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

[0046] The instant process illustrates a simple and elegant procedure for forming a solid product from a liquid containing an intimate association of an insoluble liquid drug and a stabilizing agent. The liquid, comprising an intimate association of the solvent, insoluble liquid drug and stabilizing agent, may be dried by a process, whereby the insoluble liquid drug remains in close association with the stabilizing agent such that virtually all drug is retained during the process. The product is a dry, solid as mentioned above. The dry solid product upon addition of water or an aqueous solution spontaneously reconstitutes to form an essentially clear stable liquid comprising drug micelle or drug nanodispersions loaded with a liquid biologically active agent.

[0048] The invention also relates to 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 is produced by 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, subsequently adding at least one liquid biologically active agent, such as propofol, 2-phenoxyethanol, quinaldine, methoxyflurane, and the like, to the first mixture in such a manner to load the micelle or nanodispersion therewith and form a second mixture, and treating the second mixture under conditions effective to remove the solvent therefrom while forming a substantially solid product that contains the liquid biologically active agent intimately associated with the stabilizing agent, the solid product upon rehydration being capable of forming an essentially clear stable solution in which the at least one biologically active agent is present as a nonodispersion or micelle loaded with the at least one biologically active agent.

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 prolonged circulation time associated with micellar or liposomal delivery can detrimentally affect the “on / off” properties required of an anaesthetic drug such as propofol

However, cyclodextrins are expensive and have been associated with hemodynamic adverse events.

Also, long-term stability of cyclodextrin formulations has been an issue with formulators.

More importantly, cyclodextrins have been linked with renal toxicity at high doses.

Prodrugs are also notably unstable resulting in short shelf lives or low storage temperatures to maintain their stability.

Thus, what is lacking in the art is a light-weight, dry powder or cake formed from a water immiscible liquid drug, such as propofol, that is stable in several different temperature and dilution conditions for prolonged periods, that is readily reconstituted using aqueous media to produce essentially clear, sterile liquids which do not support bacterial growth, comprising drug-loaded micelles or nanodispersions in an aqueous medium.

However, the product is supplied as a liquid and the presence of water in the inhaled anaesthetic is not always beneficial to patients with pulmonary disorders, such as plural effusion.

According to WO 01 / 64187 A2, the use of water-miscible co-solvents can have undesirable medical effects, such as superficial thrombophlebitis, intravasal, haemolytic reactions, and possible increase in formation of free propofol.

Moreover, WO 01 / 64187 A2 indicates that autoclaving may be undesirable when the formulation is filtered to sterility since autoclaving has been known to disrupt the micelles, to the extent of requiring re-emulsification.

In addition, poloxamers are detergent-like surfactants that are not readily degradable and may open-up tight junctions.

Moreover, detergent surfactants may be a source of pain upon injection and require the addition of lidocaine to reduce local pain.

The patent fails to provide the concept of solubilization of hydrophobic drugs, nor does it teach or suggest the formation of a clear, sterilizable solution containing the polymer / drug blend and subsequent lyophilization thereof, resulting in a readily dispersible micelle or nanodispersion, formed upon reconstitution.

The resulting nanoparticles are fine particles having both hydrophilic and hydrophobic components and they cannot form clear stable aqueous liquids.

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