Abstract
Purpose :
Currently, intravitreal injections (IVT) are the standard treatment for retinal diseases. However, these invasive injections require frequent visits to health care which often leads to poor patient compliance. This study explores the potential of topical drug delivery to the retina through the non-corneal route. The aim is to determine the apparent permeability (Papp) of small molecular weight compounds through ex vivo rabbit sclera and sclera-choroid-RPE (SCR).
Methods :
13 compounds were cassette dosed into a Ussing diffusion chamber system in which freshly dissected rabbit ocular tissues were placed between the two chambers. Balanced salt solution (BSS plus) was used as an experiment buffer, the chambers were mixed by bubbling with a gas mix of 5 % CO2, 10 % O2, 85 % N2 and maintained at 37°C for the 6-hour experiment. To ensure tissue integrity, transepithelial potential difference (TEP) measurements were conducted with a Voltage-current clamp (VCC MC6) and used for the calculations of the transepithelial electrical resistance (TER = ΔV/ΔI * A; ΔV difference in voltage, ΔI the applied current, and A area of the exposed tissue). Permeation of atenolol was also used as an integrity marker. The same experiment was also conducted with a Franz cell with sclera. Sample analysis was performed using liquid chromatogram mass spectrometer triple quadrupole (LC-MS QQQ) and the resulting data were analyzed with MassHunter QQQ quantitative analysis program.
Results :
The Papp values through sclera in the Ussing system ranged from 1.86 ± 2.42 *10-6 cm/s (n=11) to 7.79 ± 2.19 *10-6 cm/s (n=12) propranolol being the least and atenolol the most permeable. In the Franz system, Papp values were 2-4 times higher (p<0.01). Corresponding values through SCR were 0.030 ± 0.013 and 1.05 ± 0.41 *10-6 cm/s (n=5) for propranolol and fluconazole respectively, indicating that the sclera is significantly more permeable than the SCR (p<0.05). Tissues were confirmed to be intact.
Conclusions :
In summary, the sclera is not the main barrier for non-corneal permeation and comparing the Ussing chamber with the Franz cell is challenging. Also, the Papp values showed minor variation considering the diverse compound properties. The results give valuable information about the rate-limiting membrane in topical drug delivery and for the future development of less invasive administration routes to treat retinal diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.