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the physical model with pores (228). Characteristic of correlations of this type is the slope's value, less than 1. The origin of the smaller calculated values of permeability coefficients is unknown. A reasonable conjecture, however, is that the estimated diffusion coefficients, that is, the laws presented in equation (4), on which the permeability is based, are not quite correct for the drugs in different ocular environments. The predictability of the model is useful both for providing approximate values and distinguishing departure from simple diffusional transport. Also apparent from a comparison of the last two figures (Figs. 13 and 14) is the significance of solubility, since it is the value of Cw that controls flux by orders of magnitude.

A significant inference from the model is that if, as is the conventional behavior of a family of molecules, the solubility decreases with an increase in distribution coefficient, eventually this effect will profoundly reduce the transcorneal flux. Alternatively and conceptually, for any class of molecules with a desirable physiological response and without significant differences in potency or therapeutic index, the member of that family with the greatest promise for ophthalmic application is the one with lowest molecular weight, highest distribution coefficient, and highest aqueous solubility. However, since the last two requirements are in general inconsistent (the most soluble molecule is generally the one with lowest partition coefficient), the model helps select the molecular structure for which the flux is greatest.

Perhaps as more is learned about the molecular requirements for binding therapeutic agents to active sites of macromolecules as part of the intention to control physiological function, these simple transport requirements can be incorporated into the molecular design.

Role of Specialized Formulations

Many materials and specialized formulations have been devised with the intention of improving delivery of drugs to intraocular tissues by means of the transcorneal route. Carriers have been used both alone and in conjunction with viscosifying or responsive formulations to control concentration of the active therapeutic compound or sustain delivery. As calculations clearly demonstrate and experiments confirm, the impact on total drug availability for such systems is crucially dependent on the degree to which the vehicle is capable of sustaining residence time of the drug or drug carrier in the eye (183). The historical and current challenge remains to devise spontaneously responsive systems that are capable of being retained in the eye, sustaining the presence of the carrier without degrading its reservoir and delivery characteristics, and without producing such conventional side effects as blurring or undesirable residues.

In recent years a barrage of technologies has been developed for sustaining delivery of drug to the cornea. Corneal collagen shields and contact lenses loaded with drug have been placed directly on the cornea. But undesirable side effects including blurring, dumping of drug, packaging, and storage problems have prevented these technologies from being successful in the marketplace. Responsive polymeric systems have been more successful to date. Polymers whose solubilities and interactions are dominated by hydrogen bonding can be controlled with temperature, whose solubilities are dominated by coacervation-type interactions can be controlled by the concentration of the complementary polymer, whose solubilities are dominated by weak acid ionization can be controlled by pH, and whose solubilities are dominated by ion-pairing condensation can be controlled by ionic strength or even specific ion concentrations. Those systems utilizing mechanisms less impacted by the environment have proven more widely applicable.

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