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Effect of cyclodextrins on the solubility and stability of a novel soft corticosteroid, loteprednol etabonate.

To increase the aqueous solubility and stability of the soft corticosteroid loteprednol etabonate (LE), drug complexation using various cyclodextrins (CDs), such as gamma-cyclodextrin (gamma-CD), 2-hydroxypropyl-beta-cyclodextrin (HPBCD), maltosyl-beta-cyclodextrin (MBCD), mixture of glucosyl/maltosyl-alpha-, beta-, and gamma-cyclodextrin (GMCD), and heptakis (2,6-di-O-methyl)-beta-cyclodextrin (DMCD), were attempted. The solubilizing and stabilizing 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 CD with cosolvent solutions. After equilibration and filtration at 23 degrees C, the solubility of LE was determined by HPLC. Subsequently, the stability of LE in the solutions was also determined by following the LE concentration change in the solution for an appropriate period. CD complexation significantly increased the aqueous solubility and stability of LE. The increase in solubility displayed a concentration dependency on CDs (0-50%). Among the five CDs used, DMCD showed the highest effects on the solubility (4.2-18.3 mg/ml in 10-50% DMCD) and stability (t90 > 4 years at 4 degrees C, when LE 0.5 mg/ml was dissolved in 10% DMCD solution) of LE. By adding co-solvents, such as glycerol, propylene glycol (PG), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP-10), the solubility of LE in DMCD solutions was further increased. Degradation of LE to the corresponding metabolites, delta 1-cortienic acid etabonate (AE) and delta 1-cortienic acid (A), in aqueous CD solutions appeared to be a predicted, two-step kinetics. Differential Scanning Calorimetry (DSC) was used to assist explaining the solubilizing and stabilizing activity differences between CDs. LE/CD mixture or lyophilized LE/CD complex was scanned at a rate of 20 degrees C/min. The exothermic 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.