Instant Solubilization of Poorly Water-soluble Drugs by In-situ Loading of Aqueous Phospholipid Dispersions Suitable for Parenteral Administration

Peter Van Hoogevest; Vincent Rogue; Marko Brumec; Hervé Schwebel; Jeffry L. Grunkemeyer; Mathew L.S. Leigh

Abstract

The features of a new, in situ method for solubilizing poorly soluble drugs (SupraVail™Instant Solubilization) are demonstrated. The resulting formulations are suitable for parenteral administration in preclinical and clinical studies. The technique avoids drug precipitation upon dilution and circumvents the need for coadministration of high organic solvent concentrations. The method involves mixing a sterile solution of a poorly water-soluble drug in a water-miscible organic solvent (the “transfer medium”) with an excess of a sterile, stable, phospholipid dispersion prepared by high-shear homogenization. The influence of several mixing parameters which may affect the utility and viability of the method for two drugs, namely diazepam or cyclosporine A, are examined in detail. The resulting transparent dispersions were analyzed for presence of insoluble particles, transmission, particle size, and degree of solubilization. It is found that solubilizing efficiency is mainly determined by the drug and the phospholipid-to-drug ratio in the final dispersion. Complete and instant solubilization is obtained by using negatively charged phospholipids in the transfer medium. Variations in the mixing conditions, such as fast addition compared to slow addition, no shaking (agitation) versus shaking during mixing, stirring after mixing, and temperature variations of the lipid dispersion do not significantly affect the reproducibility of the method.

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