Nonionic Microemulsions as Solubilizers of Hydrophobic Drugs: Solubilization of Paclitaxel.

The strategy using nonionic microemulsion as a solubilizer for hydrophobic drugs was studied and is demonstrated in this work. The aqueous phase behaviors of mixed nonionic surfactants with various oils at 37 °C are firstly constructed to give the optimal formulations of nonionic microemulsions with applications in the enhanced solubilization of the model hydrophobic drug, paclitaxel, at 37 °C. Briefly, the suitable oil phase with paclitaxel significantly dissolved is microemulsified with appropriate surfactants. Surfactants utilized include Tween 80, Cremophor EL, and polyethylene glycol (4.3) cocoyl ether, while various kinds of edible oils and fatty esters are used as the oil phase. On average, the apparent solubility of paclitaxel is increased to ca. 70-100 ppm in the prepared microemulsions at 37 °C using tributyrin or ethyl caproate as the oil phases. The sizes of the microemulsions attained are mostly from ca. 60 nm to ca. 200 nm. The cytotoxicity of the microemulsion formulations is assessed with the cellular viability of 3T3 cells. In general, the cell viability is above 55% after 24 h of cultivation in media containing these microemulsion formulations diluted to a concentration of total surfactants equal to 50 ppm and 200 ppm.

Interaction between hydrophobically modified 2-hydroxyethyl cellulose and sodium dodecyl sulfate studied by viscometry and two-dimensional NOE NMR spectroscopy.

Interaction between an anionic surfactant, sodium dodecyl sulfate (SDS), and a nonionic polymer, 2-hydroxyethyl cellulose (HEC) hydrophobically modified with benzoyl chloride (bmHEC), is studied by viscometry and two-dimensional nuclear Overhauser effect NMR spectroscopy (2D NOESY) in a semidilute regime of bmHEC. The hydrophobicity of bmHEC was varied with different substitution of benzoyl group to HEC macromolecules. In general, the low-shear viscosity of 1 wt % bmHEC aqueous solution is increased with added SDS surfactant having concentration from 0 to 0.5 wt %, and then decreased significantly with a further addition of surfactant to 3 wt %. The activation energy of transient network formation in 1 wt % bmHEC aqueous solution present with SDS surfactant is found to be dependent with SDS concentration, which varies from 32.7 to 69.80 kJ/mol. The maximum activation energy takes place when 0.5 wt % SDS is added, which coincides with that of the maximal viscosity. The 2D NOESY displays that the surfactants actually interact with bmHEC not only on the hydrophobes, namely benzoyl groups, but also the polymer backbone, i.e., glucose units. In contrast, no interaction is revealed by 2D NOESY in the aqueous system containing SDS surfactant and HEC polymer.

Self-emulsifying O/W formulations of paclitaxel prepared from mixed nonionic surfactants.

Nonionic self-emulsifying oil-in-water (O/W) formulations free of Cremophore were developed as drug delivery vehicles for paclitaxel. The surfactants used included phosphatidylcholine purified from egg yolk (EPC), Tween, and Span. Oils phases were either pure components or blends from benzyl alcohol, 2-phenylethanol benzyl benzoate, and tributyrin. Among these surfactants, mixtures of EPC and Tween-80 gave really stable emulsions in proper sizes ranging from 70 to 200 nm, mainly depends on the ratio of EPC to Tween-80 and amount of oils. Paclitaxel could be well preserved without any loss in oily stocks, namely mixtures of oils and paclitaxel as well as surfactants, stored at 4 degrees C for more than 8 months. Only gentle mixing on oily stocks with aqueous diluents is enough to make paclitaxel-contained emulsions. The optimum formulation contains oils from 1 to 3 wt%, Tween-80 and EPC from 0.4 to 1.2 wt%, respectively. Consequently, near 500 ppm of paclitaxel can be contained in emulsions. Moreover, these paclitaxel-containing emulsions are compatible with commonly used injection fluids. No precipitation is observed upon preparation of emulsion from dilution of oily stocks. Negligible cytotoxicity on these emulsions assessed with NIH/3T3 cells implied their good biocompatibility and promising applications as drug delivery carriers.