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Development and in vivo testing of novel hydrochlorothiazide gastric retention formulations in healthy volunteers and stage I hypertensive patientsFarid, Samar Farghali 06 May 2004 (has links)
This thesis describes in vitro and in vivo evaluation of a gastric retention
formulation (GRF) developed at Oregon State University. The formulation was
prepared from xanthan gum and locust bean gum as gelling agents and other
formulation ingredients were added, then it was originally vacuum oven dried. The
effect of freeze drying on GRF was studied in this research. Freeze dried GRF were
evaluated for dissolution and drug release properties using hydrochlorothiazide as a
model drug. The effect of storage of GRF inside hard gelatin capsules on rate of
swelling of the capsule shell and release of GRF was also studied. Storage for up to
12 months had no effect on capsule shell swelling and release of GRF.
Gastric residence time, pharmacokinetics and bioavailability of
hydrochlorothiazide, a drug that has an absorption window limited to the upper
small intestine, from two different sizes of gastric retention formulations (GRF)
were evaluated in 12 healthy volunteers in both fed and fasted states, and compared
to immediate release tablets. Extent of bioavailability of drug from the larger
formulation in this study was comparable to IR tablets in both fed and fasted states.
Deconvolved input functions data suggest that the GRF stayed in the stomach
providing sustained drug input for 12-28 hours.
Initial blood pressure lowering and side effects of hydrochlorothiazide from
a gastric retention formulation were evaluated and compared to immediate release
tablets in 10 subjects with stage I hypertension. Gastric retention formulations
produced an average reduction in systolic blood pressure 3 mm Hg lower than IR
tablets regardless of sequence of administration. GRF also produced less blood
pressure fluctuation in most subjects than IR tablets. Most subjects reported fewer
and less severe side effects with GRF than IR tablets. / Graduation date: 2004
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