The goal of this SBIR project is to provide a colon-targeting, rapid-release metronidazole treatment for Clostridium difficile infection (CDI), an infectious disease causing gastrointestinal illnesses such as diarrhea, pseudomembranous colitis, colon perforations, or even death. Incidence and mortality of CDI has 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, and more treatment options are needed. Oral metronidazole, a nitroimidazole antimicrobial and immediate release tablet, has been prescribed as the first-line medicine for mild-to-moderate CDI as an off-label use, due to its established equal efficacy as vancomycin and low cost. However, randomized controlled trials published in the last several years indicate metronidazole, in its current formulation which achieves relatively low and inconsistent concentrations in the colon, is inferior to oral vancomycin. For metronidazole to remain a viable option for treatment of CDI, a formulation with more reliable delivery of active drug to the colon is needed. Gateway (Gateway Professional Consulting LLC, dba Gateway Pharmaceutical 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 small intestine, and add site-specificity to colon physiology. Gateway has conducted preliminary studies and in-vitro dissolution testing. A PCT patent on formulation composition and method of treatment was submitted 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 metronidazole colon-targeting in-vivo. The feasibility is measured by X-ray images, in-vivo bioavailability and fecal concentration 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 the colon using our formulation technology. The long term goal is to provide a first-line, cost-effective metronidazole treatment to CDI patients, with higher fecal concentration, improved cure rate and reduced recurrence. The product is developed with FDA-approved excipients and robust manufacturing process. A pre-IND meeting was completed with the FDA in March 2017 and confirmed no toxicology and pharmacology studies were required. This product is qualified for the request of fast track designation and priority review under Qualified Infectious Disease Product (QIDP). After the proof of feasibility in-vivo in dogs, we plan to submit an IND application and conduct clinical studies of the new product in human in Phase II.
Clostridium difficile Infection (CDI) causes diarrhea, pseudomembranous colitis, colon perforations, or even death in patients. Metronidazole, a first-line medicine of CDI encounters reduced efficacy and more relapse due to the low and inconsistent drug colon concentration from the current immediate release formulation. A formulation with more reliable delivery of active drug to the colon is needed. We will apply our colon-targeting formulation technology to improve efficacy of metronidazole.
