The development of oral insulin using the eligen technology represents a significant advance in insulin administration which is expected to improve the quality of life of diabetic patients. As clinical studies progress, a great deal of interest has focused on the process by which this technology enables insulin absorption from the intestinal lumen into the bloodstream. The eligen technology employs low molecular weight compounds (termed drug delivery agents or carriers) which interact weakly and non-covalently with insulin, increasing its lipophilicity and thereby its ability to cross the gastrointestinal epithelium. In this study we investigated the mechanism of insulin absorption across caco-2 cell monolayers with one of these drug delivery agents, N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC). Our results show that SNAC increases insulin permeability approximately ten fold across cell monolayers and does so without affecting mannitol permeability or disrupting cell membranes. Confocal microscopy and immunocytochemistry revealed that insulin is transported transcellularly without detectable alteration of the tight junctions between adjacent cells. SNAC also appears to play some role in protecting insulin from proteolytic degradation, potentially allowing for more intact insulin to be available at the site of absorption.

SNAC increases the permeability of Caco-2 monolayers to cromolyn without measurable cell damage. SNAC interacts with cromolyn mainly via ring stacking. One major mode of interaction appears to involve the insertion of the aromatic ring of SNAC between cromolyn's rings. Such interaction appears to reduce the hydration of cromolyn and thus optimize its hydrophobicity for oral absorption.

SI of any solution, including normal saline, seems to have a minor but detectable effect on the normal physiology of the lung. SI of positive control solutions resulted in most markers of immunity and lung injury being significantly elevated, notably enzyme activity and white cell infiltrate. In contrast, SI of INS produced a response similar to that of SAL. SI of INMA resulted in a small transient response characterized by a slight increase in the proportion of neutrophils at 24 h, which decreased with time and was comparable to that of SAL at 72

H-MAP has potential for increasing the pulmonary bioavailability of insulin administered through the lungs.

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