Part 1. Pulmonary delivery of free and liposomal insulin. Part 2. Host-guest interactions of beta-cyclodextrin and its derivatives with substrates: Effects of ligand structure and substrate hydrophilicity

Fang-yu Liu, Purdue University

Abstract

Part 1. $\alpha$-Chymotrypsin mediated degradation of insulin was performed to quantify the difference of dimeric and hexameric insulin relative to their rates of degradation. The degradation of dimeric insulin by $\alpha$-chymotrypsin was about three-fold higher than that of hexameric insulin. Similarly, the degradation of insulin dimers in the lung homogenate was found to be faster than that of insulin hexamers. Metabolism of insulin in rabbit lung homogenate produced two major metabolites (A and B). Only one metabolite (A) was identified in rat lung homogenate. The primary structures of metabolites were des-Phe$\sp{\rm B-1}$ (A) and des-Phe-Val$\sp{\rm B1-2}$ (B) insulin. In vivo study revealed that both insulin dimers and hexamers can produce a rapid hypoglycemic effect following intratracheal instillation of insulin solution. The initial response of hexameric insulin was slower than that of dimeric insulin possibly due to the slower rate of absorption of large molecular weight hexameric species. Dipalmitoyl phosphatidylcholine (DPPC) liposomes could enhance lung uptake of insulin as was evidenced from an increase in hypoglycemic response and plasma insulin level. This study suggests that the pulmonary route may be an effective mode for systemic delivery of peptide and protein based therapeutic agents. Part 2. The structural effect of steroids (cortisone, hydrocortisone, progesterone, and testosterone) on their complexation with $\beta$-CD was studied with phase solubility and spectroscopic techniques. The results suggested that the complexes were formed at a stoichiometric ratio of 1:2 (steroid:$\beta$-CD) and the inclusion of a steroid molecule into the first $\beta$-CD cavity is thermodynamically more favorable than the association of 1:1 complex with the second $\beta$-CD molecule except for cortisone, which exhibits anomalous behavior. Amorphous 6-acyl-o-$\beta$-CD derivatives were synthesized by esterifying the primary hydroxyl groups at the 6-position of $\beta$-CD using several acyl chlorides. The results indicated that the solubilities of 6-acyl-o-$\beta$-CD derivatives were significantly higher than that of $\beta$-CD itself, which resulted in an increase in their solubilization power. The difference in complexation with steroids between 6-acyl-o-$\beta$-CD derivatives and $\beta$-CD was investigated. A phase solubility approach was established to study weak electrolyte/cyclodextrin complexation. A mathematical model was proposed to estimate the equilibrium constants for both weak acid and conjugate base forms.

Degree

Ph.D.

Advisors

Mitra, Purdue University.

Subject Area

Pharmaceuticals

COinS