Development and evaluation of a monolithic floating dosage form for furosemide.
The poor bioavailability of orally dosed furosemide (60%), a weakly acidic drug, is due to the presence of a biological window comprised of the upper gastrointestinal tract. The purpose of the present study was to develop and optimize in vitro a monolithic modified-release dosage form (MMR) for furosemide with increased gastric residence time and to evaluate the in vivo performance of the dosage form. The principle of floatation was used to restrict the MMR to the stomach. A two-factor three-level full factorial experimental design was employed for formulation development. A flow-through cell was designed to evaluate in vitro dissolution parameters. Quadratic regression models indicated the polymer viscosity and polymer:drug ratio to be significant (p < 0.05) formulation factors in determining the duration of buoyancy and the release profile. Statistical optimization using response surface methodology with certain physiological constraints relating to gastric emptying time predicted an optimal MMR. In vivo evaluation of the optimized MMR in beagle dogs resulted in a significant increase (p < 0.05) in the absolute bioavailability for the MMR dosage form (42.9%) as compared to the commercially available tablet (33.4%) and enteric product (29.5%). Significant in vitro/in vivo correlations (p < 0.05) were obtained for the MMR using deconvolution analysis normalized for bioavailability. The floating dosage form was found to be a feasible approach in delivering furosemide to the upper gastrointestinal tract to maximize drug absorption.
Menon
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University of Cincinnati, College of Pharmacy, OH 45267-0004.
Ritschel
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WA
Sakr
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D000818:Animals; D001682:Biological Availability; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004285:Dogs; D005069:Evaluation Studies as Topic; D005665:Furosemide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D012995:Solubility; D013607:Tablets; D014783:Viscosity
D002214:Capsules; D003692:Delayed-Action Preparations; D013607:Tablets; D005665:Furosemide