DOI
https://doi.org/10.25772/VG4A-B519
Defense Date
2015
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Dr. Peter R. Byron
Second Advisor
Dr. Michael Hindle
Third Advisor
Dr. P. Worth Longest
Fourth Advisor
Dr. Masahiro Sakagami
Fifth Advisor
Dr. Aron H. Lichtman
Abstract
While realistic in vitro testing of dry powder inhalers (DPIs) can be used to establish in vitro–in vivo correlations (IVIVCs) and predict in vivo lung doses, the aerodynamic particle size distributions (APSDs) of those doses and their regional lung deposition remains unclear. Four studies were designed to improve testing centered on the behavior of Novolizer®. Different oropharyngeal geometries were assessed by testing different mouth-throat (MT) models across a realistic range of inhalation profiles (IPs) with Salbulin® Novolizer®. Small and large Virginia Commonwealth University (VCU) and Oropharyngeal Consortium (OPC) models produced similar ranges for total lung dose in vitro (TLDin vitro), while results for medium models differed significantly. While either group may be selected to represent variations in oropharyngeal geometry, OPC models were more difficult to use, indicating that VCU models were preferable. To facilitate simulation of human IPs through DPIs, inhalation profile data from a VCU clinical trial were analyzed. Equations were developed to represent the range of flow rate vs. time curves for use with DPIs of known airflow resistance. A new method was developed to couple testing using VCU MT models and simulated IPs with cascade impaction to assess the APSDs of TLDin vitro for Budelin® Novolizer®. This method produced IVIVCs for Budelin’s total lung dose, TLD, and was sufficiently precise to distinguish between values of TLDin vitro and their APSDs, resulting from tests using appropriately selected MT models and IPs. For example, for slow inhalation, TLD values were comparable in vivo and in vitro; TLDin vitro ranged from 12.2±2.9 to 66.8±1.7 mcg aerosolized budesonide while APSDs in vitro had mass median aerodynamic diameters of 3.26±0.27 and 2.17±0.03 µm, respectively. To explore the clinical importance of these variations, a published computational fluid dynamic (CFD) model was modified and coupled to accept the output of realistic in vitro tests as initial conditions at the tracheal inlet. While simplified aerosol size metrics and flow conditions used to shorten CFD simulations produced small differences in theoretical predictions of regional lung deposition, the results broadly agreed with the literature and were generally consistent with the median values reported clinically for Budelin.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-7-2015