Solid formulations of liquid biologically active agents

Abstract

The instant invention relates to a solid product comprising a liquid biologically active agent which is intimately associated to a stabilizing agent; particularly a solid product that can be reconstituted to a clear, stable, stabilized nanodispersion or loaded micelles comprising a polymer as a stabilizing agent and a liquid, preferably water immiscible, biologically active agent. The instant invention is further directed toward a process for the production of the above solid product; particularly to micelles or nanodispersions produced by hydration of a cake or powder of the solid product, produced via an effective treatment of a stabilized solution comprising for example a polymer as a stabilizing agent, such as an amphiphilic block copolymer or a small molecular weight surfactant, loaded with a liquid biologically active agent, such as propofol, an optional additive, and a suitable solvent.

1 - 20 . (canceled) 
     
     
         21 . A process for the production of a solid product suitable for reconstitution to a clear stable solution upon addition of an aqueous solution thereto, which comprises:
 (a) forming a first mixture comprising a solution of at least one stabilizing agent comprising a linear, branched or star-shaped block amphiphilic copolymer comprising a hydrophilic segment and a hydrophobic segment, the hydrophilic segment selected from the group consisting of poly(ethylene oxide), poly(N-vinylpyrrolidone), poly(N-2-hydroxypropyl methacrylamide), poly(2-ethyl-2-oxazoline), poly(glycidol), poly(2-hydroxyethylmethacrylate), poly(vinylalcohol), a polymethacrylic acid derivative, poly(vinylpyridinium), poly((ammoniumalkyl)methacrylate), poly((aminoalkyl)methacrylate) and a combination thereof and the hydrophobic segment selected from the group consisting of a poly(ester), poly(ortho ester), poly(amide), poly(ester-amide), poly(anhydride), poly(tetrahydrofuran) and a combination thereof, and at least one solvent selected from the group consisting of water and an aqueous solution, under conditions to achieve micelle or nanodispersion formation;   (b) adding propofol to said first mixture in such a manner to load said micelle or nanodispersion therewith and form a second mixture;   (c) treating said second mixture under conditions effective to remove said solvent therefrom and form a substantially solid product that contains said propofol associated with said amphiphilic copolymer, wherein said solid product upon hydration with an aqueous solution forms a clear stable solution in which said propofol is present as nanodispersion or micelle loaded with said propofol.   
     
     
         22 . A process for producing a stable nanodispersion or micelle loaded with propofol comprising:
 (a) forming a first mixture comprising a solution of at least one stabilizing agent comprising a linear, branched or star-shaped block amphiphilic copolymer comprising a hydrophilic segment and a hydrophobic segment, the hydrophilic segment selected from the group consisting of poly(ethylene oxide), poly(N-vinylpyrrolidone), poly(N-2-hydroxypropyl methacrylamide), poly(2-ethyl-2-oxazoline), poly(glycidol), poly(2-hydroxyethylmethacrylate), poly(vinylalcohol), a polymethacrylic acid derivative, poly(vinylpyridinium), poly((ammoniumalkyl)methacrylate), poly((aminoalkyl)methacrylate) and a combination thereof and the hydrophobic segment selected from the group consisting of a poly(ester), poly(ortho ester), poly(amide), poly(ester-amide), poly(anhydride), poly(tetrahydrofuran) and a combination thereof, and at least one solvent selected from the group consisting of water and an aqueous solution, under conditions to achieve micelle or nanodispersion formation;   (b) adding propofol to said first mixture to load said micelle or nanodispersion therewith and form a second mixture;   (c) treating said second mixture under conditions effective to remove said solvent therefrom and form a substantially solid product that contains said propofol associated with said amphiphilic copolymer; and   (d) hydrating said solid product with an aqueous solution to form a clear stable solution of a propofol loaded nanodispersion or micelle.   
     
     
         23 . The process according to  claim 21  further comprising adding at least one additive to said first and/or second mixture. 
     
     
         24 . The process according to  claim 21 , further comprising filtering said solution produced in step (a) to yield a sterile filtrate. 
     
     
         25 - 26 . (canceled) 
     
     
         27 . The process according to  claim 22 , wherein step (d) comprises combining said solid product with water, a saline solution or a dextrose solution. 
     
     
         28 . The process according to  claim 23 , wherein said additive is at least one member selected from the group consisting of a buffer, a cryoprotectant, an analgesic, a lyoprotectant, a bulk forming agent, poly(ethylene glycol), lactose, trehalose, mannitol, saccharides, amino acids soluble in said solvent, or combinations thereof. 
     
     
         29 . The process according to  claim 21 , wherein the step of forming the first mixture in step (a) further comprises sonicating, vortexing or heating the solution. 
     
     
         30 . The process according to  claim 22 , wherein the step of forming the first mixture in step (a) further comprises sonicating, vortexing or heating the solution. 
     
     
         31 . (canceled) 
     
     
         32 . The process according to  claim 22 , wherein said second mixture in step (b) comprises between about 0.1% to about 15% w/v of said propofol. 
     
     
         33 . The process according to  claim 21 , wherein said second mixture in step (b) comprises between about 0.1% to about 15% w/v of said propofol. 
     
     
         34 . The process according to  claim 33 , wherein said second mixture comprises between about 1% and about 10% w/v of said propofol. 
     
     
         35 . The process according to  claim 32 , wherein said second mixture comprises between about 1% and about 10% w/v of said propofol. 
     
     
         36 - 38 . (canceled) 
     
     
         39 . The process according to  claim 21 , wherein said amphiphilic copolymer comprises PVP-PDLLA. 
     
     
         40 . The process according to  claim 22 , wherein said amphiphilic copolymer comprises PVP-PDLLA. 
     
     
         41 . The process according to  claim 21 , wherein, during step (c), the solvent is removed by freeze-drying or spray-drying. 
     
     
         42 . The process according to  claim 22 , wherein, during step (c), the solvent is removed by freeze-drying or spray-drying.