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Ofloxacin (OFX) is a synthetic broad spectrum analog of second generation fluoroquinolone antibiotic. It is used for the treatment of urinary tract, prostate, skin, urinary and respiratory tract infections. Ornidazole (ORN) is a nitroimidazole derivative. It is used in the treatment of bacterial vaginosis, trichomoniasis, amoebiasis, giardiasis and infections due to anaerobic bacteria. These drugs are highly soluble in acidic media and precipitates in alkaline media thereby losing its solubility. Hence we attempted to develop a gastro retentive floating matrix type drug delivery system for Ofloxacin and Ornidazole in combined dosage form with hydroxyl propyl methyl cellulose and polyethylene oxide 18NF (PEO). The prepared floating drug delivery systems were evaluated for physicochemical characteristics, mainly in vitro release and in vivo residence time by radiographic studies. These studies revealed that tablets 300 ± 30 minutes in healthy human volunteers in fasting state and indicated that the gastric retention was increased by floating principle. Based on the physical evaluation, in vitro drug release and in vivo characteristics, it was concluded that for potential therapeutic