Abstract
Purpose :
The current first-line glaucoma treatment strategy focuses on lowering the intraocular pressure (IOP) by eye drops. However, low patient adherence and inefficiency in drug delivery through topical mechanisms complicate this treatment modality. We previously developed a sustained brimonidine delivery system with IOP reduction in rabbits for more than 28 days. This study tested the hypothesis that brimonidine and timolol can be combined in a topically retained gel/microsphere system (GMS) to provide sufficient local drug concentrations for long-term treatment of glaucoma.
Methods :
Poly(lactic-co-glycolic acid) (PLGA) was used to encapsulate brimonidine and timolol. Poly(N-isopropylacrylamide)-co-poly(ethylene glycol) (PNIPAAm-PEG) was used as the thermoresponsive gel. GMS drops included 3mg of brimonidine-loaded PLGA microspheres and 7mg of timolol-loaded PLGA microspheres in 100 μl of PNIPAAm-PEG gel. First, in vitro release of brimonidine and timolol from the GMS drops was quantified in phosphate buffer saline (PBS) by high performance liquid chromatography (HPLC). GMS drops containing blank PLGA microspheres without drugs were used as control. Next, a single drop of GMS loaded with brimonidine/timolol was administered to the right eye of normotensive New Zealand White rabbits (n=5, male, 4 months) and the left eye was used as the control eye. The rabbits were sacrificed on Day 1, Day 7, and Day 14 for eye enucleation, then the concentrations of brimonidine and timolol in aqueous humor were detected by liquid chromatography-mass spectrometry (LC–MS).
Results :
In vitro drug release results showed sustained release of both brimonidine and timolol from the GMS drops for at least 28 days. For in vivo studies, GMS drops were retained in the inferior fornix of all animals for the duration of the study. Both brimonidine and timolol could still be detected in aqueous humor 14 days after a single GMS drop administration. Average concentration of brimonidine in aqueous humor: 2.20ng/ml (Day 1); 0.97ng/ml (Day 7); 0.45ng/ml (Day 14). Average concentration of timolol in aqueous humor: 26.15ng/ml (Day 1); 8.88ng/ml (Day 7); 4.20ng/ml (Day 14).
Conclusions :
The results demonstrate that our topically retained gel/microsphere system (GMS) with brimonidine/timolol can provide noninvasive glaucoma treatment for at least two weeks. Animal studies with longer time points will be tested in the future.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.