Topical Ocular Delivery to Posterior Eye Tissues

Treatment of diseases affecting the posterior segment of the eye with intravitreal injections of drugs are effective yet invasive and associated with side effects such as retinal detachment and endophthalmitis. Rapamycin (RAP) was explored in eye research for chronic inflammatory disorders such as posterior uveitis. Tacrolimus (TAC) suspension is used to treat moderate to severe atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). This study's objectives were to formulate the hydrophobic compounds: RAP and TAC in aqueous eye drop formulations, with the overall aim of using these formulations to treat posterior uveitis, AKC and VKC, respectively. A thin-film hydration method was used to encapsulate RAP and TAC within the chitosan-based amphiphile: N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ). The formulations were characterised, and their stability studied under three storage conditions for one month. The biocompatibility of GCPQ was assessed by measuring the IC50 value in a standard MTT assay. Experimental autoimmune uveitis (EAU) was used as a mice model to explore how RAP would clinically function on retinal disease. The ocular biodistribution of the formulations was studied in healthy rabbits, and LC-MS/MS analysed the ocular tissues. Nanoparticles formulations (GCPQ: RAP, 0.2% w/v) and (GCPQ: TAC, 0.1% w/v) were produced with characteristics within the ocular comfort range. The formulations were stable on refrigeration for one month. GCPQ demonstrates good biocompatibility in vitro with IC50 ranging from 0.44–4.5 mg/mL. On topical application in vivo, GCPQ delivered RAP to the rabbit choroid-retina one-hour post-dosing at concentration 145±49 ng/g of tissue. The topical application of GCPQ: RAP 0.2% w/v on EAU mice model suppressed the disease progression. The TAC concentrations in rabbit cornea and conjunctiva one-hour post-dosing were 4452±2289 and 516±180 ng/g of tissue, respectively. A topical ocular aqueous RAP and TAC eye drop formulations have been prepared with the ability to deliver sufficient drugs to the relevant ocular surface tissues