Controlled Delivery of Bile Acids to the Colon. Issue 12 (1st December 2020)

• Record Type: Journal Article
• Authors: Steiger, Christoph; Phan, Nhi V.; Sun, Haoying; Huang, Hen-Wei; Hess, Kaitlyn; Lopes, Aaron; Korzenik, Joshua; Langer, Robert; Traverso, Giovanni
• Is Part Of: Clinical and translational gastroenterology. Volume 11:Issue 12(2020)
• Page Start: e00229
• Publication Date: 2020-12-01
• Subjects: Stomach -- Diseases -- Periodicals; Intestines -- Diseases -- Periodicals; Gastroenterology; Gastrointestinal Diseases; Liver Diseases; Intestines -- Diseases; Stomach -- Diseases; Periodical; Periodicals; Fulltext; Internet Resources; Periodicals; Electronic journals; 616.33
• DOI: 10.14309/ctg.0000000000000229
• Languages: English
• ISSNs: 2155-384X

Abstract

Abstract : INTRODUCTION: Bile acids, such as chenodeoxycholic acid, play an important role in digestion but are also involved in intestinal motility, fluid homeostasis, and humoral activity. Colonic delivery of sodium chenodeoxycholate (CDC) has demonstrated clinical efficacy in treating irritable bowel syndrome with constipation but was associated with a high frequency of abdominal pain. We hypothesized that these adverse effects were triggered by local super-physiological CDC levels caused by an unfavorable pharmacokinetic profile of the delayed release formulation. METHODS: We developed novel release matrix systems based on hydroxypropyl methylcellulose (HPMC) for sustained release of CDC. These included standard HPMC formulations as well as bi-layered formulations to account for potential delivery failures due to low colonic fluid in constipated patients. We evaluated CDC release profiles in silico (pharmacokinetic modeling), in vitro and in vivo in swine (pharmacokinetics, rectal manometry). RESULTS: For the delayed release formulation in vitro release studies demonstrated pH triggered dose dumping which was associated with giant colonic contractions in vivo. Release from the bi-layered HPMC systems provided controlled release of CDC while minimizing the frequency of giant contractions and providing enhanced exposure as compared to standard HPMC formulations in vivo. DISCUSSION: Bi-phasic CDC release could help treat constipation while mitigating abdominal pain observed in previous clinical trials. Further studies are necessary to demonstrate the therapeutic potential of these systems in humans.