Topical Gel/Microsphere Eyedrop for Combined Delivery of Brimonidine and Timolol: A Comparative Study With Traditional Eye Drops in Rabbits

Abstract

Purpose: Topical eye drops combining multiple antiglaucoma agents are often required when monotherapy fails to reduce intraocular pressure (IOP). However, their effectiveness is compromised by low bioavailability and poor patient compliance. To address these issues, we developed a novel gel/microsphere eye drop (GME) containing brimonidine and timolol, aimed at enhancing ocular bioavailability, reducing dosing frequency, and improving patient compliance.

Methods: The GME system comprises separate formulations of brimonidine-loaded and timolol-loaded polymer microspheres within a thermoresponsive hydrogel, enabling simple off-the-shelf preparation. We examined the in vitro drug release, compared the biodistribution with traditional eye drops, and assessed pharmacodynamic effects in New Zealand white rabbits and Dutch Belted rabbits.

Results: Brimonidine and timolol reached high concentrations in the aqueous and vitreous humor at 1 hour following eye drop administration, declining to nearly undetectable levels by 24 hours. The GME system at a similar dose extended the drug release to 27 days with initially lower drug levels but decreasing more slowly. The GME system also resulted in significantly lower plasma drug concentrations than eye drops, suggesting a reduced risk of systemic side effects. Neither the GME nor eye drops significantly reduced IOP in normotensive rabbits.

Conclusions: The GME system presents a promising alternative to traditional eye drops for controlled drug release in ocular applications, enabling sustained drug delivery while minimizing systemic exposure and thereby potentially enhancing the safety and efficacy of ocular therapies.

Translational relevance: The GME system bridges basic research and clinical application by providing a controlled-release platform that sustains drug delivery, reduces systemic side effects, and enhances patient adherence.

Figure 1.

(A) Loading capacity of brimonidine and timolol loaded microspheres and (B) in vitro drug release from GME.

Figure 2.

Drug concentration (ng/mL) in aqueous humor. (A) Brimonidine concentration following eye drop administration. (B) Brimonidine concentration following GME administration. (C) Timolol concentration following eye drop administration. (D) Timolol concentration following GME administration. OS, untreated control left eye; OD, treated right eye; BT, brimonidine; TM, timolol. There were three rabbits for the eye drops group and four rabbits for the GME group, any drug concentration below the limit of detection was not shown.

Figure 3.

Drug concentration (ng/mL) in vitreous humor. (A) Brimonidine concentration following eye drop administration. (B) Brimonidine concentration following GME administration. (C) Timolol concentration following eye drop administration. (D) Timolol concentration following GME administration. OS, untreated control left eye; OD, treated right eye; BT, brimonidine; TM, timolol. There were three rabbits for the eye drops group and four rabbits for the GME group, any drug concentration below the limit of detection was not shown.

Figure 4.

Drug concentration (ng/mL) in plasma following eye drop administration (A) and GME administration (B). There were three rabbits for the eye drops group and four rabbits for the GME group, any drug concentration below the limit of detection was not shown.

Figure 5.

Ocular drug concentration(ng/mL) after 1 day for different rabbit models. (A) Brimonidine concentration in aqueous humor. (B) Timolol concentration in aqueous humor. (C) Brimonidine concentration in vitreous humor. (D) Timolol concentration in vitreous humor. OS, untreated control left eye; OD, treated right eye; BT, brimonidine; TM, timolol; NZW, New Zealand white rabbits; DB, Dutch Belted rabbits. There were four rabbits in the group, any drug concentration below the limit of detection was not shown.

Figure 6.

Drug concentration(ng/mL) in plasma after 1 day for different rabbit models. NZW, New Zealand white rabbits; DB, Dutch Belted rabbits. ***P < 0.001. There were four rabbits in the group, any drug concentration below the limit of detection was not shown.

Figure 7.

IOP change compared to baseline IOP. (A) IOP after eye drop administration in New Zealand white rabbits. (B) IOP after eye drop administration in Dutch Belted rabbits. (C) IOP after GME administration in New Zealand white rabbits. (D) IOP after GME administration in Dutch Belted rabbits. NZW, New Zealand white rabbits; DB, Dutch Belted rabbits; OS, untreated control left eye; OD, treated right eye. *P < 0.05. There were four rabbits in the group.