Ion-sensitive in situ hydrogels of natamycin bilosomes for enhanced and prolonged ocular pharmacotherapy: in vitro permeability, cytotoxicity and in vivo evaluation

Abstract

Delivery of therapeutic molecules into the deeper ocular compartments is mainly hampered by short precorneal residence and limited transmembrane permeability of topically administered drugs. Hence, the current study was undertaken to fabricate the ion-sensitive in situ gels of natamycin (NT) bilosomes (NB) for efficient ocular delivery. The effect of cholesterol and sodium taurocholate proportion on the properties of the bilosomes were studied and the formulation with better physicochemical properties was optimized and utilized to derive the in situ gelling system (IG). The impact of type/composition of gelling agent on the formation and characteristics of the hydrogel was investigated. The hydrogel formed from IG with 0.3% w/v gellan gum showed optimal viscoelastic and adhesive characteristics. The ocular safety and cytocompatibility of NB and its IG was confirmed by corneal histology and in vitro cytotoxicity evaluation. A 6- to 9-fold enhancement in the transcorneal flux of NB demonstrated efficient ocular penetration of bilosomes. Moreover, the superior mean dose normalized NT levels in the ocular tissues of rabbits treated with optimized NB and IG illustrated the effectiveness of bilosomes loaded ion-sensitive in situ hydrogels as a potential platform for the improved and prolonged ocular pharmacotherapy.

Gellan Gum BasedSol-to-GelTransforming System of Natamycin Transfersomes Improves Topical Ocular Delivery

“…The vials were placed in a reciprocating water bath (Precision; Fisher Scientific), operated at 100 rpm and at 34°C, and the time taken to form hydrogel was recorded. These vials were inspected visually every hour, for 12 hours, and the time point where the hydrogel dissolved or broke was recorded as the GRT (Nagesh et al, 2012;Paradkar and Parmar, 2017;Janga et al, 2018).…”

“…The viscosity measurements were recorded from Rheocalc software (Brookfield Engineering Laboratories, Inc., MA). Similarly, the hydrogel viscosity was determined by adding 500 ml mixture of FNG and STF (50:7) in the sample holder plate (Morsi et al, 2017;Janga et al, 2018).…”

“…The color intensity was measured at 570 nm using the m-Quant universal microplate spectrophotometer (Bio-Tek Instruments, Inc., Winooski, VT). The percentage of cell viability following exposure to the test formulations was calculated relative to that of the negative control (Janga et al, 2018). Transcorneal Permeability.…”

“…Several nanocarrier-loaded stimuli-responsive (pH/temperature) in situ gel systems, such as solid lipid nanoparticles, polymeric nanoparticles, and nanoemulsions, which are vesicular system laden in situ gels, were reported to prolong drug residence in the precorneal space and improve permeability across the cornea (Kumar et al, 2013;Ibrahim et al, 2016;Pandurangan et al, 2016;Morsi et al, 2017;Paradkar and Parmar, 2017). Recently, we demonstrated the success of an ion-activated sol-to-gel-transforming system of bilosomes as a suitable ocular drug delivery platform (Janga et al, 2018).…”

Research progress in the application of in situ hydrogel system in tumor treatment

“…When a dilute solution of alginate is introduced to solutions of monovalent or divalent metal ions (K þ , Na þ , Ca 2þ ), a translucent hydrogel can immediately form in situ. Deacetylated gellan gum can immediately form a threedimensional gel network structure when it encounters monovalent or divalent cations (K þ , Na þ , Ca 2þ ), thus can also be used in situ hydrogel anti-tumor drug delivery system (Rupenthal et al, 2011;Janga et al, 2018;Yang et al, 2018). Due to the good biocompatibility, hydrophilicity and low toxicity related to commonly biogenic nature of drug carrier materials, this type of hydrogel deserves indepth studies and exploitment (Pareek et al, 2017;Shang et al, 2018).…”