Measurement and Prediction of Timolol Diffusion with and Without Simulated Tear Flow

1. Measurement and Prediction of Timolol Diffusion with and Without Simulated Tear Flow Rowe T.E1, Akande J.A 1A, Reed K.2 AOphthalmic Formulation Development, 1Encompass Pharmaceutical Services, Norcross, GA; 2Ophthalmic Formulation Development, Encompass Pharmaceutical Services, Hawthorn Woods, IL. 2452 Purpose Discussion Results To correlate in vitro trans corneal diffusion of Timololunder static and simulated tear flow conditions to published animal pharmacokinetic data. Rate of Diffusion of Timolol XE and Solution Across Rabbit Cornea Rate of Elimination of Timolol from Donor Compartment • Under simulated tear flow conditions: • Relative AUC and total % Timolol (180 min) values correctly indicate that a large increase in aqueous humor concentrations should result when Timoptic XE® is administered as indicated in the summary tables. • In addition, the maximum rate of corneal diffusion appears to occur for a longer time for Timoptic XE® than for the Timolol solution. This is in agreement with the later aqueous humor tmax value given for Timoptic XE® as compared to Timolol solution. Introduction It is recognized that the topical delivery of medications to the eye is challenged by the elimination of drug formulations from the pre-corneal area by tear flow. A Franz diffusion cell was modified to include simulated tear flow to better assess the impact of formulation changes on the diffusion of active moieties across isolated rabbit corneas. To test this model, an in Vitro trans-corneal diffusion study comparing Timoptic (solution) and Timoptic XE (gel) was performed under both static and simulated tear flow conditions. The amount of Timolol that diffused across the cornea as well as the amount of Timolol retained in the pre-corneal (donor) area were compared. In vitro data was compared to published data regarding the total extent (AUC) and rate of diffusion of Timolol in the aqueous humor of rabbits1. Percent Timolol Delivered Timolol AUC Conclusion Cross corneal diffusion profiles are an important parameter in predicting ocular drug disposition. The in vitro transcorneal diffusion of Timolol, when using simulated tear flow, compared favorably with the comparative differences of Timoptic® and Timoptic XE as seen in the in-vivo rabbit pharmacokinetic (PK) profiles The animal PK profiles are, in turn, reflective of the clinical efficacy of Timoptic® and Timoptic XE. A model which implements simulated tear flow appears to be more predictive of Timolol ocular pharmacokinetic profiles and more properly evaluates the impact of formulation changes on the in vivo corneal diffusion profile than a static in vitro corneal diffusion model. Methods • Frozen mature rabbit corneas were thawed in DMEM and evaluated for apparent surface damage, swelling and opacity • Rabbit corneas were placed on specially adapted spherical diffusion Franz Cells maintained at 34°Cand dosed with 0.3 mg (about 2 drops) of Timoptic or Timoptic XE. • For the dynamic experiments the pre corneal layer was initially flushed with PBS at an increased flow rate immediately post-dosage to simulate reflex tear flow then reduced to a basal flow rate for the of the duration of the experiment.Pre-corneal flow was applied for static diffusion experiments • To evaluate drug retention and extent of absorption characteristics of each Timolol formulation, eroded solution from the pre-corneal layer was collected at intervals for analysis. Receiver chamber solution was also sampled at selected intervals. • Analysis of samples were performed via HPLC • Relative AUC and total Timolol values correctly indicate that a large increase in aqueous humor concentrations should result when Timoptic XE is administered rather than solution Conclusion Discussion • Comparison of the in-vitro Isolated Cornea Models to In vivo data • The literature source* indicates that: • Relative AUC values of Timolol in the aqueous humor of rabbits are 1.0 • for the solution and 2.43 for Timoptic XE®. • Relative Cmax values are 1.0 for the solution and 1.69 for Timoptic XE®. • tmax Values of 30 min are obtained for Timolol solution and 60 min for • Timoptic XE®. • In Vitro trans corneal diffusion indicates: • Under static conditions: • Relative AUC and total % Timolol values were not in agreement with the • increased Timoptic XE aqueous humor levels seen from the animal PK data • nor were they in the correct rank order. Results Diffusion of Timolol Across Rabbit Cornea under Static Conditions. N = 7 Diffusion of Timolol Across rabbit Cornea with Simulated Tear Flow. N = 7 References • Addicks J. Pharmaceutical research, Vol. 4. 1984 • *Burgalassi et. al. J. Ocular Pharm. Therapeutics,Vol.16, No 6, 2000. pp 497-409. • Chiang C. J. Ocular Pharm. Therapeutics,Vol.12, No 4, 1996 . pp 471-481. • Edman, P. Biopharmaceutics of Ocular Drug Delivery Standard static diffusion did not distinguish any differences between Timoptic and Timoptic XE There were significant differences in the characteristics of Timolol solution and Timoptic XE with simulated flow