Tunability, Reproducibility and Mathematical Modeling of Triamcinolone Acetonide Release From the I-Vation TA Intra-Ocular Drug Delivery Device

Abstract

Purpose: : The I-vation^TM TA intravitreal drug delivery implant is an intra-vitreal drug delivery system that can provide sustained release of Triamcinoalone Acetonide (TA) to the back of the eye for greater than 1 year. Three dosages formulations were developed which demonstrate the ability to tailor the drug release rate and achieve lot to lot reproducibility of elution characteristics. The formulations developed each contained 100, 500, and 925 mcg of TA, respectively. In an extension of this work, a mass transport mathematical model was developed that accurately predicts I-vation TA’s long term in-vitro elution behavior by fitting data to short duration time course drug elution experiments.

Methods: : A product development process was used that incorporated Quality by Design (QbD) elements. This included, but was not limited to, exploring the formulation and process design spaces through design of experiments and conducting mathematical modeling to obtain drug release characteristics.Drug release data was obtained using an elution method designed to maintain the product at sink conditions for mass transfer. I-vation TA implants were immersed in phosphate buffered saline (PBS), pH 7.4, 37ºC and aliquots were assayed at appropriate time intervals for drug content via UV-VIS spectroscopy. The mathematical model developed is based on a parabolic partial differential equation (PPDE) describing unsteady diffusion with Neumann boundary conditions. The PPDE was solved using Matlab®. The model parameters were extracted using an error minimization algorithm.

Results: : In-vitro cumulative drug elution curves developed exhibited significant dose separation for the three different formulations developed. At 60 days the 100, 500, and 925 mcg dosage forms (3 lots each) exhibited cumulative drug elution amounts of 20 ± 4, 60 ± 5, and 150 ± 10 mcgs respectively. The mass transport model indicated that at 365 days the 100, 500, and 925 mcg dosages would have eluted 80, 190, and 525 mcgs of their payload, respectively.

Conclusions: : The I-vation^TM intra-vitreal drug delivery system can be engineered to provide a tailored drug release rate with sustained and repeatable delivery. A mass transfer model has been developed that can accurately fit and predict long term cumulative drug elution from I-vation^TM TA with 21 days or less real time data.

Keywords: corticosteroids • retina • computational modeling