Development of an in vitro model to estimate mass transfer from the anterior cavity

Abstract

Knowledge of drug mass transfer from the anterior chamber via the iris-lens barrier has important implications for the development of front of the eye medicines that can also deliver drugs to the vitreous cavity. Here, the design and evaluation of a novel in vitro model that estimates anterior clearance (CL) kinetics is described. To mimic some aspects of the human eye to aid with pharmaceutical modelling, the model incorporated a simulation of aqueous inflow from the ciliary inlet at the physiological flow rate, two CL elimination pathways [anterior hyaloid pathway and retina choroid sclera (RCS) pathway], human cavity dimensions and use of simulated vitreous fluid (SVF). An eye movement platform that incorporated 3 different eye movements (smooth pursuit, microsaccadic and saccadic) was tested against the control (no movement) to observe any difference in anterior kinetics profile and drug convection to the posterior cavity. Both timolol and brimonidine injected in the intracameral space were evaluated in the new in vitro prototype. An initial release study with one selected eye movement (smooth pursuit) with timolol (6.8 ± 0.4 µg, 30 μL) and brimonidine (15.3 ± 1.5 µg, 30 μL) showed half-life values of 105.3 and 97.8 min respectively in the anterior cavity (AC) space. Another study evaluated the effect of all eye movements against control with both drugs with higher doses of timolol (146.0 ± 39.1 μg, 25 μL) and brimonidine (134.5 ± 39.5 μg, 25 μL). The amounts of timolol in the back of the eye (RCS membrane and outflow) were 0.07 ± 0.05%, 1.36 ± 0.88%, 1.55 ± 1.03% and 0.98 ± 0.06% by 8 h with smooth pursuit, microsaccadic, saccadic and no movement respectively; whereas brimonidine amounts were 0.70 ± 0.21%, 0.94 ± 0.40%, 1.48 ± 1.02%, and 0.76 ± 0.33% respectively. A small amount of both drugs was seen in other compartments in the model (lens part, iris part, hyaloid membrane part and silicone cornea). These results indicate that this model can be used to determine transfer of small molecules via the iris-lens barrier to help optimise front of the eye formulations to treat tissues further back in the eye.

Real-Time Monitoring Platform for Ocular Drug Delivery

“…Here, this model was used to understand the advanced capabilities of the microfluidics in testing the pressure of two membranes [ 25 ], which have not been previously demonstrated. Though not shown in this current manuscript, the RCS model helped develop the intracameral model ( Table 1 ) [ 26 ], which has been used to extensively understand the capabilities of the microfluidic system and the eye movement platform for intracamerally administered small molecules.…”

“…Micro-saccadic eye movements correspond to visual fixation and have a low magnitude of the angle displacement (0.55 ± 0.07°) covered in a short time frame (13 ms) that is repeated at an average of 1.25 s [ 51 ]. The effect of these three eye movements has been previously demonstrated in vitro with intracameral small molecules (timolol and brimonidine) [ 26 ]. The release of intravitreally injected small molecules and biologics in the posterior inflow model, ciliary inflow model and RCS model has also been extensively demonstrated [ 25 ].…”

“…PT-100 measurements ranged from −50°C to 250 °C with a tolerance of ±0.15 + 0.002 × temp (in °C). The program variables (acceleration and temperature) and graph readouts were recorded (drug release with and without eye movements have been previously reported [ 25 , 26 ]).…”

“…In recent years, there has been progress in designing and reporting ocular in vitro models for preclinical testing in research. In vitro models have been designed to evaluate protein stability in simulated vitreous fluids (SVF) [ 19 ], to understand the effects of eye movements (EyeMos system) [ 20 , 21 ], and to evaluate the effect of SVF and aqueous outflow on drug release/clearance times (PK-Eye™ models) [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. PK-Eye™ model variants™ have also been reported in the literature [ 29 , 30 ].…”

“…Various PK-Eye™ prototypes have been designed over the years to predict mass transfer and have been used for different testing purposes. These include the first-generation PK-Eye™ model [ 22 ], posterior inflow model [ 25 ], ciliary inflow model [ 25 ], retina-choroid-sclera (RCS) model [ 25 ] and an intracameral prototype [ 26 ]. The effects of diffusion and convection on drug clearance after drug administration from both the back and front of the eye have been previously investigated by varying port placement, and by altering membrane dimensions and properties.…”