EFFECTS OF PHOSPHOLIPID CHAIN-LENGTH, CONCENTRATION, CHARGE, AND VESICLE SIZE ON PULMONARY INSULIN ABSORPTION

Purpose. Non drug loaded lipid vesicles have been investigated as prom oters of pulmonary insulin absorption. Methods. Physical mixtures of l iposomes with insulin were delivered intratracheally to rats by direct instillation method at an insulin dose level of 1 U/kg. Results. The overall hypoglycemic response, represented by area above the curve (AA C), correlated linearly with the lipid concentration for both the neut ral and charged liposome-insulin preparations. The strongest response was observed with the positively charged liposomes followed by negativ ely charged and neutral liposome-insulin mixtures. Further toxicologic al studies indicated that charge-inducing agents, i.e., stearylamine a nd dicetylphosphate, can cause apparent disruption of pulmonary epithe lial cells. From the difference of overall hypoglycemic response (AAC) among various formulations, it appears that the stronger hypoglycemic effect following positively charged liposome-insulin mixture is due t o the membrane destabilizing effect of stearylamine. Optimum hypoglyce mic effect was observed with a medium acyl-chain lipid (C10). The cumu lative hypoglycemic response appeared to correlate inversely with the acyl carbon number of the phospholipid component from C10 to C18. The overall hypoglycemic effect does not appear to change within the lipos omal size range of 0.1 mu m - 1.98 mu m, indicating that insulin absor ption following intratracheal instillation is independent of the vesic le size within the range studied. Conclusions. Phospholipid promoted i nsulin pulmonary absorption is significantly dependent on the concentr ation, charge and acyl chain length of the phospholipids.