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ABSTRACT
Introduction: The sclera is considered the ‘static barrier,’ a main barrier for transscleral drug delivery. The characterization of passive and iontophoretic transport across the sclera in vitro is the first step toward our ability to predict transscleral drug delivery. Although previous studies have investigated this topic, the quantitative structure permeation relationships (QSPR) for passive and iontophoretic transscleral transport are not available.
Areas covered: This review evaluated previous results of transscleral passive and iontophoretic transport in vitro and examined QSPR for transscleral permeation of small permeants and macromolecules. Passive permeation data in the literature were compared with respective to the animal species employed in the studies. Data variability was investigated. Electrotransport theory and the mechanisms of iontophoresis were reviewed and used to analyze the iontophoresis data.
Expert opinion: QSPR was examined for passive transscleral permeation, showing correlations between logarithm of permeability coefficient and logarithm of molecular weight. Potential causes of data variability were proposed. QSPR were established for electroosmosis using the molecular weight of neutral permeants and for iontophoresis enhancement using the molecular weight and charge of ionic permeants. However, QSPR for charged macromolecules were empirical; iontophoretic flux enhancement was significantly smaller than Nernst-Planck model prediction due to complicating factors.
Article highlights
Passive and iontophoretic transport across the sclera in vitro has been investigated in the literature. However, establishing quantitative structure permeation relationships (QSPR) for passive and iontophoretic transscleral transport remains challenging owing to insufficient availability of data and large data variability observed for both transscleral passive and iontophoretic transport.
Diffusion theory with hindered transport describes transscleral passive transport. Permeant-to-sclera binding affects the transport behavior by significantly prolonging the transport lag times that could affect the apparent permeability coefficients measured in the studies.
Direct-field effect and electroosmosis are the major transport mechanisms of transscleral iontophoresis. Due to the structure of sclera and the experimental settings commonly used in transscleral permeation experiments, the modified Nernst-Planck equation can be used to analyze transscleral iontophoretic transport.
For transscleral passive transport, macromolecules demonstrate larger variability than small molecules, which could be related to the long transport lag time in insufficiently long permeation studies and possible influence of convective solvent flow effect on the apparent permeant flux.
For transscleral iontophoretic transport of neutral molecules, flux enhancement expressed in Peclet number can be predicted using molecular weight and current density.
For transscleral iontophoretic transport of charged molecules, particularly macromolecules, significant discrepancy between experimental data and theoretical prediction was found, likely due to the influencing factors such as electrophoretic effect and counterion condensation and the difficulty to accurately predict the electrophoretic mobilities of macromolecules.
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Declaration of Interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.