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T. E. Rowe, J. M. Akande, K. Reed; Measurement and Prediction of Timolol Diffusion With and Without Simulated Tear Flow. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2452.
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Comparison of in vitro trans corneal diffusion of timolol under static and simulated tear flow conditions to compare results from published animal pharmacokinetic data.It is recognized that the topical delivery of medications to the eye is challenged by the flow of tears removing formulation from the pre corneal area. An in vitro corneal diffusion model that incorporates flow conditions into the donor compartment better mimics in vivo appearance of the drug in the aqueous humor.
Rabbit corneas were placed on specially adapted spherical Franz Cells. Samples of Timoptic or Timoptic XE were placed on the cornea. Experiments were performed with and without buffer flowing across donor compartment. Permeate drug in the receiver was collected over time. When donor compartment flow was implemented, additional samples were collected through the outlet flow port of the donor compartment. The amounts of Timolol that diffused across the cornea were compared to the published total extent (AUC) of Timolol in the aqueous humor of rabbits1.
There were significant differences in the diffusion charactistics when comparing diffusion rates with and without simulated tear flow. While a static standard diffusion model could not distinguish any differences in diffusion rate, the distinction between Timoptic and Timoptic XE® was clear when a simulated tear flow was instituted. The comparison of the diffusion rate using simulated tear flow compared favorably with the comparative differences seen in the pharmacokinetic profiles in rabbits which in turn are reflective of the clinical efficacy of Timoptic and Timoptic XE
Cross corneal diffusion profiles are an important parameter in predicting ocular drug disposition. A model which implements simulated tear flow appears to be more predictive than a simple diffusion model and should more properly evaluate the impact of formulation, changes on the corneal diffusion profile.
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