Full Factorial Design, Optimization, In vitro and Ex vivo Studies of Ocular Timolol-Loaded Microsponges

Purpose: Timolol maleate (TMM) is a hydrophilic model drug. The aim of this study was to formulate TMM-loaded microsponges to sustain TMM release and improve its corneal permeability compared with TMM-aqueous solution. Methods: The modified quasi-emulsion solvent diffusion technique (water/oil/oil) was used to prepare TMM-loaded microsponges. The impact of the polymer type (X₁) and drug:polymer ratio (X₂) were studied and optimized, using full factorial design. The production yield (PY) %, entrapment efficiency (EE) %, particles size (PS), and TMM released % after 6 h were selected as dependent variables. Depended on the desirability value by using the Design-Expert® software version 11, the optimized formulation was selected and subjected to further studies, such as scanning electron microscopy (SEM), porosity determination, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), ex vivo permeation study, and corneal hydration level. Results: The optimized formulation composed of TMM: EC within the proportion 1:9 exhibited PY of 96.55 ± 4.01%; EE of 72.00 ± 6.08%; PS (d₉₀) of 6283.33 ± 145.71 nm and released 42.12 ± 3.93% of TMM after 6 h. Particles appeared porous with spherical shape. Thermal analysis proved that the drug has been homogeneously dispersed in its amorphous state. The optimized formulation showed higher corneal permeability about 1.45-fold higher than TMM-aqueous solution in a period of 6 h. Conclusions: The modified quasi-emulsion diffusion technique (water/oil/oil) is suitable for improving EE of hydrophilic drug (TMM) and the optimized TMM-loaded microsponge was succeeded to retard the release of TMM and improve its corneal permeability.