The Effect of Ocular Pigmentation on Transscleral Delivery of Triamcinolone Acetonide

Abstract

Purpose: To determine the capacity and kinetics of the binding between triamcinolone acetonide (TA) and the ocular pigment for a better understanding of the transscleral delivery. Methods: In the in vitro study, natural melanin (sepia officinalis, Sigma-Aldrich) was incubated at 37°C with different concentrations of TA and the binding capacity/binding affinity was measured. The TA releasing profile from the melanin was also studied through repeated incubation of TA-melanin in fresh phosphate-buffed saline. In the ex vivo study, the effect of the choroidal pigment on the trans sclera/choroid permeability of TA was investigated through Franz-type vertical diffusion cells using both a TA suspension and a saturated TA solution.Results: The amount of TA bound to melanin increases with the increase of the TA concentration and with an increase in the incubation time. A Scatchard analysis revealed that the maximum number of moles of TA bound to melanin is predicted to be 22.43 nmol/mg, with a binding affinity of K = 2.4 · 10 -5 nM -1 . TA released from a pigment showed a fast phase within the first 24 h and a slow phase thereafter. About 40% of the bound TA released in the first day and 73.94% of accumulative release was observed after 5 days. The TA suspension showed more TA penetration through the scleral-choroid complex than the saturated solution (P = 0.0104). The apparent permeability coefficients for the suspension across the sclera-choroid of pigmented and albino rabbits are 7.48 -1.53 · 10 -6 cm/s and 10.78 -2.49 · 10 -6 cm/s, respectively. Conclusions: TA can bind to and release from the ocular pigment, which may extend the TA ocular half-life and therapeutic duration when TA is delivered through a subtenon injection. A further in vivo study is warranted to validate the findings and to quantitate the magnitude of the difference between pigmented and albino animals.

Safety of intradiscal delivery of triamcinolone acetonide by a poly(esteramide) microsphere platform in a large animal model of intervertebral disc degeneration

“…This may be due to the limited amount of tissue available for extraction and analysis (1/4 IVD) combined with TAA levels in the NP around the detection limit. On the other hand, TAA is known to bind to proteins [61], thereby extending its half-life and therapeutic duration, as has been shown for ocular pigments in applications for eye diseases [62]. Hence, another possible explanation for the presence of TAA in the AF opposed to the NP might be the binding of TAA to ECM proteins, which are more abundantly present in the AF than in the NP.…”

Understanding Molecular Drivers of Melanin Binding To Support Rational Design of Small Molecule Ophthalmic Drugs

“…An initial set of 72 chemically diverse small molecules was selected for method development. These compounds were first measured in a small-scale binding assay as reported elsewhere . Subsequently, the same compound set was used as a reference set during the optimization of the HT method as described in the Experimental Section.…”

“…The elimination rate of the compound from melanosomes governed by its dissociation rate from melanin and membrane permeability is expected to be a key determinant for the ocular half-life and the steady state concentration . Whereas the release kinetics from the pigmented tissue is an important parameter defining the concentration–time profile, there have been very limited attempts to address this release process experimentally. , In this context, there is a need to better understand the kinetic aspects of melanin binding of small molecules to warrant the opportunity to access novel treatments for the back of the eye.…”

Safety and pharmacodynamics of suprachoroidal injection of triamcinolone acetonide as a controlled ocular drug release model

“…Development of a safer ocular drug delivery route has become an unmet need. Our group has been focusing on periscleral drug delivery which includes transscleral [15][16][17][18][19] and suprachoroidal routes. The current study was designed to compare traditional subtenon drug delivery with the emerging technique of suprachoroidal drug delivery in the context of medical care of posterior segment eye diseases.…”