The value of oral exposure enabling formulation strategies at these early phases of lead optimization is very contingent on having a clear understanding of the potential reasons for poor oral exposure of a given lead or template (Amidon et al., 2003). It must be recognized that the decision to use a formulation enabling technology has the potential to begin guiding optimization in favor of delivery by that particular formulation strategy. This potential must be recognized and accepted as a possible outcome of incorporating enabling formulations into the optimization process. Enabling formulations can be very useful for proof of concept testing in which very little is known about the target and adequate blood levels for testing are difficult to obtain. The enabling formulation can allow verification of template activity and establish whether this template warrants further resource investment to engineer in adequate oral exposure without enabling formulations.
The use of enabling formulation strategies is most effective when there is clear evidence that the drug has poor water solubility but has a very high permeability. Solubility limitations can either be due to dissolution rate limitations or actual solubility limitations that govern flux rates across the membrane. (Oh et al., 1995; Rohrs subsequent chapter). To avoid dissolution rate limitations it is desirable for the solid form of the drug to undergo dissolution at a rate approaching that of absorption of the drug from the GI-lumen. The dissolution rate, or the rate at which a certain mass of molecules can "escape" the solid phase and enter the bulk medium, becoming available for absorption, is described by the Noyes-Whitney equation where k is a constant that is related to the hydrodynamics of the dissolution medium and conditions, A is the surface area in contact with the medium, Cs is the saturation solubility of the compound in that media, and C is the concentration of "free" compound in the media. Under sink conditions, i.e. where C<<Cs, the dissolution rate becomes directly proportional to the saturation solubility of the compound, Cs (Hamlin et al., 1965). While the dissolution rate can be increased by altering k through the changes in hydrodynamic constraints of the particular situation, (i.e. increases in media agitation or decreases in solution viscosity), the scientist has minimal control over this variable in the GI lumen. More commonly, efforts are undertaken to increase surface area through
particle size reduction, increase Cs through formation of high energy solid forms or minimize C by creating sink, or near sink, conditions in the dissolving media.
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