Abstract
Purpose :
Efficient absorption of ophthalmic medications require fast drug dissolution in tear fluid to counter rapid fluid turnover and loss via the naso-lacrimal duct resulting in absorption of <5% of drug. For glaucoma, efficient absoprtion into tissues may positively impact treatment options. We have hypothesized that currently available therapies can be transformed into highly effective treatments via lipid-based nano-carriers.
An anti-glaucoma agent that can effectively both lower intraocular pressure for hypotensive patients and enhance ocular blood flow for normotensive patients is of great clinical benefit. Brinzolamide (BZ) has the potential to become an effective first-line therapy for patients, upon improvement of its permeation through the diffusive pathlength from anterior to posterior tissues. Tested in rabbit eyes, (Naageshwaran, 2021), the bioavailability of BZ via corneal absorption is a mere 0.10%.
We have hypothesized that an enhancement of drug uptake throughout the eye will result in a longer duration of drug in target tissue and consequently achieve significant enhancement in IOP reduction and optic nerve blood flow. We encapsulated BZ within the lipid nanoparticle platform, Ocusurf™ to effectively enhance drug uptake in the target tissue (ciliary bodies), and improve drug concentrations in both anterior and posterior tissues. OcuSurf is a liquid-crystalline dispersion with mean particle size < 200 nm and at physiological pH.
We present enhancement of transport of LNP-BZ (compared to Azopt) through cornea and scleral tissues, via Franz Diffusion cells. We also demonstrate higher drug uptake by deeper ocular tissues in-vivo, compared to Azopt. Additionally, we present physiochemical attributes of LNP-BZ compared to Azopt.
Methods :
Ex-vivo studies were performed through corneal membranes and permeated drug quantitated by HPLC. In-vivo PK studies were performed in rabbits and tissues analyzed by LC/MS/MS. Irritation was assessed in a rabbit model, using a Draize grading scale.
Results :
High permeation rates of drug were observed in the OcuSurf-BZ cohort, through in-vivo and in-vitro studies, with lower BZ permeation rates in the Azopt cohorts. OcuSurf-BZ eye-drops were well tolerated in rabbit eye, with twice-daily dosing over 3 days. OcuSurf-BZ LNP were demonstrated to be stable.
Conclusions :
OcuSurf-BZ enables efficient permeation into ocular tissues, including deeper posterior compartments of the eye.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.