Assessment of subconjunctival delivery with model ionic permeants and magnetic resonance imaging

• Published in: Pharmaceutical research 2004-12, Vol.21 (12), p.2175-2184
• Main Authors: Li, S Kevin, Molokhia, Sarah A, Jeong, Eun-Kee
• Format: Article
• Language: English
• Subjects: Animals; Conjunctiva - drug effects; Conjunctiva - metabolism; Dose-Response Relationship, Drug; Drug Delivery Systems - methods; Magnetic Resonance Imaging - methods; Osmolar Concentration; Permeability - drug effects; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - metabolism; Rabbits
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-004-7669-3

The objective was to assess the permeation and clearance of model ionic permeants after subconjunctival injection with nuclear magnetic resonance imaging (MRI). New Zealand white rabbit was the animal model and manganese ion (Mn2+) and manganese ethylenediaminetetraacetic acid complex (MnEDTA2-) were the model permeants. The current study was divided into three parts: in vitro, postmortem, and in vivo. Transscleral passive permeation experiments were conducted with excised sclera in side-by-side diffusion cells in vitro. Subconjunctival delivery experiments were conducted with rabbits postmortem and in vivo. The distribution and elimination of the probe permeants from the subconjunctival space after subconjunctival injections were determined by MRI. The data of excised sclera in vitro suggest large effective pore size for transscleral transport and negligible pore charge effects upon the permeation of the ionic permeants. The permeability coefficients of Mn2+ and MnEDTA2- across the sclera in vitro were 3.6 x 10(-5) cm/s and 2.4 x 10(-5) cm/s, respectively. Although relatively high sclera permeability was observed in vitro, subconjunctival injections in vivo did not provide significant penetration of Mn2+ and MnEDTA2- into the globe; permeant concentrations in the eye were below the detection limit, which corresponds to less than 0.05% of the concentration of the injection solution (e.g., less than 0.02 mM when 40 mM injection solution was used). The volume of the subconjunctival pocket and the concentration of the permeants in the pocket were observed to decrease with time after the injection, and this could contribute to the lower than expected subconjunctival absorption in vivo. Different from the results in vivo, experiments with rabbits postmortem show significant penetration of Mn2+ and MnEDTA2- into the globe with the permeants primarily delivered into the anterior segment of the eye. This difference suggests blood vasculature clearance as a main barrier for passive transscleral transport. The data also show that the pars plicata/pars plana is the least resistance pathway for passive transscleral drug delivery of the polar permeants, and there are indications of the presence of another barrier, possibly the retinal epithelium and/or Bruch's membrane, at the back of the eye. Subconjunctival delivery of the ionic permeants in vivo cannot be quantitatively predicted by the in vitro results. MRI is a noninvasive complementary technique to traditional ph