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.

What is claimed is: 
     
         1 . A solid product suitable for reconstitution to an essentially clear, stable solution upon addition of an aqueous reconstituting solvent thereto, said solid product comprising an intimate mixture of
 at least one stabilizing agent, and   at least one liquid biologically active agent loaded within said stabilizing agent, in such a manner that said liquid biologically active agent is intimately associated with said stabilizing agent in a substantially solid product;   whereby upon hydration with a reconstituting aqueous solvent or solution, said solid product forms said essentially clear stable solution in which said at least one biologically active agent is present as stable nanodispersions or micelles loaded with said at least one biologically active agent.   
     
     
         2 . A solid product according to  claim 1 , which comprises about 0.1% to about 25% w/w of said biologically active agent. 
     
     
         3 . A solid product according to  claim 2 , which comprises about 1% to about 12% w/w of said biologically active agent. 
     
     
         4 . A solid product according to  claim 1 , wherein said liquid biologically active agent is insoluble in water. 
     
     
         5 . A solid product according to  claim 1  wherein said liquid biologically active agent is adapted for use as an intravenous injection. 
     
     
         6 . A solid product according to  claim 1  wherein said liquid biologically active agent is an anaesthetic agent. 
     
     
         7 . A solid product according to  claim 1  wherein said liquid biologically active agent is selected from the group consisting of propofol, 2-phenoxyethanol, quinaldine, methoxyflurane, and combinations thereof. 
     
     
         8 . A solid product according to  claim 6  wherein said anaesthetic agent is propofol. 
     
     
         9 . A solid product according to  claim 1  which is obtained by lyophilizing or spray-drying a mixture of said at least one stabilizing agent, said at least one liquid biologically active agent and at least one solvent therefore. 
     
     
         10 . A solid product according to  claim 1  wherein said stabilizing agent is selected from the group consisting of dispersing agents and surfactants. 
     
     
         11 . A solid product according to  claim 1  wherein said stabilizing agent comprises a dispersing agent. 
     
     
         12 . A solid product according to  claim 11  wherein said dispersing agent is an amphiphilic copolymer. 
     
     
         13 . A solid product according to  claim 12  wherein said amphiphilic polymer is a linear, branched or star-shaped block polymer. 
     
     
         14 . A solid product according to  claim 12  wherein said amphiphilic polymer includes a hydrophilic part that comprises at least one member selected from the group consisting of poly(ethylene oxide), poly(N-vinylpyrrolidone), poly(N-2-hydroxypropylmethacrylamide), poly(2-ethyl-2-oxazoline), poly(glycidol), poly(2-hydroxyethylmethacrylate), poly(vinylalcohol), polymethacrylic acid derivatives, poly(vinylpyridinium), poly((ammoniumalkyl)methacrylate), poly((aminoalkyl)methacrylate) and combinations and derivatives thereof; and a hydrophobic segment selected from the group comprising a poly(ester), poly(ortho ester), poly(amide), poly(ersteramide) poly(anhydride), poly(prophylene oxide), poly(tetrahydrofuran) and combinations thereof. 
     
     
         15 . A solid product according to  claim 14  wherein said hydrophobic segment comprises a poly(ester) selected from the group consisting of poly(e-caprolactone), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poly(hydroxyl-alkanoates), poly(β-malic acid), and derivatives thereof. 
     
     
         16 . A solid product according to  claim 12  wherein said amphiphilic copolymer consists of PVP-PDLLA. 
     
     
         17 . A solid product according to  claim 1  wherein said stabilizing agent comprises a surfactant. 
     
     
         18 . A solid product according to  claim 17  wherein said surfactant is selected from the group comprising lauryl sulphate, hexadecyl pyridinium chloride, polysorbates, sorbitans, poly(oxyethylene) alkyl ethers, poly(oxyethylene alkyl esters and combinations thereof. 
     
     
         19 . A solid product according to  claim 9  wherein said solvent is selected from the group consisting of water, t-butanol, n-butanol, dioxane, pyridine, pyrimidine, piperidine, sodium phosphate buffer pH 7.4 and mixtures thereof. 
     
     
         20 . A solid product according to  claim 19  wherein said solvent comprises water. 
     
     
         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 forming a first mixture comprising a solution of at least one stabilizing agent and at least one solvent, under conditions to achieve micelle or nanodispersion formation;
 adding at least one liquid biologically active agent to said first mixture in such a manner to load said micelle or nanodispersion therewith and form a second mixture;   treating said second mixture under conditions effective to remove said solvent therefrom while forming a substantially solid product that contains said liquid biologically active agent intimately associated with said stabilizing agent, said solid product upon hydration being capable of forming a clear stable solution in which said at least one biologically active agent is present as nanodispersion or micelle loaded with said at least one biologically active agent.   
     
     
         22 . A process for the production of a stabilized nanodispersion or loaded micelle containing a liquid biologically active agent which comprises hydrating a solid product as defined in  claim 1 , under conditions to provide said stabilized nanodispersions or loaded micelle. 
     
     
         23 . Process according to  claim 21  which comprises adding at least one additive to said first and/or second mixture. 
     
     
         24 . The process according to  claim 21  which comprises filtering said solution to yield a sterile filtrate. 
     
     
         25 . The process according to  claim 21  wherein said solvent is selected from the group consisting of water, t-butanol, n-butanol, dioxane, pyridine, pyrimidine, piperidine, sodium phosphate buffer pH 7.4 and combinations thereof. 
     
     
         26 . The process according to  claim 25  wherein said solvent consists of water. 
     
     
         27 . The process in accordance with  claim 22  wherein said step of hydrating includes combining said solid product with a sufficient amount of water, saline solution or dextrose solution. 
     
     
         28 . The process in accordance with  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, e.g. polyvinylpyrrolidone, lidocaine, poly(ethylene glycol), lactose, trehalose, mannitol, saccharides, amino acids soluble in said solvent, or combinations thereof. 
     
     
         29 . The process in accordance with  claim 21  wherein said forming step further includes at least one dissolution enhancing means selected from the group consisting of sonicating, vortexing and heating. 
     
     
         30 . The process in accordance with  claim 21  wherein said stabilizing agent is at least one member selected from the group consisting of a polymer, a copolymer, a small molecular weight surfactant, and combinations thereof. 
     
     
         31 . The process according to  claim 21  wherein said liquid biologically active agent is water insoluble. 
     
     
         32 . The process according to  claim 21  wherein said water insoluble liquid biologically active agent is selected from the group consisting of propofol, 2-phenoxyethanol, quinaldine, and methoxyflurane, and combinations thereof. 
     
     
         33 . The process according to  claim 21  which comprises adding between about 0.1% to about 15% w/v of said liquid biologically active agent to said first mixture. 
     
     
         34 . The process according to  claim 33  which comprises adding between about 1% and about 10% w/v of said liquid biologically active agent to said first mixture. 
     
     
         35 . The process according to  claim 32  wherein said liquid biologically active agent comprises propofol. 
     
     
         36 . A clear liquid consisting of a stable nanodispersion or micelle comprising a hydrating solvent and a solid product as defined in  claim 1 . 
     
     
         37 . A method of medical treatment which comprises administering to a patient a clear liquid as defined in  claim 36 . 
     
     
         38 . A device for producing solid formulations of liquid biologically active agents comprising
 a container,   means for adding at least one stabilizing agent and at least one solvent into said container,   mixing means operable with said container to form a first mixture of said stabilizing agent and said solvent under conditions to achieve micelle or nanodispersion therein,   means for subsequently adding a liquid biologically active agent to said first mixture and to form a second mixture,   means operating said mixing means under conditions to treat said second mixture to load said micelle or nanodispersion with said biologically active agent, and   means for treating said loaded micelle or nanodispersion to form a solid product containing said liquid biologically active agent intimately associated with said stabilizing agent and substantially free of said solvent.