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PROJECT SUMMARYThe goal of this SBIR project is to provide a colon-targeting, rapid-release metronidazole treatment forClostridium difficile infection (CDI), an infectious disease causing gastrointestinal illnesses such asdiarrhea, pseudomembranous colitis, colon perforations, or even death. Incidence and mortality of CDIhas been increasing since 2000, due to the emergence of more virulent strains of C. difficile bacteria.Currently there are only two FDA-approved treatment for CDI, oral vancomycin and fidaxomicin, andmore treatment options are needed. Oral metronidazole, a nitroimidazole antimicrobial and immediaterelease tablet, has been prescribed as the first-line medicine for mild-to-moderate CDI as an off-labeluse, due to its established equal efficacy as vancomycin and low cost. However, randomized controlledtrials published in the last several years indicate metronidazole, in its current formulation whichachieves relatively low and inconsistent concentrations in the colon, is inferior to oral vancomycin. Formetronidazole to remain a viable option for treatment of CDI, a formulation with more reliable delivery ofactive drug to the colon is needed. Gateway (Gateway Professional Consulting LLC, dba GatewayPharmaceutical LLC) has developed a prototype formulation of metronidazole colon delivery, as mini-tablets surrounded by a new coating combination that will avoid premature drug release in lower smallintestine, and add site-specificity to colon physiology. Gateway has conducted preliminary studies andin-vitro dissolution testing. A PCT patent on formulation composition and method of treatment wassubmitted in 2017. In this SBIR, due to the significant difference of in-vitro dissolution with in-vivo GIT,we propose to further study formulation factors in-depth, and to test the feasibility of metronidazolecolon-targeting in-vivo. The feasibility is measured by X-ray images, in-vivo bioavailability and fecalconcentration level of the new formulation compared to the immediate release tablet. Mongrel hound-cross dogs are used for the in-vivo feasibility study due to their similarity in colon physiology to human.A successful outcome of this SBIR will be proven feasibility of metronidazole reliable delivery in thecolon using our formulation technology. The long term goal is to provide a first-line, cost-effectivemetronidazole treatment to CDI patients, with higher fecal concentration, improved cure rate andreduced recurrence. The product is developed with FDA-approved excipients and robust manufacturingprocess. A pre-IND meeting was completed with the FDA in March 2017 and confirmed no toxicologyand pharmacology studies were required. This product is qualified for the request of fast trackdesignation and priority review under Qualified Infectious Disease Product (QIDP). After the proof offeasibility in-vivo in dogs, we plan to submit an IND application and conduct clinical studies of the newproduct in human in Phase II.

Li, Lianli
Gateway Pharmaceutical, LLC
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