Pharmacokinetic Studies of Enteric and Delayed Release Formulations of Locally Bioavailable Drugs (LBD) Targeting the Colon



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STATEMENT OF PROBLEM: Familial Adenoma Polyposis (FAP) is a debilitating condition that has a severe impact on the physical and psychological health, independence, and quality of life of an affected patient. Celecoxib is a selective COX-2 inhibitor class of NSAIDs that is undeniably effective against FAP. On-target off-organ cardiovascular toxicity prevents the use of Celecoxib as a treatment for FAP. A new selective COX-2 inhibitor, 6A1, is less systemically bioavailable due to its ability to undergo enterohepatic recycling (EHR). EHR delivered a variable quantity of 6A1 to the target tissue, colon, subject to variation amongst individuals UGT enzyme expression and ß-glucuronidase expression within the bacteria microbiomes that inhabit the gut. The body of this work aims to lower the therapeutic dose and the total systemic exposure (AUC) while increasing 6A1 concentration in the colon by capitalizing upon the complementary interplay between the EHR, novel coating techniques, and biodegradable polymer formulations. METHOD: Pack drug powder (6A1), formulated 6A1 microparticulate, and image tracers inside size 9 hard gelatin capsules (S9C), coated with an inner layer of polylactic glycolic acid (PLGA 8515) with optimum thickness to serve as delayed-release coating via erosion mechanism and an outer pH-sensitive Eudragit S100 (ES100) coat to serve as an enteric coating. The control group used the uncoated hard gelatin capsules. Novel vacuum spin coating technique and parameters, as well as new solvent systems, were also investigated. The S9C were administered via oral gavage (control vs. coated capsules) to F344 rats (n=5), fed ad libitum. The location of the control and coated capsules within the gastrointestinal tract and 6A1 systemic concentration were monitored simultaneously using Perkin Elmer IVIS Lumina III XRMS and UPLC-MS/MS. 6A1 and its metabolites were also quantified from the ex vivo (liver and colonic mucosa) tissues collected at the endpoints of the study. RESULTS: Pharmacokinetic study data of 6A1 and its metabolites (glucuronide and sulfate) proved the capsules release was delayed beyond 5 hours, released its contents within the colon, and had a dose-normalized AUC (nghr/mLmg) indicating systemic exposure of 6A1 is 9.04% of the systemic exposure of Celecoxib. The colonic concentration results of a 4-day multiple dosing 6A1 coated capsule study (20 mg/ Kg BID, 2682 ng/g formulation 1 and 1916 ng/g formulation 2) was comparable to 4-day multiple dosing 6A1 powder suspension study (40 mg/Kg BID, 3300 ± 300 ng/g).
CONCLUSION: The study validated an innovative colonic drug system. A combined approach of both pH-dependent and time-dependent particulate systems is highly desirable for use in a colon-specific drug delivery system. The approach has proven to reduce systemic drug concentrations, thus may reduce the side effects of the drug. Ultimately, treatment for other gastrointestinal tract diseases may benefit from the knowledge gained through this research.



Colonic Drug Delivery, Enterohepatic Recirculation Drugs, Locally Bioavailable Drugs