Functions of Lipids for Enhancement of Oral Bioavailability of Poorly Water-Soluble Drugs 707 Impact of the GI-tract on Lipids and Lipid-Based Formulations The GI-tract basically influences the performance of lipid-based formulations as triglycerides and their derivatives are quantitatively hydrolyzed prior to absorption. After a meal, the presence of lipid digestion products induces secretion of pancreatic and biliary fluids which alter the luminal environment of the small intestine [5]. The lipid digestion products, being better water-soluble than the parent triglyceride, are solubilized within bile salt mixed micelles and for their subsequently delivered to absorptive cells of the GI-tract. The chemistry and nature of the interaction of lipid digestion products with the aqueous contents of the GI-tract change as a function of digestion and solubilization. Digestion of triglycerides Intestinal absorption of the products of lipid digestion is the result of three sequential processes, which involve (i) dispersion of fat globules (ingested lipids) to yield a coarse emulsion of high surface area, (ii) enzymatic hydrolysis of the fatty acid glyceryl esters (primarily triglyceride lipids) at the oil/water interface and (iii) dispersion of the lipid digestion products into an absorbable form [6]. Salivary glands secrete lingual lipase and gastric mucosa secretes gastric lipase, which initiate triglyceride (TG) hydrolysis to the corresponding diglyceride (DG) and fatty acid (FA) within the stomach. The pH-optimum ranges for lingual and gastric lipase from 3 to 6, and medium chain triglycerides are hydrolyzed at a faster rate than long chain triglycerides [7]. TG are preferably hydrolysed by pancreatic lipase, an interfacial enzyme, which preferentially acts at the surface of emulsified TG droplets to quantitatively convert TG into the corresponding 2-monoglyceride (MG) and two fatty acids (FA). Optimum activity is observed when oleate is the fatty acid, and it decreases towards shorter chain triacylglycerols and soluble carboxyl esters substrates. Bile salts at concentrations usually present in the duodenum inhibit binding of pancreatic lipase at the oil-water interface. Further classes of biliary-derived lipids are the phospholipids (e.g., phosphatidylcholine, PC) playing an important role as solubilisers for lipid digestion products. Prior to absorption, PC is hydrolyzed by phospholipase A2 to lysophophatidylcholine (lyso-PC), with the majority of PC present in the intestine secreted in bile (10–20 g/day) with only modest dietary influence. Model for the sequential steps involved in lipid digestion is given in Fig. 1. Physical chemistry, absorption and solubilisation of lipid digestion products Bile plays a key role in solubilisation of lipid digestion products and poorly water-soluble drugs [4]. The presence of lipid digestion products as well as cholecystokinin-mediated contraction of the gall bladder and relaxation of the sphincter of Oddi leads to expulsion of bile, with peak flow occurring approximately 30 min after ingestion of a meal. Typical concentrations of bile salts in the fasted intestine are 4–6 mM compared with post- prandial concentrations of 10–20 mM [8]. The inclusion of the lipidic components decreases the critical micelle concentration (CMC) and an increase the size and solubilisation capacity of the micelles, e.g., the inclusion of lecithin and MG decreases the CMC of mixed micellar systems to values less than 1 mM. Therefore, it is likely that the CMC of mixed bile salt systems present in the intestine is surpassed even in the fasted Sci Pharm. 2011; 79: 705–727