Abstract
Purpose :
The permeability of the cornea to topically applied formulations is a major factor determining their clinical efficacy. Various agents could influence the corneal permeation including Benzalkonium chloride (BAC) or surfactants which help lipophilic agents solubilization. The purpose of the study was to evaluate the permeation of different Latanoprost formulations through an in vitro reconstructed human 3D corneal tissue model (EpiCornealTM).
Methods :
EpiCorneal tissues are comprised of normal human corneal epithelial cells and attain morphology, barrier properties, and gene expression similar to the human cornea. 3 different formulations of 0.005% Latanoprost were tested: A. preservative-free (PF) and surfactant-free (SF) formulation; B. same SF formulation but containing BAC 0.02%; and C. different PF formulation but containing Macrogolglycerol hydroxystearate 40 (MGHS 40) at 5%. 100 μL of 1:5 diluted formulations were applied onto the EpiCorneal tissue surface and incubated at standard cell culture conditions (37○C, 5% CO2, 95% RH). Samples were collected after 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hr permeation and analyzed with a validated HPLC method for Latanoprost acid (LAT) detection (active form). Barrier integrity (TEER, Transepithelial Electrical Resistance) was determined before and after the permeation. For each formulation, plots of the cumulative amount of LAT that permeated through the tissue versus time were constructed. From the steady state flux region of the plot (<4 h), the permeation coefficient (Papp) was calculated.
Results :
The transport profile of LAT formulations was linear from 2 to 12 hours for C and from 1 to 4 hours for A and B and then curved to reach a plateau. A and B had a similar permeation pattern, comparable at each timepoint. Papp was fastest and comparable for A and B (~8.5 cm.s-1); C had the lowest Papp (3.14 cm.s-1). Tissue integrity was maintained in all experiments.
Conclusions :
The absence or presence of BAC within the formulations A and B did not influence the permeation profile as similar LAT cumulative amount and Papp were obtained. However, formulation C resulted in a lower and slower permeation pattern when compared to formulations A and B which may be due to the presence of MGHS 40. Thus, the EpiCorneal tissue model allowed us to anticipate the pharmacokinetics of LAT and the excipients' role. The results were confirmed in an in vivo rabbit model study.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.