Proposed Mechanism For Enhanced Oral Bioavailability With Supersaturatable Selfemulsifying Drug Delivery Systems

In Chapter 12 of this book, which deals with SEDDS formulations of poorly soluble lipophilic drugs (1), it was suggested that the enhanced oral bioavailability seen with the SEDDS formulations can be explained by improved presentation of the poorly soluble drug to the enterocyte brush border region. This could be achieved by equilibration of the emulsion/microemulsion (E/ME) arising from contact of the SEDDS formulation with water or by equilibration of the drug in the remnant E/ME with the aqueous medium. The drug in the aqueous medium could become absorbed by the aqueous diffusional pathway or the drug could equilibrate with the BAMM with delivery to the enterocyte brush border membrane by collisional contact. Alternatively, the E/ME remnant could simulate the behavior of the BAMM in delivering the poorly soluble drug to the enterocyte brush border region.

In this chapter, it was found that the S-SEDDS formulations containing a small amount of HPMC (~40 mg/g of formulation) can result in generation of a supersaturated state that can be maintained for a few hours and this leads to enhanced absorption of poorly soluble, lipophilic drugs. The following discussion supports this proposed mechanism.

The existence of the supersaturated state was shown in our in vitro dissolution test where the drug filtrate concentration for a S-SEDDS formulation of PNU-91325 showed a maximum value of about 420 /xg/ml at 30 minutes (Fig. 2C, S-SEDDS with HPMC). However, the SEDDS formulation of PNU-91325, without HPMC, gave a drug filtrate concentration of only about 30 ^g/ml at three hours in the dissolution/precipitation test and thus, the approximate degree of supersaturation with the S-SEDDS formulation of PNU-91325 is 420/30 or about 14.

The approximately 10-fold (and higher) degree of supersaturation observed with the S-SEDDS formulation of PNU-91325, paclitaxel, and Drug X suggests that intestinal absorption should be markedly increased as a result of the supersaturated state. Based on intestinal flux theory, a drug with an aqueous solubility of only approximately 5 ^g/ml or less and a 200-mg dose would be expected to be incompletely absorbed in humans assuming a maximum permeability (plateau region) and a particle size of the drug in the micron range (51-55). The 10-fold improvement of the aqueous concentration of the drug from the supersaturatable formulations should allow complete absorption of 200 mg under the same circumstances.

The ability to generate a supersaturated state with HPMC with the S-SEDDS formulations is probably associated with the formation of a widely spaced cellulosic polymer network created by the HPMC chains in water, which, according to the literature, consists of "cellulosic bundles resulting in a tenuous network of swollen clusters with hydrophobic substituents surrounded by sheaths of structured water" (56,57). Studies on the mechanism responsible for inhibiting crystallization of drugs in aqueous solutions containing HPMC suggest that the HPMC polymer chain may inhibit nucleation as well as crystal growth by adsorption of the HPMC molecules onto the surface of the nuclei or on to the surface crystals (15,23,58). The general applicability of the cellulosic polymers in inhibiting crystallization of many pharmaceutical substances is widely reported (16-18,20,22,26,28,29,31).

In conclusion, the mechanism responsible for the enhanced intestinal absorption of poorly soluble drugs from S-SEDDS formulations containing HPMC is probably due to enhanced presentation of the drug to the enterocyte brush border region by the aqueous pathway due to the increased free drug levels achieved by supersaturation, and along with enhanced presentation of the drug to the enterocyte brush border by mimicking or equilibrating with the BA/BAMM pathway (1).

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