Study of ocular transport of drugs released from a sustained release device

dc.contributor.advisorWang, Nam Sunen_US
dc.contributor.authorKim, Hyuncheolen_US
dc.contributor.departmentChemical Engineeringen_US
dc.description.abstractDelivering ocular therapeutics to a target site with minimal side effects requires detailed information about the distribution and elimination pathways. This knowledge can guide the development of new drug delivery devices. In this study, we investigated the movement of two drug surrogates, H-110, which is lipophilic, and Gd-DTPA, which is hydrophilic, released from polymer-based implants using a fluorescein technique and magnetic resonance imaging (MRI). We also studied the pharmacokinetics of intravitreally injected triamcinolone acetonide, a low water soluble drug used for treating sight-threatening diseases such as diabetic retinopathy and choroidal neovascularization associated with age-related macular degeneration (AMD). At 24 hour post implantation, H-110 released from an intravitreal implant was detected in the subretinal space. However, following a subconjunctival implant, very little H-110 fluorescence was detected in the subretinal region. H-110 most likely reached the subretinal space from an intravitreal implant by diffusion through the vitreous and retina. However, most of the H-110 released from a subconjunctival implant is thought to dissipate through the choroidal blood flow. Concentration profiles of Gd-DTPA, which was released from an intravitreal implant in a New Zealand white rabbit, approached pseudo-steady state within 7 to 8 hours and showed gradients at the rabbit's vitreous-retina border suggesting that diffusion was occurring into the retinal-choroidal-scleral membrane. Parametric analysis with a finite element mathematical model of the rabbit eye yielded for Gd-DTPA a diffusion coefficient of 2.8 × 10-6 cm2/sec in the vitreous and a permeability of 1.0 × 10-5 cm/sec in the composite retina-choroid-sclera membrane. Gd-DTPA concentration decreased away from the implant. Such regional concentration variations throughout the vitreous may have clinical significance when the ubiquitous eye diseases are treated using a single positional implant. Subconjunctival implants in vivo delivered a mean total of 2.7 µg of Gd-DTPA over 8 hours into the vitreous representing only 0.12% of the total amount of compound released from the implant in vitro. No Gd-DTPA was detected in the posterior segment of the eye. Ex vivo, the Gd-DTPA concentration in the vitreous was 30 fold higher suggesting the elimination of significant in vivo barriers to the movement of drugs from the subconjunctival space into the vitreous. We developed a new preservative-free formulation for intravitreal injections of triamcinolone acetonide for the treatment of diabetic macular edema, and choroidal neovascularization associated with AMD in human clinical trials at the National Institutes of Health. A pharmacokinetic study in rabbits was done to estimate elimination rate of two injection amounts of triamcinolone acetonide, 4 mg and 16 mg, from the vitreous. From our pharmacokinetic model, we found the half-lives for 4 mg and 16 mg injection in the vitreous to be 18.6 days and 37.6 days, respectively. We subsequently estimated the half-lives of 1 mg and 8 mg triamcinolone acetonide injection in order to predict therapeutic exposure in human. There are three components in this thesis: the study of lipophilic H-110 transport with fluorescence, the study of hydrophilic transport of Gd-DTPA with MRI, and the pharmacokinetic analysis of triamcinolone acetonide. They have each contributed to further insights into our fundamental understanding of drug movement in the eye and the implication on optimal therapeutic delivery.en_US
dc.format.extent3358276 bytes
dc.relation.isAvailableAtDigital Repository at the University of Marylanden_US
dc.relation.isAvailableAtUniversity of Maryland (College Park, Md.)en_US
dc.subject.pqcontrolledEngineering, Chemicalen_US
dc.subject.pqcontrolledEngineering, Biomedicalen_US
dc.subject.pqcontrolledHealth Sciences, Ophthalmologyen_US
dc.titleStudy of ocular transport of drugs released from a sustained release deviceen_US


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