Development of a novel intragastric controlled release delivery system for simultaneous delivery of metronidazole, tetracycline hydrochloride, colloidal bismuth subcitrate and an H2 receptor antagonist: Used in eradication of Helicobacter pylori associated ulcer.

摘要

This work is essentially focused on the design, development and evaluation of a novel gastroretentive delivery system intending to deliver metronidazole, tetracycline hydrochloride, colloidal bismuth subcitrate and famotidine simultaneously for the treatment of Helicobacter pylori associated peptic ulcer.; Metronidazole and tetracycline hydrochloride used along with bismuth were named "gold standard therapy" as one of the most effective regimens in the eradication of H. pylori.; In this work an HPLC method was developed for simultaneous determination of metronidazole, tetracycline hydrochloride, epitetracycline hydrochloride and famotidine, with good linearity, accuracy, recovery and reproducibility.; Based on the developed analytical methods, preformulation studies were successfully performed, which included the studies on the drug solubility, compatibility, and stability in both solid and liquid states in accordance with International Conference on Harmonization (ICH) guidelines. Results indicated that drugs in combinations were stable in the solid state with no chemical or physical incompatibility.; For delivery system design, swelling and erosion properties of hydroxypropyl methylcellulose (HPMC K100LV, K4M, and K15M) and polyethylene oxide (PEO WSR N60, WSR301, and WSR303) matrices as drug carriers were evaluated. In general water uptake was more rapid in PEO than in HPMC regardless of molecular weight. HPMC exhibited more swelling and less erosion relative to equivalent molecular weight PEO resulting in a slow but continuous increase in swelling layer thickness.; Based on the results from preformulation studies and nature of polymer and excipient behavior, several multiple-layer drug delivery systems were developed and optimized for desirable in vitro performance. Overall, the delivery systems simultaneously delivered four active ingredients to the upper GI tract with different release rates and these were evaluated under different hydrodynamic conditions. Specifically, famotidine and colloidal bismuth subcitrate layer was designed to disintegrate within 15 minutes of contacting the dissolution fluid, while metronidazole and tetracycline hydrochloride were released over 8 hours from the floating delivery system by the near-zero-order kinetics.; The developed system lacks the limitations of current triple therapy and may provide for achievement of high and prolonged local drug delivery, reducing dosing frequency and number of pills, reducing side effects, and potentially improving therapeutic outcome and enhancing patient compliance.