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 . A solid product suitable for reconstitution to an essentially clear, stable solution upon addition of an aqueous reconstituting solution thereto, said solid product comprising an intimate mixture 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   propofol loaded within said stabilizing agent to form a substantially solid product free of organic solvent;   whereby upon hydration with a reconstituting aqueous solution, said solid product forms said essentially clear stable solution in which said propofol is present as stable nanodispersions or micelles loaded with said propofol.   
     
     
         2 . The solid product according to  claim 1 , which comprises about 0.1% to about 25% w/w of said propofol. 
     
     
         3 . The solid product according to  claim 2 , which comprises about 1% to about 12% w/w of said propofol. 
     
     
         4 . (canceled) 
     
     
         5 . The solid product according to  claim 1 , wherein said propofol is adapted for use as an intravenous injection. 
     
     
         6 - 8 . (canceled) 
     
     
         9 . The solid product according to  claim 1  which is obtained by lyophilizing or spray-drying an aqueous solution comprising a mixture of said stabilizing agent, and said propofol. 
     
     
         10 - 14 . (canceled) 
     
     
         15 . The solid product according to  claim 1 , wherein said hydrophobic segment comprises a poly(ester) selected from the group consisting of poly(ε-caprolactone), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poly(hydroxyl-alkanoates), poly(β-malic acid), and derivatives thereof. 
     
     
         16 . The solid product according to  claim 1 , wherein said amphiphilic copolymer consists of PVP-PDLLA. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . The solid product according to  claim 9 , wherein said solvent is selected from the group consisting of water and an aqueous solution. 
     
     
         20 . The solid product according to  claim 19 , wherein said solvent is water. 
     
     
         21 - 38 . (canceled)