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.

Description

BACKGROUND OF THE INVENTION [0001] a) Field of the Invention [0002] This invention relates to the preparation of a solid product in the form of a cake, a powder, or the like, by mixing a solvent comprising water, an aqueous solution, at least one non-aqueous organic solvent, or combinations thereof, with at least one stabilizing agent, and subsequently adding at least one liquid biologically active agent to the above mixture; and treating the whole under conditions to give the above solid product which is substantially solvent free. More particularly, the invention relates to the above solid product and a method for rapid reconstitution thereof in an aqueous media, whereby an essentially clear, lipid free, sterile, stable aqueous product is formed containing nano-dispersions or micelles of the aforementioned stabilizing and biologically active agents; and to a method of treating a patient in need of said biologically active agent by administration of said stable aqueous product ther...

AI Technical Summary

Benefits of technology

[0037] Another objective of the invention is to provide a formulation that reduces or eliminates any sensation of pain upon administration commonly, which has been associated with currently marketed formulations.

[0038] It is a further objective of the instant invention to provide, once reconstituted, a liquid medical formulation that i

Problems solved by technology

Extreme care must be taken during manufacture to thoroughly distribute the propofol in the emulsion, as large droplet sizes of propofol in the blood stream have been linked to embolism in humans.

This causes visual inspection for foreign particles in the formulation by the anesthesiologist, to be more difficult.

The presence of the egg lecithin and soybean oil in these emulsions also makes them highly susceptible to microorganism growth and allergic reactions.

Some of these preservatives have been known to cause adverse reactions in humans.

Similarly, the chelating properties of EDTA are of concern to the FDA due to their unfavorable effects on cardiac and renal function.

Moreover, these emulsions cannot be effectively sterilized using standard sterilizing filters, as they are too thermodynamically unstable and tend to separate under the shear force required.

Such emulsions are also unstable versus dilution and/or mixing with saline, dextrose or other medication containing solutions.

Furthermore, the presence of egg lecithin as an emulsifier and soybean oil as a solubilizer may produce anaphylactic and anaphylactoid reactions in persons allergic to eggs and/or soybeans.

Propofol emulsions are known to be thermodynamically unstable, that is, the oil and water components have a tendency to separate when diluted, sheared, cooled, heated, or mixed with other solutions.

Furthermore, this separation is accelerated when the formulation is stored at low temperatures, i.e. below 2° C., or at elevated temperatures, i.e. above 25° C. In addition, these lipid-based emulsions have been associated with pain at the injection site, often causing the concomitant use of a topical anaesthetic upon injection.

However, each of the above procedures is associated with certain drawbacks, especially when considering the delivery of “on/off” type anaesthetics, such as propofol.

For example, the method based on the use of surfactant micelles to solubilize hydrophobic drugs can be inherently problematic in that some of the surfactants are relatively toxic (e.g. Cremophor EL®) and that precipitation of hydrophobic drugs may occur when subjected to dilution.

Other methods of preparation yield poor entrapment efficiencies (e.g. equilibration methods), relatively large particle sizes (emulsions), or are time-consuming.

Finally, the prolonge

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