Formulation and physiological and biopharmaceutical issues in the development of oral lipid-based drug delivery systems

The rapidly increasing availability of drug receptor structural characteris tics has permitted the receptor-guided synthesis of potential new drug mole cules. This synthesis strategy frequently results in the creation of polycy clic and highly hydrophobic compounds, with attendant poor oral bioavailabi lity resulting from low solubility and slow dissolution rate in the primari ly aqueous contents of the gastrointestinal (GI) tract. In an attempt to im prove the solubility-limited bioavailability associated with these compound s, formulators have turned to the use of lipid excipients in which the comp ounds can be solubilized prior to oral administration. This new class of ex cipients presents the pharmaceutical scientist with a number of new challen ges at all stages of the formulation development process, beginning with th e excipient selection and stability assessment of the prototype formulation , up to and including scale-up and mass production of the final market-imag e product. The interaction of lipid-based formulation with the gastrointest inal system and associated digestive processes presents additional challeng es and opportunities that will be understood more fully as we begin to unra vel the intricacies of the GI processing of lipid excipients. For example, an increasing body of evidence has shown that certain lipids are capable of inhibiting both presystemic drug metabolism and drug efflux by the gut wal l mediated by p-glycoprotein (PGP). An, it is well known that lipids are ca pable of enhancing lymphatic transport of hydrophobic drugs, thereby reduci ng drug clearance resulting from hepatic first-pass metabolism. This review addresses the current state of knowledge regarding oral lipid-based formul ations development and scale-up issues and the physiological and biopharmac eutical aspects pertinent to the development of an orally bioavailable and efficacious dosage form.