Purpose: Poor bioavailability of Pefloxacin Mesylate (PM) from conventional ocular formulations is mainly due to increased pre-corneal elimination, non-productive absorption, transient residence time, and less permeability of corneal epithelium. The conventional solution has high instillation rate for clinical efficacy. There is a need to improve the residence time of the drugs which may decrease the frequency of distribution. Therefore, in present study we have developed and characterized PM in-situ gelling ocular drop in order to increase residence time and ocular bio-availability.
Methods: In-situ forming eye drops were prepared by using different proportions of thermo-sensitive tri-block co polymer (Poloxamer 407), low viscosity grade Chitosan, Methocel E4M (as viscosity imparting agent) with cross linking agent. The pH of formulations was adjusted to 6.8 using 0.1 M NaOH. Developed formulations were further subjected to various evaluation parameters like assessment of gelation temperature, drug content, rheological study, in-vitro drug release study, iso-tonicity, sterility testing, and In-vivo eye irritation study. Finally, In-vivo pre corneal residence study and in-vivo pharmacokinetic study of optimized PM ocular drop were also performed in the eyes of New Zealand albino rabbits to evaluate the pharmacokinetic significance of optimized formulation in comparison to conventional ocular drop.
Results: Transparent, clear and sterile in situ gelling ophthalmic drops of nearly 289 mOsmol/L osmolarity were successfully prepared. Gelation temperature and drug content of prepared PM formulations were found 28.5 to 38.2 °C and 0.30 to 0.31 % W/W respectively. The sol gel conversion at physiological environment (35±0.5 0C, pH-7.4) was found in three formulations only. Rheological study confirmed pseudo-elastic flow behavior of all formulations. In vitro drug release study suggested that all the prepared formulations showed non fickian (anomalous) drug release (n = 0.517-0.788) and Highest linearity for Higuchi and korsmeyer peppas model. Further, optimized formulation (t80% = 5.41hrs) was founded iso-tonic, sterile and non-irritant. The precorneal residence time was found to be 4 fold higher than the conventional formulation. In-vivo pharmacokinetic study exhibited that optimized formulation significantly increased ocular bioavailability (AUC0-t 975.20±86.23 µg*min/mL) and residence time (t½= 4.7 hrs) of pefloxacin in contrast to conventional drop (AUC0-t 389.87±42.51µg*min/mL, t½= 2.1 hrs.
Conclusion: The study revealed that optimized formulation containing Poloxamer 407 (16%), Chitosan (0.1%) and Methocel E4M (1 %w/w) with cross-linking agent significantly increased ocular bioavailability and residence time. So, they can be viable alternates for ocular drug delivery of Pefloxacin Mesylate in future. However, further pharmacodynamic (PD) studies required for the evaluation of clinical efficacy.