Pulmonary insulin absorption enhancement by bile salts and liposomes

Yuping Li, Purdue University

Abstract

The pulmonary route of drug delivery is traditionally used for localized therapy of respiratory diseases. However, the large absorptive surface area of the lungs and the highly distributed vasculature in the alveoli make this organ a potentially very useful site for systemic absorption of drugs. Peptides and proteins that undergo extensive GI degradation or are poorly absorbed through other alternative routes have been demonstrated to afford an improved bioavailability when administered through the lungs (Hoover et al., 1992). Nevertheless, the pulmonary route is still considerably less efficient than the injectable route due to the presence of a protective permeability barrier which limits drug absorption across the pulmonary wall. Studies were initiated to explore feasible absorption enhancers for the pulmonary delivery of insulin. A bile salt has been found to be an effective absorption promoter for pulmonary insulin absorption in this investigation and the mechanisms of bile salt-mediated pulmonary insulin absorption have been postulated. The stability study of insulin biodegradation by $\alpha$-chymotrypsin in the presence of the bile salt and bile salt-fatty acid mixed micelles has demonstrated that the incorporation of a fatty acid has greatly accelerated insulin biodegradation. The investigation of formulation variables revealed that an increase in the viscosity of an aqueous formulation can facilitate insulin absorption. Hypotonicity elicits a significantly improved hypoglycemic response due to the possible alveolar epithelial damage. A comparison of three different pharmacodynamic calculations with regard to predicting insulin plasma availability indicates that pharmacodynamic equivalence method appears to yield better correlation with absolute bioavailability than any other calculations. The feasibility of utilizing blank liposomes as carriers for pulmonary delivery of insulin has also been examined in this study. The results demonstrated that blank liposomes can improve insulin absorption significantly. Moreover, a physical mixture of liposomes with insulin is more effective in terms of pulmonary insulin absorption than liposomally entrapped insulin. The observation of insulin uptake by isolated pulmonary cells also verified that the endocytotic process could be a major transport mechanism responsible for liposome-mediated insulin pulmonary uptake.

Degree

Ph.D.

Advisors

Mitra, Purdue University.

Subject Area

Pharmaceuticals|Pharmacology

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