Solid formulations of liquid biologically active agents
View Patent ↗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 a mixture of
at least one amphiphilic copolymer of poly(N-vinylpyrrolidone)-poly(lactide),
and
at least one water-insoluble, biologically active agent that is liquid at room temperature loaded within said amphiphilic copolymer so that said biologically active agent is associated with said amphiphilic copolymer in a 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 at least one biologically active agent is present as stable nanodispersions or micelles loaded with said biologically active agent.
2. The solid product according to claim 1 , which comprises about 0.1% to about 25% w/w of said biologically active agent.
3. The solid product according to claim 2 , which comprises about 1% to about 12% w/w of said biologically active agent.
4. The solid product according to claim 1 , wherein said biologically active agent is adapted for use as an intravenous injection.
5. The solid product according to claim 1 , wherein said biologically active agent is an anaesthetic agent.
6. The 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.
7. The solid product according to claim 5 , wherein said anaesthetic agent is propofol.
8. The solid product according to claim 1 , which is obtained by lyophilizing or spray-drying a mixture of said at least one amphiphilic copolymer, said at least one biologically active agent and a solvent of water or phosphate buffer.
9. The solid product according to claim 8 , wherein said solvent is water.
10. The solid product according to claim 1 , wherein the amphiphilic copolymer is poly(N-vinylpyrrolidone)-b-poly(d,l-lactide) (PVP-PDLLA).
11. 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 amphiphilic copolymer of poly(N-vinylpyrrolidone)-polylactide, 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 at least one water-insoluble biologically active agent that is liquid at room temperature to said first mixture in such a manner to load said micelle or nanodispersion therewith and form a second mixture; and
(c) treating said second mixture under conditions effective to remove said solvent therefrom while forming a solid product that contains said biologically active agent associated with said amphiphilic copolymer, wherein said solid product upon hydration with a second aqueous solution forms a clear stable solution in which said biologically active agent is present as nanodispersion or as a micelle loaded with said biologically active agent.
12. The process according to claim 11 , further comprising, after step (c), hydrating the solid product to produce a stabilized nanodispersion or loaded micelle.
13. The process according to claim 11 , further comprising adding at least one additive to said first and/or second mixture.
14. The process according to claim 11 , further comprising filtering said solution produced step (a) to yield a sterile filtrate.
15. The process according to claim 12 , wherein said step of hydrating includes combining said solid product with a sufficient amount of water, saline solution or dextrose solution.
16. The process according to claim 13 , 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, lactose, trehalose, mannitol, saccharides, amino acids soluble in said solvent, and combinations thereof.
17. The process according to claim 11 , wherein said forming step further includes at least one dissolution enhancing means selected from the group consisting of sonicating, vortexing and heating.
18. The process according to claim 11 , wherein said water insoluble biologically active agent is selected from the group consisting of propofol, 2-phenoxyethanol, quinaldine, and methoxyflurane, and combinations thereof.
19. The process according to claim 11 , wherein the amphiphilic copolymer is poly(N-vinylpyrrolidone)-b-poly(d,l-lactide) (PVP-PDLLA).