Title:  Emulsion vehicle for poorly soluble drugs

United States Patent:  6,458,373

Issued:  October 1, 2002

Inventors:  Lambert; Karel J. (Woodinville, WA); Constantinides; Panayiotis P. (Bothell, WA); Quay; Steven C. (Edmonds, WA)

Assignee:  Sonus Pharmaceuticals, Inc. (Bothell, WA)

Appl. No.:  003173

Filed:  January 5, 1998

An emulsion of .alpha.-tocopherol, stabilized by biocompatible surfactants, as a vehicle or carrier for therapeutic drugs, which is substantially ethanol free and which can be administered to animals or humans various routes is disclosed. Also included in the emulsion is PEGylated vitamin E. PEGylated .alpha.-tocopherol includes polyethylene glycol subunits attached by a succinic acid diester at the ring hydroxyl of vitamin E and serves as a primary surfactant, stabilizer and a secondary solvent in emulsions of .alpha.-tocopherol.

SUMMARY OF THE INVENTION

In order to meet these needs, the present invention is directed to pharmaceutical compositions including: .alpha.-tocopherol, a surfactant or mixtures of surfactants, with and without an aqueous phase, and a therapeutic agent wherein the composition is in the form of an emulsion, micellar solution or a self-emulsifying drug delivery system. In a preferred form, the solution is substantially ethanol-free.

The pharmaceutical compositions can be stabilized by the addition of various amphiphilic molecules, including anionic, nonionic, cationic, and zwitterionic surfactants. Preferably, these molecules are PEGylated surfactants and optimally PEGylated .alpha.-tocopherol.

The amphiphilic molecules further include surfactants such as ascorbyl-6 palmitate; stearylamine; sucrose fatty acid esters, various vitamin E derivatives and fluorine-containing surfactants, such as the Zonyl brand series and a polyoxypropylene-polyoxyethylene glycol nonionic block copolymer.

The therapeutic agent of the emulsion may be a chemotherapeutic agent preferably a taxoid analog and most preferably, paclitaxel.

The emulsions of the invention can comprise an aqueous medium when in the form of an emulsion or micellar solution. This medium can contain various additives to assist in stabilizing the emulsion or in rendering the formulation biocompatible.

The pharmaceutical compositions of the invention are typically formed by dissolving a therapeutic agent in ethanol to form a therapeutic agent solution. .alpha.-tocopherol is then added to the therapeutic agent solution to form an .alpha.-tocopherol and therapeutic agent solution. Next, the ethanol is removed to form a substantially ethanol-free .alpha.-tocopherol and therapeutic agent solution. The substantially ethanol free .alpha.-tocopherol and therapeutic agent solution is blended with and without an aqueous phase incorporating a surfactant to form a pre-emulsion. For IV delivery the pre-emulsion is then homogenized to form a fine emulsion. For oral delivery, the pre-emulsion is typically encapsulated in a gelatin capsule.

Claim 1 of 14 Claims

We claim:

1. A pharmaceutical composition, comprising a chemotherapeutic agent, wherein the chemotherapeutic agent is at least one of a taxoid, a taxane, or a taxine; a tocopherol; tocopherol polyethylene glycol succinate; polyethylene glycol; a surfactant; and an aqueous phase; wherein the composition is an emulsion or a microemulsion having an oil phase and a water phase, and wherein all of the chemotherapeutic agent is in the oil phase.
 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.