Efficacy of pulmonary insulin delivery in diabetic rats: Use of a model-based approach in the evaluation of insulin powder formulations

Publication Type:

Journal Article


Journal of Controlled Release, Volume 127, Number 3, pp. 257-266 (2008)



DOI Name (links to online publication)



n-trimethyl chitosan microparticles; supercritical carbon dioxide; pulmonary delivery; insulin; pk-pd modeling; nonmem; trimethyl chitosan chloride; in-vivo evaluation; inhaled insulin; absorption enhancement; alveolar macrophages; protein delivery; drug-


The potential of N-trimethyl chitosan (TMC) with two degrees of quaternization (DQ), TMC20 (DQ 20%, as a mucoadhesive) and TMC60 (DQ 60%, as a mucoadhesive and a permeation enhancer), and dextran (as a non-mucoadhesive and non-permeation enhancer) microparticles as carriers for pulmonary delivery of insulin was studied in diabetic rats. The impact of the powder formulation on insulin bioavailability and its pharmacological effect was evaluated using a population pharmacokinetic-pharmacodynamic (PKPD) model. Insulin-loaded microparticles were prepared by a supercritical fluid (SCF) drying technique. They had a median volume diameter and median volume aerodynamic diameter of about 6-10 mu m and 4 mu m, respectively. The PK of insulin in the diabetic rats was analyzed by a one-compartment disposition model and the PD was described by the minimal model of glucose disappearance. The bioavailability of the pulmonarily administered dextran-, TMC20- and TMC60-insulin microparticles relative to subcutaneously (SC) administered insulin, was 0.48, 0.59 and 0.95, respectively. Histological examinations of the rats' lungs did not show any local adverse reactions after single administration of insulin powders. The pharmacodynamic model could describe the insulin-glucose relationship and pharmacodynamic efficiency of insulin formulations, which was about 0.6* 10(-5) ml/mu U, irrespective of the formulations. The current findings suggest that TMC microparticles are a promising vehicle for pulmonary delivery of insulin. (C) 2008 Elsevier B.V. All rights reserved.