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MaryJane Rafii, Alex Lewis, Jordan Attwood, Vernard Woodley, Shervin Liddie, Wenzheng Hu, Robin J Goody, Matthew S Lawrence, Barbara M Wirostko; Intravitreal tolerance and ocular pharmacokinetics in nonhuman primates of a carboxymethylated hyaluronic acid/polyethylene glycol diacrylate polymer useful for sustained drug delivery. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4166.
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© ARVO (1962-2015); The Authors (2016-present)
Developing drug delivery polymers that are well tolerated in the eye and achieve pharmacokinetic profiles that result in sustained therapeutic effect presents a promising strategy for improving the clinical efficacy and safety of existing and new drug candidates for retinal disease and other ophthalmic disorders. Studies were designed to evaluate a novel, biodegradable, fluorophore-loaded, carboxymethylated hyaluronic acid (CMHA) polymer crosslinked with polyethylene glycol diacrylate (PEGDA) in primates.
The ocular tolerance and fluorophore retention of CMHA loaded with the small molecule fluorophore tag, Alexa Fluor® 488, was evaluated in African green monkeys by fluorophotometry and slit lamp exam following intravitreal (IVT) injection (n=4 eyes) and compared to saline controls (n=2 eyes), allowing minimally invasive, nonterminal quantification of fluorophore abundance and test article safety. CMHA was injected via 30 gauge needle as either a pre-gelled polymer (n=2), or immediately after formulation of constituents but prior to complete gelling (n=2) to evaluate the impact of the time of gel formation relative to intravitreal delivery on tolerance and pharmacokinetics.
Both pre-gelled and post-gelled Alexa Fluor® 488 tagged CMHA were well tolerated with detectable ocular response to test article limited to a minor vitreous cell infiltrate in one eye receiving the post-gelled polymer, which fully resolved at 12 weeks. Alexa Fluor® 488 signal was detected at an elevated level until week 8, peaking immediately post-injection, and substantially returned to baseline by week 12. Intraocular pressure and flare photometer measures of anterior chamber protein remained within normal limits and similar to controls.
A novel, crosslinked CMHA-based hydrogel is well tolerated in the nonhuman primate vitreous and extends release of an incorporated fluorophore over a 2-month interval presenting a clinically meaningful sustained release profile. Release kinetics and ocular safety appears largely independent of whether hydrogel formation occurs before or after IVT delivery, expanding the flexibility with which formulation and delivery might be pursued. Such a hydrogel presents a formulation strategy to improve sustained delivery of existing and candidate ocular therapeutics.
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