Long-term In Vivo Efficacy of an Engineered Polymer Thin-Film Co-delivery Device for Treatment of Glaucoma

Abstract

Purpose : Glaucoma treatment is challenging due to poor patient compliance with daily eye drop medications, therefore a controlled, long-term drug delivery method, especially for patients who require combination therapy is needed. We developed intraocular device prototypes to provide controlled release of Timolol Maleate and Brimonidine Tartrate using polycaprolactone (PCL) thin films. Release kinetics were determined in vitro, and effects on intraocular pressure (IOP) reduction were evaluated in vivo in normotensive rabbits over 13 weeks.

Methods : The device was made by stacking two PCL films and loaded with Timolol and Brimonidine to create a single co-delivery device. In vitro drug release rates were measured by submerging each drug compartment in PBS at 37^oC. 16 adult New Zealand white rabbits were anesthetized and a corneal incision with a 2.6mm slit knife was used to insert the device into the anterior chamber. Drug-loaded (n=12) or empty (n=4) devices were implanted in the left eye. Contralateral eyes were used as untreated controls. IOP was measured with a handheld tonometer (TonoVet) once a week. Statistical analysis was performed with a one-way ANOVA to compare the IOP change over 13 weeks for device implanted eyes and untreated eyes.

Results : In vitro release rates of the devices were 1.75 μg/day for Timolol and 0.48 g/day for Brimonidine over 60 days. Pre-surgery baseline IOP of device-implanted and contralateral eyes were 11±2.1 mmHg and 9.4±1.8 mmHg, respectively. Within 7 days, the IOP of the device-implanted eyes dropped by 4.4±2.9 mmHg, while the untreated eyes increased by 1.3±2.3 mmHg; corresponding to an average decrease of 37% and increase of 18%, respectively. Over 13 weeks, the drug-loaded device treated eyes resulted in a statistically significant cumulative reduction in IOP compared to untreated contralateral eyes (p<0.01) and empty device treated eyes (p<0.05). There was no significant difference in cumulative IOP reduction between empty device treated eyes and untreated contralateral eyes.

Conclusions : The intracameral PCL co-delivery device attained zero-order release of Timolol and Brimonidine in vitro at therapeutic concentrations for at least 60 days, and demonstrated significant IOP-lowering in vivo throughout the 13-week study period. With further optimization, the co-delivery device shows promise for glaucoma patients who require more than one hypotensive agent.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.