Optimization and evaluation of encapsulated brimonidine tartrate-loaded nanoparticles incorporation in situ gel for efficient intraocular pressure reduction

Brimonidine tartrate (BRT) is a water-soluble anti-glaucoma drug that is available in ophthalmic solution (Alphagan Z(R)). Various ocular barriers prevent permeation and precorneal retention of the drugs within the corneal region. In this study, BRT encapsulated vitamin E-tocopheryl polyethylene glycol succinate (TPGS)-polycaprolactone (PCL) nanoparticles were prepared to improve permeation through different physiological barriers of eyes. Optimized formulation comprising of PCL (0.4% w/v) and vitamin E TPGS (0.5% w/v) was characterized. It was revealed that formulation exhibited 243.40 +/- 5.21 nm, 0.103 +/- 0.020, 78.87 +/- 5.32% and +3.23 +/- 0.01 mV of mean particle size, polydispersibility index (PDI), percentage entrapment efficiency (%EE), and zeta potential respectively. Furthermore, optimized BRT loaded nanoparticles were incorporated into a poloxamer based in situ system and was characterized. In vitro study confirmed that around 93.91 +/- 3.12% was the highest recorded of cumulative drug release in simulated aqueous humor over 24 h. Optimized formulation upon in vivo ocular irritability and tolerability tests were found to be well tolerated with no signs of irritation. A significant difference in percentage of intraocular pressure (IOP) reduction between marketed eye drop and optimized nanoparticles based in situ gel was observed in the glaucoma induced rabbit model. These experimental data revealed that nanoparticles based thermosensitive in situ gel could be utilized to enhance corneal residence time and ensure consistent IOP reduction.