Co-Delivery of Timolol and Brimonidine with a Polymer Thin-Film Intraocular Device

Abstract

Purpose: We developed a polycaprolactone (PCL) co-delivery implant that achieves zero-order release of 2 ocular hypotensive agents, timolol maleate and brimonidine tartrate. We also demonstrate intraocular pressure (IOP)-lowering effects of the implant for 3 months in vivo. Methods: Two PCL thin-film compartments were attached to form a V-shaped co-delivery device using film thicknesses of *40 and 20 mm for timolol and brimonidine compartments, respectively. In vitro release kinetics were measured in pH-and temperature-controlled fluid chambers. Empty or drug-loaded devices were implanted intracamerally in normotensive rabbits for up to 13 weeks with weekly measurements of IOP. For ocular concentrations, rabbits were euthanized at 4, 8, or 13 weeks, aqueous fluid was collected, and ocular tissues were dissected. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Results: In vitro studies show zero-order release kinetics for both timolol (1.75 mg/day) and brimonidine (0.48 mg/day) for up to 60 days. In rabbit eyes, the device achieved an average aqueous fluid concentration of 98.1 -68.3 ng/mL for timolol and 5.5 -3.6 ng/mL for brimonidine. Over 13 weeks, the drug-loaded co-delivery device resulted in a statistically significant cumulative reduction in IOP compared to untreated eyes (P < 0.05) and empty-device eyes (P < 0.05). Conclusions:The co-delivery device demonstrated a zero-order release profile in vitro for 2 hypotensive agents over 60 days. In vivo, the device led to significant cumulative IOP reduction of 3.4 -1.6 mmHg over 13 weeks. Acceptable ocular tolerance was seen, and systemic drug levels were unmeasurable.

Considerations for Polymers Used in Ocular Drug Delivery

“…PCL's crystalline properties make it an excellent choice for thin films and cell delivery due to its ability to maintain structural integrity through late stages of degradation. Experimental work done by Shuamo et al (55) and Samy (56) present PCL thin films capable of extended drug release with limited intraocular inflammation. Additionally, PCL has shown promise as an intraocular drug delivery vehicle, with recent experimental work focusing on embedding nanoparticles within contact lenses, injectable in situ forming hydrogels, nanoparticle emulsions and suspensions, microparticles, and capsules for treatment of several diseases including glaucoma and wet AMD (57)(58)(59)(60)(61)(62).…”

Special Features of Polyester-Based Materials for Medical Applications

“…Intracameral PCL implants show the advantage of bypassing the corneal epithelial barrier and enhance the quantity of drug delivered to the target tissues, in contrast with topical administration. Compared to particles that can degrade more rapidly and can show burst release, the developed systems containing a PCL reservoir can present longer and continued zero-order release due to a larger drug payload, along with increased control over the diffusive polymer barrier [ 209 ].…”

Neuartige Wirkstoffabgabesysteme für die Glaukomtherapie: Hürden und Lösungsansätze für die Formulierung

“…In-vitro-Freisetzungstests ergaben eine anhaltende Freisetzung beider Wirkstoffe über 60 Tage. Eine in-vivo-Studie belegt eine AID-Senkung über 13 Wochen [250]. Das Titanimplantat iDose ist mit einer Travoprost-Formulierung befüllt und von einer Membran bedeckt, durch die der Wirkstoff langsam in die Vorderkammer des Auges abgegeben wird.…”