This dissertation describes formulation of a gastric retention device (GRD)
and sustained release (SR) hydrochlorothiazide beads at Oregon State University.
Formulation condition and amounts of excipients had significant influence on
characteristic of the GRD. The GRD containing SR hydrochlorothiazide beads was
employed to assess bioavailability/bioequivalency study in healthy subjects. An
original GRD was retained in the stomach with food and completed the drug
release. However, this original GRD failed to stay on an empty stomach, leading to
lower bioavailability than an immediate release (IR) tablet due to insufficient
rigidity. The original device was modified to be more rigid, and this more rigid
device successfully stayed on an empty stomach and achieved completion of the
drug release at a slow release rate, the bioavailability and the drug effect on diuresis
increased compared to the drug in an IR tablet. Less amount of
hydrochlorothiazide at a slow release rate achieved equivalent diuresis to higher
amount of the drug at a rapid release rate, which indicated slow drug release
resulted in higher efficiency of hydrochlorothiazide. In vivo/in vitro correlation of
hydrochlorothiazide in a modified GRD and an IR tablet was established to predict
in vivo profile with in vitro dissolution profile prior to a clinical study.
Pharmacokinetic/pharmacodynamic of nicotine was reviewed in terms of a
relationship between plasma nicotine concentrations and pharmacological changes
including heart rate and craving. Considering craving and development of
tolerance to nicotine effect on cardio-acceleration, a dosing regimen with a
combination of rapid input and constant slow input was suggested to improve
smoking cessation.
A simulation study was carried out to verify the current regulatory policy on
assessing bioequivalency of enantiomeric drugs. First-order dissolution and
absorption process, and nonlinear stereo-specific pre-systemic and systemic
metabolism was taken into account to establish a pharmacokinetic model for the
simulation. Four different dissolution profiles, within- and between-subject
variability, dose and sample size were considered to simulate 1000 cross-over
bioequivalency trials under standard bioequivalency criteria. Probability of false
positives was determined to evaluate the current policy. The simulation study
validated the importance of individual enantiomer pharmacokinetic for assessing
bioequivalency study of the chiral drugs. / Graduation date: 2003
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/32550 |
| Date | 23 April 2003 |
| Creators | Kwon, Hyojong |
| Contributors | Ayres, James W. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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