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Figure 8 Comparison of time-release profiles from three different preparations of betaxolol: (----)

drug solution representing marketed product, (----) suspension formulation, (----) gel formulation.

down the canaliculi into the lacrimal sac, and continues into the gastrointestinal tract. It is due to this mechanism that significant systemic effects for certain potent ophthalmic medications have been reported (200-202). This also is the mechanism by which a patient may occasionally sense a bitter or salty taste, typical of therapeutic ammonium salts, following the use of eyedrops. The influence of drop size on bioavailability has been investigated thoroughly for conventional formulations and is significant (203). Even for nonconventional viscoelastic formulations, drop volume can be expected to influence efficacy and needs to be optimized (204). The clinical significance of drainage is so well recognized that manual NLO has been recommended as a means of improving the therapeutic index of antiglaucoma medications (205). Once the dynamics of tear-flow excess have taken their course, steady-state hydrodynamics can be expected.

Loss of drug from a precorneal volume has been investigated both in vivo and in vitro. These studies relate to both design of dosage forms as well as investigations of transport, bioavailability, and pharmacokinetics. Simultaneous release profiles of drugs and adjuvant from an artificial in vitro reservoir, designed with its volume to be characteristic of the eye, can be correlated simply with exposure for transmembrane transport (206). An example of release profiles and the influence of dosage form from one of these models, the Controlled Release Analytical System (CRAS) model, is shown in Figure 8.

Simple hydrodynamic analysis of the in vitro mechanism indicates that the elution concentration, in the absence of absorption, is a linear kinetic process, with a release profile that scales as the ratio of the tear production to the volume of the tear reservoir, Vt/Vt- Specifically where NB(t) is the time-dependent total amount eluted from volume in time t, VT the volume of the reservoir, VT the flow rate through reservoir (alternatively Qr), and N\ the

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