Purpose: Background: Studies have shown cyclooxygenase-2 (Cox-2) enzyme is elevated in the colorectal polyposis. Most marketed non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit Cox-2 enzyme reduces colonic polyposis formation but also inhibit its isozyme, Cox-1. The inhibition of Cox-1 leads to gastrointestinal toxicity, cardiovascular (CV) toxicity, internal bleeding, and stomach ulcers [1-3]. Thus, the prolonged administration of NSAIDs as preventive care for rapid tumor development and colorectal cancer is not feasible.
Purpose: The purpose of this study is to utilize novel vacuum spin-coating technique in combination with the leading biodegradable polymer formulation previously discovered to delay the release of an active pharmaceutical ingredient (API, (1-(4-Aminosulfonyl)-[3-(2-(2’-hydroxybenzyloxy)-methyl)-5-(4-methylphenyl) pyrazole) to the lower gastrointestinal tract, specifically the colon. It is hypothesized that this approach will reduce systemic exposure (AUC) and enhance the API’s use as a prophylactic care such as target. If successful this approach could be applied to deliver other drugs such as probiotics/probiotics, bile related, immunomodulators to the colon as well as other tissues.
Methods: The current study used F344 rats, fed ad libitum, and API coated capsules administered via oral gavage to closely simulate a prophylactic treatment for polyposis formation. F344 rats are chosen as the background model for the polyposis in rat colon (Pirc) model. Pharmacokinetic studies and in vivo imaging (Perkin Elmer IVIS Lumina III XRMS) of the coated gelatin capsules were done. Coated capsules location within the gastrointestinal tract and the API systemic concentration were monitored simultaneously.
Results: The control and coated capsule pharmacokinetic in vivo groups have similar systemic exposure (AUC_avecontrol of 350.753ng and AUC_avecoated of 376.488ng) at the given dose of 25mg/Kg. The in vivo imaging and the pharmacokinetic study confirm the coated capsules’ ability to withstand the acidic environment of the stomach. The control could not withstand stomach pH and rapidly released the API. Therefore, the control T_maxave is an earlier (4 hours) compared to the coated capsules group (6 hours). The UPLC/MS2 AB Sciex API 5500 Qtrap validated method with LLOQ of 0.3ng did not detect API concentration in blood samples of the coated capsules study group before 6 hours. The blue dye/barium sulfate imaging tracer was observed to have stained different intestinal segments and in excrement from the animals (n=3) upon ex vivo examination at 4,8, and 10 hours after gavage.
Conclusion: Coated capsules delayed the release of API and enhanced its use as prophylactic care. A supplemental goal of this research is necessary to achieve a better imaging agent for the targeted, delayed-release capsules. Additionally, the long-term efficacy study using the above approach to compare the API concentration systemically versus the target at steady state is in progress to elucidate the pharmacodynamics of API. The completion of these studies using the F344 Pirc model will help establish the pharmacodynamic mechanisms of such drug delivering system. The success of these study has the potential to translate into clinical care for FAP patients as preventive care.
1. Kirkby NS, L.M., Harrington LS, Leadbeater PD, Milne GL, Al-Yamani M, Adeyemi O, Warner TD, Mitchell JA, Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system. Proc Natl Acad Sci U S A, 2012. 109(43): p. 7.
2. Laine, L., et al., Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology, 2003. 124(2): p. 288-92.
3. Bhosale, U.A., et al., A cohort study to evaluate cardiovascular risk of selective and nonselective cyclooxygenase inhibitors (COX-Is) in arthritic patients attending orthopedic department of a tertiary care hospital. Niger Med J, 2014. 55(5): p. 417-22.
Noah Shroyer– Associate Professor- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas
Will Hauser– IVIS Illumina Imaging Engineer, PerkinElmer, Inc., Texas
Ming Hu– Professor of Pharmaceutics, University of Houston, Houston, Texas