#140 Formulation and optimization of Levofloxacin hemihydrate thermosensitive otic in-situ gel for the treatment of otitis media

Abstract

Otitis media is a middle ear infection that clears within a week but requires repeated administration of the drug. Topical available marketed solution when instilled, rapidly eliminated from ear cavity if the patient had not kept the head inclined. To overcome the issues related to the conventional drop, in the presented study, Levofloxacin hemihydrate was incorporated in a poloxamer-based temperature-sensitive otic in-situ gel system to prolong the duration of action, better patient compliance, greater convenience, and ease of administration. Levofloxacin hemihydrate temperature triggered in-situ gelling system was prepared by the cold method using poloxamer 188, Poloxamer 407 alone or in combination with bioadhesive polymers like Natrosol 250M, HPMC K4M, and Klucel HF in variable ratios. On the basis of primary evaluation, 32 factorial design was applied (Design Expert 13 software from Stat Ease Inc., USA) to investigate the combined influence of two independent variables (X1-poloxamer; X2-HPMC K4M) on dependent variables (Y1-gelation time, Y2-gelation temperature, and Y3- drug release). Based on the factorial design, nine formulations were prepared, and response values Viz. gelation time, gelation temperature, and drug release were studied. The selected formulations were further characterized for suitability using pH, viscosity, spreadability, and drug content. Statistical validation of all batches was carried out using ANOVA provision in the software. Optimization by graphical and numerical methods was carried out by fixing maximum and minimum responses for each factor and response. The software suggested nine batches showed gelation time 30±1.0 sec - 300±1.00 sec, gelation temperature 35.33±1.15 °C - 47.66±0.7 °C and drug release in between 92.20±4.12%-99.70±3.02%. The response surface plot and counterplot of nine experimental runs on each response suggested that gelation time, gelation temperature, and drug release were decreased when the concentration of poloxamer 407 and HPMC K4M was increased. This may be due to an increase in pseudoplastic and viscoelastic behavior of poloxamer 407 and increased swelling characteristics of viscosity generating hydrophilic polymer HPMC K4M. An optimized batch containing poloxamer 20% and HPMC K4M 0.5% showed observed responses were close to values predicted by the optimization technique. The optimized batch had a gelation time of 52.33±1.15 sec, gelation temperature 34.33±1.15 °C, and in-vitro release 96.42 ± 3.72%. The 32 factorial design was found to be suitable for the development of an otic in-situ gelling system. Optimized Levofloxacine hemihydrate otic in-situ gel formulation can be used in topical application for Otitis media management.