We demonstrate that therapeutically useful amounts of insulin are absorbed by the nasal mucosa of human beings when administered as a nasal spray with the common bile salts. By employing a series of bile salts with subtle differences in the number, position, and orientation of their nuclear hydroxyl functions and alterations in side chain conjugation, we show that adjuvant potency for nasal insulin absorption correlates positively with increasing hydrophobicity of the bile salts' steroid nucleus. As inferred from studies employing various concentrations of unconjugated deoxycholate and a constant dose of insulin, insulin absorption begins at the aqueous critical micellar concentration of the bile salt and becomes maximal when micelle formation is well established. These and other data are consistent with the complementary hypotheses that bile salts act as absorption adjuvants by (i) producing high juxtamembrane concentrations of insulin monomers via solubilization in mixed bile salt micelles and (ii) forming reverse micelles within nasal membranes, through which insulin monomers can diffuse through polar channels from the nares into the blood stream.Certain small peptides can be absorbed through the nasal mucosa as a "snuff" or directly from aqueous solution (1-5). However, efficacy of absorption is typically low and variable (1-5), and therapeutically important peptides of larger molecular size, such as insulin, are not absorbed to any appreciable degree (6). Within the gastrointestinal tract, bile salts promote the transmembrane movement of endogenous and exogenous lipids (7) and the transmembrane and/or paracellular movement of several small endogenous and exogenous polar molecules-e.g., water (7), inorganic electrolytes (7), polyethylene glycols (8), and oxalate (9). Because of these functions, as well as their detergent-like properties on biomembranes (10), bile salts are potential adjuvants for transmucosal delivery of drugs and have been widely explored for this purpose (11-17). Although there is abundant physical-chemical information concerning the micellar properties of bile salt molecules as well as their interactions with membrane and exogenous lipids (18,19), little is known about the mechanisms by which these molecules might enhance transmucosal absorption of drugs (17). As shown by us and others, bile salts promote the nasal absorption of insulin in man (20, 21) as well as in laboratory animals (6, 22). Nevertheless, previous studies in rats, employing a range of bile salt species, failed to define any useful structure-function relationships (23). We now report structure-function studies on a series of naturally occurring bile salts by testing their ability to enhance insulin absorption across the human nasal mucosa when administered intranasally as an insulin/bile salt spray. Dramatic differences in insulin absorption were observed between closely related bile salt species; the pattern was shown to be determined by the hydrophilic-hydrophobic balance (24) of the hydroxyl-substituted steroi...

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When prairie dogs (Cynomys ludovicianus) are fed a diet containing cholesterol, a marked increase in gallbladder mucin secretion parallels the evolution of cholesterol supersaturated bile. Gelation of mucin precedes the precipitation of cholesterol liquid and solid crystals and the development of gallstones. Aspirin given to prairie dogs inhibited mucin hypersecretion and gel accumulation and prevented gallstone formation without influencing the cholesterol content of supersaturated bile. This suggests that gallbladder mucin is a nucleation matrix for cholesterol gallstones.