmaceutical active, and wherein the volume of liquid added for reconstitution is equivalent to the first volume. 
     
     
         7 . The method of  claim 5 , wherein the liquid is a solvent for the pharmaceutical active. 
     
     
         8 . A packaged sterile pharmaceutical active comprising a sterile, lyophilized pharmaceutical active hermetically sealed within an evacuated container; wherein the pressure within the evacuated container is less than about 300 Torr (40 kPa). 
     
     
         9 . The package of  claim 8 , wherein the container is selected from the group consisting of a rigid container, a non-rigid container, and a variable-volume container. 
     
     
         10 . The package of  claim 8 , wherein the sterile, lyophilized pharmaceutical active comprises paclitaxel. 
     
     
         11 . The package of  claim 8 , wherein the sterile, lyophilized pharmaceutical active comprises an albumin. 
     
     
         12 . The package of  claim 11 , wherein the pharmaceutical active comprises at least about 50 wt. % of the albumin and wherein the albumin is a human serum albumin. 
     
     
         13 . The package of  claim 12 , wherein the pharmaceutical active comprises at least about 75 wt. % of the human serum albumin. 
     
     
         14 . The package of  claim 13 , wherein the pharmaceutical active comprises at least about 85 wt. % of the human serum albumin. 
     
     
         15 . The package of  claim 8 , wherein the sterile pharmaceutical active-containing composition comprises a nanoparticle of human serum albumin. 
     
     
         16 . The package of  claim 8 , wherein the pressure within the evacuated container is less than about 100 Torr (13 kPa). 
     
     
         17 . The package of  claim 16 , wherein the pressure is less than about 25 Torr (3325 Pa). 
     
     
         18 . The package of  claim 17 , wherein the pressure is less than about 5 Torr (667 Pa).