Bile salt/lecithin mixed micelles optimized for the solubilization of a poorly soluble steroid molecule using statistical experimental design.
Bile salts and lecithin combine physiologically to form mixed micelles which aid the solubilization and absorption of dietary fats and drug molecules. In this series of experiments, we have shown how experimental design procedures aid the optimization of a formulation incorporating a bile salt, lecithin, and water with fluticasone propionate (FP) as the model poorly soluble drug. The initial inclusion of a categorical variable ruled out the use of classic response surface designs; therefore the experimental design was constructed using a d-optimal selection from a candidate set of all possible experimental combinations. A separate 2-factor central composite design was used to determine the optimum lecithin and bile salt concentrations over an extended range after the categorical variable had been eliminated. It has been demonstrated that an increase in either lecithin or cholic acid concentration produces an increase in solubility of FP, while sodium taurocholate appears to depress the solubility of FP compared with the other two bile salts. The increase in solubility associated with the increase in bile salt and lecithin is further demonstrated by a linear relationship between FP solubility and the total lipid in the formulation. The influence of molar ratio of lecithin to bile salt in the formulation is also significant. The physical properties of the mixed micellar system (solution turbidity and viscosity ranking) were used to further discriminate between formulations. The optimization showed that the dominant effect was the lecithin, which improves the solubilizing characteristics of the formulation with increasing concentration. The effect of salt concentration is less marked though slightly quadratic in nature. The overall increase in solubility demonstrated was from <1 microg/mL in water to 205 microg/mL in the optimized mixed micellar system.
Pharmaceutical Development, GlaxoSmithKline R&D, Ware, UK. gavin.a.magee@gsk.com
Gavin A
GA
Magee
Jane
J
French
Bob
B
Gibbon
Chris
C
Luscombe
D001647:Bile Acids and Salts; D002627:Chemistry, Physical / Q000379:methods*; D015233:Models, Statistical; D010713:Phosphatidylcholines
D001647:Bile Acids and Salts; D010713:Phosphatidylcholines