(4cv) Ophthalmic Drug Delivery System: From Tear Dynamics to Contact Lenses

Traditional ophthalmic drug delivery via eye drops accounts for more than 90% of current ocular drug administration. Unfortunately, drop instillation is an inefficient route since only 1-5% of the applied drug enters the cornea while the remaining drains or is absorbed by the bloodstream leading to side effects. Nevertheless, topical ophthalmic drug delivery remains the primary application modality to the human eye. This research focuses on improving the pharmacokinetic (PK) accuracy of topical ocular drug delivery by a tear-dynamic-based continuum model, and on developing new silicone hydrogel (SiHy) soft contact lens materials as extended drug delivery vehicles. The aims of my research are to improve the ophthalmic drug delivery prescription so that FDA approval of formulation and dosage is expeditious and to develop a long term solution for extended drug delivery.

 I. Tear-Dynamic-Based Pharmacokinetics Model for Topical Ophthalmic Drug Delivery

Classical PK models are limited to measuring concentrations in ocular tissues over time following single or multiple administration, which prevents quantitative bioavailability predictions for changes in formulation or dosage regimen. We propose a compartmental description of human tear dynamics that quantifies drug pharmacokinetics (PK) by topical administration including bioavailability in each compartment of the anterior eye. The tear supply/drainage system is divided into 5 compartments: upper and lower menisci, upper and lower conjunctival sacs, and tear film. A transient description is employed for each compartment for tear volume, salinity, and drug concentration. Compartments are coupled to each other and to drug delivery through kinetic routes.

This tear-dynamic-based PK model predicts the effect of drop size and dosing sequences on the drug loss to conjunctiva and tears drainage, which is directly related to the systemic side effects of drug delivery. Another case study predicts precorneal residence time of a fluorescent tracer mixed with commercial artificial tears. The viscosity of solution depends on the concentration of active agent. Although dilution reduces the initial high viscosity, thickness of precorneal tear film increases and tear drainage rate decrease, thus extending drug residence time. These predictions are consistent with clinical observations.

The proposed tear-dynamics model is the first attempt to develop a topical ocular drug-delivery model based on compartmental tear dynamics. The model is especially useful for optimizing drug formulations and dose regimens for both normal and dry-eye subjects and, thus, for streamlining FDA approval. Further, quantitative prediction of conjunctival uptake can be integrated with available PK models to improve drug uptake prediction accuracy in both the anterior and posterior segments of eye. The new model is suitable for quantifying ocular drug delivery by other vehicles including contact lens, and emulsion and nanoparticle suspensions. 

II. Extended Ophthalmic Drug Delivery by Soft Contact Lenses

Contact lenses serve as an alternative ocular drug delivery vehicle due to higher drug bioavailability and potentially enhanced patient compliance. However, current commercial hydrogel contact lenses do not provide sufficient transport resistance, usually releases the included drug for no longer than a few hours. Our approach to achieving extended and controlled ocular drug delivery focuses on creating biocompatible transport barriers within commercial hydrogel contact lenses by using vitamin E as a diffusion-barrier material. Nanosized vitamin E barriers are created in a prefabricated contact lens by soaking the lens in a solution of vitamin E in ethanol, followed by rapid extraction of ethanol in water. Transport rates for several drugs with various hydrophobicity and surface activity were successfully modeled proving the validity of the approach.  We also investigate the impact of the vitamin E barriers on transport of ions and oxygen, and on other properties relevant to the safety of contact lens wear.  Finally we conducted the in vivo animal experiments in glaucoma model of Beagle dogs to deliver a glaucoma drug through the vitamin E loaded contact lenses. Our combination of in vitro, in vitroexperiments along with mathematical models for transport prove that glaucoma and several other ophthalmic diseases can be treated effectively with vitamin E impregnated contact lenses. 

-- Peer-Reviewed Publications

1. C.-C. Peng, C. Cerretani, R. J. Braun, C. J. Radke, Adv Colloid Interface Sci (2013), accepted 
2. C. Cerretani, C.-C. Peng, A. Chauhan, C. J. Radke, Contact Lens & Anterior Eye, 35 (2012) 260-265
3. C.-C. Peng, M.T. Burke, B.E. Carbia, C. Plummer, A. Chauhan, J Controlled Release, 162 (2012) 152-158
4. C.-C. Peng, A. Chauhan, J Membrane Sci, 399-400 (2012) 95-105
5. C.-C. Peng, A. Ben-Sholmo, E. MacKay, C.E. Plummer, A. Chauhan, Curr Eye Res, 37 (2012) 204-211
6. C.-C. Peng, M. T. Burke, A. Chauhan, Langmuir, 28 (2012) 1478-1487
7. C.-C. Peng, A. Chauhan, J Controlled Release, 154 (2011) 267-274
8. C.-C. Peng, L.C. Bengani, J. Leclerc, C. Gupta, A. Chauhan, J Drug Deliv Sci Tech, 21 (2011) 111-121
9. J. Kim, C.-C. Peng, A. Chauhan, J Controlled Release, 148 (2010) 110-116
10. C.-C. Peng, Jinah Kim, Anuj Chauhan, Biomaterials, 31 (2010) 4032-4047