Functions of Lipids for Enhancement of Oral Bioavailability of Poorly Water-Soluble Drugs 711 The API accumulated at the surface of the absorptive epithelium is taken up by enterocytes. Certain drugs and surfactants reduce the activity of efflux transporters in the GI-wall and, hence, increase the fraction of drug absorbed. Because of the interplay between P-gp and CYP3A4 activity, this mechanism may reduce intracellular metabolism as well. Non-digestible lipids, including mineral oils, sucrose polyesters and others, are not absorbed from the gut lumen. They remain in the gastrointestinal lumen, tend to retain the lipophilic drug within the oil, and thus, may limit the absorption of the drug. Consequently, lipids that are not affected by negative effects of surfactant such as medium chain monoglycerides, fatty acids, and monoesters of fatty acids are preferred as vehicles for lipid delivery systems. Mean emulsion droplet diameter: The mean emulsion droplet diameter is a parameter indicating the quality of self- emulsifying formulations. The droplet size of SEDDS upon dilution with aqueous media is primarily influenced by the type and concentration of emulsifier: The higher the concentration of emulsifier, the smaller the emulsion droplet and the faster the drug release. Two techniques are commonly used to determine the mean emulsion droplet diameter: low angle laser light diffraction is applied for emulsions with droplet sizes > 1µ and quasi-elastic light scattering for investigations of submicron dispersions. [15–17]. In addition, the mean emulsion droplet diameter seems to be a very critical factor for prediction of the in-vivo performance of undigested lipid-based formulations, such as long chain triglycerides in case of Cyclosporine (Neoral® versus Sandimmune®) [18]. Nevertheless, in case of predigested lipids such as medium chain monoglycerides or propylene glycol monoester of C8-C10 fatty acids, the mean emulsion droplet diameter may not be crucial in-vivo. Lipophilicity of the API Highly hydrophobic drugs (log P > 6) can be taken up into the lymphatic system by partitioning into chylomicrons in the mesentery vein [19] which has been demonstrated to be crucial for the absorption of the anti-malaria compound halofantrine [20, 21]. Furthermore, highly lipophilic retinoids are known to be transported in the intestinal lymph after oral administration. Type of lipids Drug release The nature or type of lipids is important because digestible lipids may influence absorption in a manner differing from that of non-digestible lipids. Commonly used digestible lipid vehicles are listed in table 1. The lower the melting point of the fatty acid, the higher is the amount of drug absorbed. Primarily, the characteristics of drug and lipid as well as their aqueous solubility are key factors that control drug release and absorption from lipid-based formulations [22]. Other issues to be considered are whether the drug is formulated in oil, SEDDS or emulsified form, the absorption pathway of the drug, the droplet size of the emulsion present in the intestine, the type of surfactants, the metabolic pathway of the lipids and the changes in gastric motility due to presence of lipids. Sci Pharm. 2011; 79: 705–727