Nasal absorption of insulin: enhancement by hydrophobic bile salts.

Abstract

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...

Fate of aerosolized recombinant DNA-produced alpha 1-antitrypsin: use of the epithelial surface of the lower respiratory tract to administer proteins of therapeutic importance.

“…It has a vastly larger surface area (and thus a much larger potential absorptive surface) compared to the nasal, buccal, or rectal surfaces, sites that have been evaluated for administration of proteins (41,42). In this regard, the use of the lower respiratory tract may obviate the need to augment absorption per unit area, as has been suggested for the nasal epithelium using absorption enhancers such as bile salts, surfactants, or acrylic resins (43)(44)(45). Furthermore, unlike the gastrointestinal tract, the lower respiratory tract surface is not a hostile environment to proteins.…”

Potentials and Limitations of Bile Acids and Probiotics in Diabetes Mellitus

“…The amount of insulin absorbed also increases with increasing hydrophobicity of the bile salt. The order of bile salts' ability to increase insulin absorption is DCA>CDCA>CA>UDCA (Gordon et al 1985b). When sodium deoxycholate, the most hydrophobic bile salt, is co-administered with insulin, the absorbed insulin causes more than 30% reduction in blood glucose levels in diabetic subjects (Moses et al 1983).…”

“…Large peptides such as insulin are not easily absorbed through the nasal mucosa when administered via a nasal spray (Hirai et al 1978). Insulin must be transported between or through the apical and basal membranes of columnar cells, basal cells and capillary endothelial cells of blood vessels ( Figure 5) (Gordon et al 1985a;Li et al 1992). However, it must first cross the mucous layer which varies in thickness averaging between 5 and 20 mm in depth.…”

“…The study concluded that deoxycholate caused the greatest solubilising effect on the nasal mucosa while taurocholate caused the least effect. Another study (Gordon et al 1985a) was carried out in human, to investigate the physicochemical properties of bile salts and their relations to the permeation effect in nasal drug delivery. As expected, the rate of absorption of drug molecules was directly correlated to the bile salt's lipophilicity and their permeation effect.…”

Influence of Bile Salts as Excipients in Ranitidine, Aminophylline and Phenobarbital Tablets on Dissolution Rate

“…Beside their physiological role, micellar solutions of bile acids can solubilizate poorly soluble organic substances [5]. Furthermore, bile acids have a promoting effect in the transport of some polar drugs [6]. It has also been shown that the glycosylated derivates of bile acids facilitate transport of insulin and calcitonin through cell membrane [7].…”