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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.
Purpose
To correlate in vitro trans corneal diffusion of Timolol under static and simulated tear flow
conditions to published animal pharmacokinetic data.
Rate of Diffusion of Timolol XE and
Solution Across Rabbit Cornea
Introduction
120
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
Results
Diffusion of Timolol Across rabbit Cornea
with Simulated Tear Flow. N = 7
d
35.0
70.0
30.0
Rate of Elimination of Timolol from
Donor Compartment
Timoptic XE
Diffusion (mg/min)
0.00140000
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.
Diffusion of Timolol Across Rabbit
Cornea under Static Conditions. N = 7
Discussion
Results
Timoptic XE
0.00120000
Timolol Solution
Timolol Solution
Timoptic XE
100
80
0.00100000
0.00080000
0.00060000
0.00040000
0.00020000
0.00000000
0
50
100
150
200
Time after dosing (mins)
% of Initial Dose
2452
Measurement and Prediction of Timolol Diffusion with and Without Simulated Tear Flow
60
40
20
0
0
Percent Timolol Delivered
Product Donor Cell
Condition
Timolol Static – No
Solution
flow
Timoptic Static – No
XE®
flow
Timolol Simulated
Solution tear flow
Timoptic Simulated
XE®
tear flow
%
Delivered
at 180
mins
Relative %
Delivered at
180 Min
62.0
1.00
59.1
0.95
12.4
1.00
29.3
2.36
20
40
60
80
100
Time after Dosing (mins)
Timolol AUC
Product
Donor Cell
Condition
Timolol
Solution
Static – No
flow
6036 ± 691
1.00
Timoptic
XE®
Static – No
flow
5164 ± 1265
0.86
Timolol
Solution
Simulated
tear flow
1585 ± 460
1.00
Timoptic
XE®
Simulated
tear flow
3342 ± 517
2.11
AUC
Relative
AUC
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
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®.
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.
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 invivo rabbit pharmacokinetic (PK) profiles The
Conclusion
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.