Nasal delivery of insulin: Mechanistic studies and pharmacokinetic pharmacodynamic modeling and analysis

Diabetes Mellitus affects an estimated 50 million people worldwide, and most diabetic patients require parenteral insulin therapy. For many patients, this is painful and inconvenient, and may lead to noncompliance and possible fatal hyperglycemia. Studies have demonstrated that the nasal route offers a promising alternative in delivering insulin at therapeutic levels.; The primary objective of this dissertation was to develop and characterize an intranasal delivery system for insulin. To meet this objective, the following specific aims were established and achieved: (i) Development of a chronic diabetic model; (ii) Design of a physiologically-relevant pharmacokinetic (PK)-pharmacodynamic (PD) model and its characterization for intravenous and intranasal administration; (iii) Investigation of potential enhancers and adjuvants for the enhancement of insulin bioavailability; and, (iv) Exploration of transport pathways for insulin across the nasal mucosa.; Alloxan, a pancreatic {dollar}{bsol}beta{dollar} cell-specific diabetogenic, was used to establish a chronic diabetic model in the rabbits. Intravenous PK/PD studies in normal and diabetic animals suggested that disposition of insulin follows a single-compartment kinetics, and PK and PD parameters obtained were observed to be dose-dependent. Two simultaneous PK/PD models, specifically, the sigmoidal Emax (SM) and indirect response (IRM) models, were applied and their utility to predict responses were evaluated. The results demonstrated that the IRM more accurately represents the physiological mechanism of insulin action, and fitted the observed data better.; Various formulation strategies were assessed for development of a nasal formulation of insulin with a higher bioavailability. The use of microspheres prepared from slow-degrading polymers, blended with chitosan, was found to be ineffective because of suboptimal loading and incomplete release.; Different classes of enhancers were also evaluated for their potential application using the nasal formulations. In the presence of enhancers, such as bile salts and dihydrofusidates, the systemic bioavailability of insulin was increased by as much as 5-fold. The presence of chitosan, a mucoadhesive natural cationic polymer, at levels of 0.5-2.0%, did not increase insulin absorption, in contrast to some current literature (2-3% vs. almost 20% reported). Further studies showed that these enhancers exert their absorption-promoting effects by perturbing the membrane layer and removing the ciliated cells in the posterior nasal cavity. Through the use of confocal laser scanning microscopy, a widening of the tight junctions was also observed and a predominantly paracellular route of absorption was followed.; A physiologically-relevant pharmacokinetic model which has accounted for nasal disposition of insulin, after degradation and mucociliary clearance, was developed. Using in vitro experimental values for enzymatic degradation and permeation. and literature values for mucociliary clearance, the model yielded both a more accurate fit of the data and a means to simulate and predict PK/PD responses. Furthermore, a simultaneous pharmacokinetic-pharmacodynamic relationship, in which the PK model was linked to the PD indirect model, was used to describe glycemic response following intranasal insulin administration.