Biocompatibility and Pharmacokinetic Analysis of an Intracameral Polycaprolactone Drug Delivery Implant for Glaucoma

Abstract

PurposeWe developed polycaprolactone (PCL) implants that achieve zero-order release of a proprietary ocular hypotensive agent (DE-117) over 6 months.MethodsThe release rates of DE-117–loaded PCL devices were tuned based on an established predictive model and confirmed by in vitro release studies. Devices containing DE-117 and empty devices were implanted intracamerally in normotensive rabbits for up to 8 weeks' duration. Devices were retrieved after rabbits were euthanized and evaluated for tissue adherence. The drug remaining in each device was analyzed by high performance liquid chromatography. Drug distribution in ocular tissues was measured by liquid chromatography coupled with a tandem mass spectrometry (LC/MS/MS).ResultsIn vitro release of DE-117 showed zero-order release with a release rate of 0.5 μg/day over 6 months. Implantation in rabbit eyes demonstrated that the devices were well tolerated in the intracameral space. Quantification of DE-117 and hDE-117 (the hydrolyzed active form of DE-117) in ocular tissues (cornea, iris-ciliary body, aqueous humor, and vitreous humor) indicated sustained release of DE-117 and its conversion to hDE-117 when released from the device. Analysis of drug remaining in the device found that concentration of hDE-117 was below the limit of detection, indicating the encapsulated drug was protected from hydrolysis in the device.ConclusionsProof-of-concept PCL drug delivery devices containing DE-117 show promise as a long-term glaucoma treatment based on their zero-order drug release profile in vitro, biocompatibility in vivo, and effective distribution of released drug in relevant ocular tissues.

24-Month Phase I/II Clinical Trial of Bimatoprost Sustained-Release Implant (Bimatoprost SR) in Glaucoma Patients

“…By providing sustained IOP-lowering effects, drug-delivery systems such as Bimatoprost SR may help to address this unmet need. These new delivery systems may delay the need for more invasive (surgical) treatment by more precisely targeting the drug to sites of action [30,35,36], while providing IOP-lowering effects and tolerability profiles comparable to those of topical therapy [28,37,38]. Other sustained-release products are in various phases of clinical development, including ENV515 (Envisia Therapeutics, Durham, NC, USA), OTX-TIC (Ocular Therapeutix, Bedford, MA, USA), and iDose (Glaukos Corporation, Laguna Hills, CA, USA) for intracameral delivery of travoprost.…”

Sustained drug delivery platforms – A new era for glaucoma treatment

“…In 2016, Kim et al were the first to report success with an intracameral DE-117-loaded polycaprolactone (PCL) implant, inserted to the anterior chamber (AC) through a clear corneal incision, for the treatment of glaucoma. [45] In a more recent study in 16 normotensive rabbits, the same group found a statistically significant IOP reduction in eyes implanted with the DE-117 PLC compared with untreated eyes and placebo PCL devices. [46] Tolerability was good and rates of iris trauma and hyphema during the implantation procedure were lower (19%) than in the previous study (29%).…”

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma

“…In a randomized, investigator‐masked, active‐controlled multicentre phase 3 trial in Japanese patients comparing DE‐117 versus latanoprost 0.005%, the compound wasshown to be similarly effective, although the IOP change from baseline in mean diurnal IOP for DE‐117 and latanoprost was 0.63 mmHg in favour of latanoprost (Lu et al ., ). Attempts are also being made to use it in long‐term intracameral delivery devices (Kim et al ., ). The compound was also shown to be effective in Xalatan non‐responsive patients (Ropo et al ., ).…”