Abstract
Purpose :
Conventional anterior drug delivery methods are ineffective due to the low bioavailability caused by static and dynamic barriers which result in rapid drug clearance. Due to the longer clearance time of mucins compared with tears, we hypothesize that Phenylboronic Acid (PBA), a known mucoadhesive, based micelles can enhance drug delivery to the anterior eye. PBA based micelles can increase retention time, bioavailability, and can be used with a wide array of drugs.
Methods :
Poly(L-lactide)-b-poly(methacrylic acid-co-3-acrylamidophenylboronic acid) block copolymer micelles previously developed in the Sheardown lab were synthesized by free radical polymerization. Nuclear magnetic resonance (NMR) was used to confirm structure and molecular weight. Drug release studies were completed with micelles loaded with high (0.75 μg/mL) and low dose (0.50 μg/mL) of Cyclosporine A (CycA) in dialysis tubing released into simulated tear fluid, changed at regular intervals over a two-week period. Drug was detected via high-performance liquid chromatography (HPLC). Micelles were further dissolved and contents were removed to measure remaining drug concentration. Timolol, Latanoprost, Atropine, Dexamethasone, and Clarithromycin were tested for compatibility based on logP values and their entrapment efficiencies were determined using HPLC.
Results :
NMR showed similarities between the micelles tested and those previously synthesized in terms of structure and molecular weight. Micelles showed the capability of sequestering 50% more drug compared to Restasis with preliminary studies showing loading capabilities beyond 1.00 μg/mL. Figure 1 shows a sustained CycA release with no initial burst compared to the control. The drug release profile follows pseudo-zero-order kinetics up until day 6, where all the drug has been released and the remaining drug is cleared with the micelles. The study on entrapment efficiencies showed that a drug with a logP value of 1.28 displayed poor entrapment efficiency (3.7 ± 2.9%) while drugs with logP values of 2.79 and 4.28 showed good entrapment efficiencies of 69.3 ± 1.3% and 23.7 ± 1.2% respectively.
Conclusions :
Anterior drug delivery methods can be improved by using PBA based micelles due to their ability to produce a sustained release as well as improve bioavailability through increased drug residence time.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.