Safety, Tolerability & Pharmacokinetics of Sustained Release Latanoprost (LAT) From Intravitreal Injection of a Semi-Solid in-situ Forming Implant

Abstract

Purpose : SiSu® technology is a phase-inverting drug delivery platform that forms a semi-solid in-situ forming implant when injected into an aqueous milieu. SiSu® is designed to release effective levels of drugs within the eye by diffusion and controlled degradation of the polymer into safe non-toxic compounds. These experiments aimed to study the safety, tolerability and implant degradation within the rabbit vitreous cavity and the pharmacokinetics of LAT release following intravitreal injection.

Methods : Two eyes of New Zealand Rabbits received an intravitreal injection of 20-60µl of formulation containing escalating dosages of LAT (500-3000µg). The excipient polymer was modified to optimise the drug release profile. Animals were followed up to 8 months. Aqueous humour (AH) LAT concentration was measured at regular intervals during this period. Clinical examinations of the posterior segment were performed to identify potential adverse events and to evaluate the morphology of the polymer over time.

Results : The polymer was well tolerated in the rabbit eye with no intraocular inflammation or serious ocular adverse events, polymer fragmentation or migration noted over follow up. The implant began to degrade and shrink in size from three months post-injection, with all drug released by 5 months. AH LAT concentrations within the anticipated human therapeutic window (0.2-30 ng/ml) were maintained for 3-4 months post-injection. Modification of implant formulation through polymer specification, co-solvent percentage and drug load enabled improve prolonged drug release over time.

Conclusions : SiSu® technology can deliver sustained release of latanoprost in the rabbit eye after intravitreal injection. The implant is safe and well tolerated with no ocular adverse events observed during follow up. AH concentrations of latanoprost within the human therapeutic range can be achieved for up to 3-4 months post injection in rabbit which should reflect 4-6 months duration in human. Adjusting implant formulation will enable even longer sustained drug release. This technology has future potential to deliver sustained release of drugs which may reduce the need for regular eye drops and help address the challenge of non-adherence in glaucoma patients.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Fig.1. Latanoprost implant (20µL) in rabbit VH

 

Fig.2 LAT-acid conc. in Rabbit AH after 20 µL inj. of 2000 µg of LAT-ester