Effect of cyclodextrins on the solubility and stability of a novel soft corti-costeroid, loteprednol etabonate

To, increase the aqueous solubility and stability of the soft corticosteroi d loteprednol etabonate (LE), drug complexation using various cyclodextrins (CDs), such as gamma-cyclodextrin (gamma-CD), 2-hydroxypropyl-beta-cyclode xtrin (HPBCD) maltosyl-beta-cyclodextrin (MBCD), mixture of glucosyl/maltos yl-alpha-, beta-, and gamma-cyclodextrin (GMCD), and heptakis (2,6-di-O-met hyl-beta-cyclodextrin (DMCD), were attempted. The solubilizing and stabiliz ing effects of CD by itself or combined with various co-solvents were also investigated. Micronized (5 micron) LE was mixed in various aqueous CD or C D with cosolvent solutions. After equilibration and filtration at 23 degree s C, the solubility of LE was determined by HPLC. Subsequently, the stabili ty of LE in the solutions was also determined by following the LE concentra tion change in the solution for an appropriate period. CD complexation sign ificantly increased the aqueous solubility and stability of LE. The increas e in solubility displayed a concentration dependency on CDs (0-50%). Among the five CDs used, DMCD showed the highest effects on the solubility (4.2-1 8.3 mg/ml in 10-50% DMCD) and stability (t(90) > 4 years at 4 degrees C, wh en LE 0.5 mg/ml was dissolved in 10% DMCD solution) of LE. By adding co-sol vents, such as glycerol, propylene glycol (PG), polyvinyl alcohol (PVA). an d polyvinylpyrrolidone (PVP-10), the solubility of LE in DMCD solutions was further increased. Degradation of LE to the corresponding metabolites, Del ta(1)-cortienic acid etabonate (AE) and Delta(1)-cortienic acid (A), in aqu eous CD solutions appeared to be a predicted, two-step kinetics. Differenti al Scanning Calorimetry (DSC) was used to assist explaining the solubilizin g and stabilizing activity differences between CDs. LE/CD mixture or lyophi lized LE/CD complex was scanned at a rate of 20 degrees C/min. The exotherm ic peak found in the DSC diagram with LE/DMCD sample, but not with LE/HPBCD samples, suggests a stronger complex formed between LE and DMCD, resulting in higher solubility and stability of LE in DMCD than in HPBCD.