Simulating infusion rate and plasma levels for matrix-based and reservoir-based implants.
Drug delivery from a diffusion-based system can be simulated using the transport-of-diluted-species module in Comsol Multiphysics™. To predict how fast a drug diffuses from the active layer into a dissolution vessel or a physiological body, each compartment of the delivery system is defined with its own solubility and diffusivity parameters, with fluxes defining the interaction between compartments. Permeability properties are most often determined using flat-film test methods described in the literature.
The in-vitro release rate in a dissolution vessel (under sink conditions) can differ significantly from the in-vivo infusion rate in the human body. Local saturation of the drug may limit the infusion rate into systemic circulation. A one-compartment pharmacokinetic model, built from clearance, distribution volume and permeability, determined via animal studies and scaled allometrically to humans, is added to predict drug plasma levels after administration.
Simulated using arbitrary molecular weight, drug solubility, diffusivity and pharmacokinetic values. The implant is 2 mm thick and 20 mm long, containing 50 wt% crystalline drug. Permeability across the surrounding tissue membranes was varied to study its influence on infusion rate and plasma levels.
At high tissue permeability, the infusion rate closely tracks the in-vitro release rate (a Higuchi-type matrix release profile). As permeability decreases, plasma levels decrease, release approaches zero order, and time-to-Cmax increases.
Same 2 mm × 20 mm implant, but only the outer 100 µm layer is loaded with crystalline drug. As with the fully-loaded matrix, plasma levels decrease with decreasing tissue permeability and release approaches zero order.
Once the outer layer's drug is depleted, the release rate falls to zero. By adjusting outer-layer thickness, the duration of drug delivery can be tuned precisely, using no more drug than necessary.
A reservoir-based implant (2 mm × 20 mm, with a 60 µm membrane and 50 µm active layer) was simulated at drug loads of 10 wt%, 20 wt% and 30 wt% to study the effect on implant duration.
Implant duration increases with increasing drug load. Once the active layer's drug is depleted, release falls to zero. As with the outer-layer matrix design, drug load can then be tuned to the desired delivery duration without excess drug.
