Development of a Water-soluble Form of Umifenovir Through the Synergistic Action of a Surfactant and a Hydrotropic...

The aim of this study was to develop a water-soluble form of umifenovir (UMF) through the synergistic action of the non-ionic surfactant Brij35 and choline bitartrate (ChB), and to investigate the solubility, aggregation and diffusion.

UMF solubilization was assessed using the saturation shake-flask method. The hydrodynamic radii and aggregation behavior of Brij35 micelles were characterized by light scattering. UMF diffusion rate was investigated using a Franz diffusion cell and an artificial membrane.

Introduction of ChB into the UMF/Brij35 system reduced the degree of association with Brij35 micelles and the micelle/water partition coefficient, increased the solubilizing capacity, and modulated the aggregation behavior of Brij35 and permeability. The increase in total (micelle-associated and freely dissolved) drug solubility of UMF in buffer рН 7.4 in the system with the minimal Brij35 concentration (0.45%) was 18.4%, whereas upon addition of ChB (1.0%) - 35.2%. However, calculation of the molecularly dissolved fractions (f_free) of the compound showed that the increase in solubility of the freely dissolved drug in the system with ChB was only 10.6%. This finding is of fundamental importance because only the molecularly dissolved form of a drug can cross biological membranes. Optimization of membrane permeability in the UMF/Brij35 (0.45%)/ChB (1.0%) system was achieved by increasing the fraction of molecularly dissolved UMF molecules in the presence of ChB.

This study highlights the advantage of simultaneously using low concentrations of Brij35 and ChB to achieve a synergistic action for maximal improvement in UMF solubility with a minimal reduction in permeability.