Importance of Unilamellar Vesicles

When human jejunal contents obtained during digestion of a lipid meal were ultracentrifuged, three distinct layers were isolated and included a solid pellet at the bottom of the tube on which was layered an intermediate, micellar solution phase topped by an oily layer (101). The oily layer was found to consist primarily of TG, partial glycerides, and FAs; the intermediate micellar solution layer consisted of bile salts, FAs, and MGs; and the pellet was composed primarily of calcium salts of FAs (soaps). When Porter and Saunders (115) carefully compared the micellar solution phase obtained after ultracentrifugation of intestinal contents to that prepared by passing the unprocessed intestinal contents through a series of filters with progressively smaller pores (the smallest being 100 nm in diameter), mild turbidity was noted, regardless of the method of preparation; in addition, these investigators noted the existence of a lipid concentration gradient in these samples. The importance of these observations was not fully realized until subsequent studies of in vitro fat digestion, conducted under light microscopy by Patton and Carey (116), identified the existence of a "viscous isotropic phase" within the micellar solution phase, which consisted of a liquid crystalline mixture of MG and FA. Thus, in addition to disc-shaped, bile salt mixed micelles, the aqueous phase may contain liquid crystalline vesicles (121). However, Carey et al. (33) proposed that when lumenal bile salt concentrations exceed the critical micellar concentration, lipid digestion products are incorporated into lipid-saturated, disc-like mixed micelles with a hydrodynamic radius of approximately 200 A in size. However, when the amount of lipid in the aqueous phase increases further, formation of liquid crystalline vesicles (liposomes) with a hydrodynamic radius of 400 to 600 A occurs, a process which does not require bile (33,117). This finding may explain the reasonably good fat absorption seen in patients with low intraluminal bile salt concentration (118) or in patiens with bile fistulae (119). Thus, Carey et al. (33) proposed that the liquid crystalline vesicles play an important role in the uptake of FA and MG by enterocytes in these diseased states. Though it is generally assumed that absorption of highly lipophilic drug occurs solely through micellar solubilization, the possibility that liquid crystalline vesicles may also play a role in promoting the absorption of these drugs cannot be ruled out.

Because liquid crystalline vesicles and mixed micelles coexist in the small intestinal lumen and constantly exchange MG, FA, and bile salt molecules, their relative roles in the uptake of FA and MG was unresolved for quite some time. A recent investigation by Heubi et al. (120) using a combination of human and lymph fistula rat studies has clearly demonstrated that the absorption of FA can be mediated by bile salt—lipid vesicles but that the absorption of cholesterol is mediated solely by micelles.

Shoemaker and Nichols (122) observed that bile salts and lysophospho-lipids form submicellar aggregates. These submicellar aggregates coexist with artificial PL vesicles in an aqueous medium. Shortly thereafter, these investigators provided convincing evidence that these submicellar aggregates serve as an efficient shuttle mechanism for the transfer of lysophospholipids between membranes (123). The existence of these submicellar aggregates in the intestinal lumen and their role in delivering lysophospholipids as well as lipid soluble molecules and drugs to enterocytes for absorption remains to be explored.

Intestinal epithelial cells have an apical brush border membrane made up of many microvilli which impacts the uptake of lipid digestion products and lipophilic drugs. For example, the microvilli of the intestinal epithelial cells have a width of about 100 nm. The space between the microvilli is much smaller, ranging between 5 to 20 nm. Thus, to access the space between the microvilli, lipid carrying vehicles cannot be larger than the width of the gaps themselves. Consequently, the lipid vesicles and nanoparticles that are commonly used to transport drugs into the gastrointestinal tract are probably not able to enter the space between the microvilli. However, submicellar and micellar particles are able to penetrate the gap thereby facilitating the uptake and transfer of lipid soluble molecules from the vesicles to the membrane of the microvilli, implicating the inportant interaction that must occur between a lipid-based formulation the the endogenous lipid handling system in order for efficient drug absorption to occur.

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