Abstract
Objective: To study fixed-dose combinations (FDC) of antibacterial and antiprotozoal products (ofloxacin and azoles), prescribed for the treatment of diarrhea.
 Methods: Rationality of these FDC products was verified by assessing parameters such as drug content and release by assay and dissolution tests, respectively mentioned in the Indian Pharmacopoeia (IP). Amount of drug solubilized and permeated as per the Biopharmaceutics Classification System (BCS) was determined. Ex vivo permeation study was performed on the gut of goat using the everted gut sac technique. Antimicrobial efficacy in terms of minimum inhibitory concentration (MIC) was assessed using agar well diffusion method against Shigella boydii, the causative agent for diarrhea. Comparative studies were performed on an individual as well as combination doses of antibacterial and antiprotozoal products for the synergistic effects to assess the rationale of these FDC.
 Results: The BCS solubility of ciprofloxacin (CPX), norfloxacin (NFX) and tinidazole (TNZ) was high in acidic medium (pH 1-5) and decreased at pH above 5. The assay studies showed that the individual drug contents of FDC were within the IP limits. In vitro dissolution results for both, individual drugs and their combination illustrated 99 % drug release within 30 min in 0.01N HCl. Ex vivo permeation of TNZ was higher than CPX and NFX in individual drugs. No significant change in the permeation rate was observed for individual drugs and their FDC. CPX and NFX exhibited more antimicrobial activity in terms of inhibitory zones than their FDC with antiprotozoal TNZ, above 2.5 µg/ml MIC. The pharmaceutical, biopharmaceutical and antimicrobial evaluation study showed the similarity of FDC with the individual drugs.
 Conclusion: The study showed no significant data to justify the therapeutic advantage of FDC over individual drugs.
Highlights
Fixed-Dose Combinations (FDC) comprised of two or more different drugs as a single formulation are explored for a plethora of diseases for synergistic effects and patient compliance [1, 2]
According to Biopharmaceutics Classification System (BCS) classification of drugs, CPX and NFX belongs to class IV and TNZ belongs to class II
From the solubility result of CPX, NFX and TNZ, it indicated that the absorption site can be in the upper part of the gastrointestinal tract and less amount of drug might be absorbed through the small intestine and colon [18]
Summary
Fixed-Dose Combinations (FDC) comprised of two or more different drugs as a single formulation are explored for a plethora of diseases for synergistic effects and patient compliance [1, 2]. The rationality of FDC is defined by similar pharmacokinetics, yet the diverse mechanism of action; without supra-additive toxicity of the individual actives and formulation components [3]. Ciprofloxacin (CPX) and norfloxacin (NFX) are broad-spectrum quinolone antibiotics known to inhibit bacterial DNA replication by impeding the functions of bacterial DNA gyrase enzyme. They are mainly explored in the treatment of urinary tract infection, cystitis, prostatitis, respiratory tract skin and joint infections [6, 7]. Tinidazole (TNZ) is a nitroimidazole derivative used in the treatment of intestinal amoebiasis, giardiasis, trichomoniasis, active against anaerobic bacteria and protozoa [8, 9]
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