Open AccessControlled Delivery of Bile Acids to the Colon
Author(s) -
Christoph Steiger,
Nhi V Phan,
Haoying Sun,
Hen-Wei Huang,
Kaitlyn Hess,
Aaron Lopes,
Korzenik Joshua,
Robert D. Langer,
Giovanni Traverso
Publication year - 2020
Publication title -
clinical and translational gastroenterology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.673
H-Index - 35
ISSN - 2155-384X
DOI - 10.14309/ctg.0000000000000229
Subject(s) - in vivo , medicine , irritable bowel syndrome , pharmacokinetics , pharmacology , controlled release , constipation , abdominal pain , bile acid , gastroenterology , biology , microbiology and biotechnology
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.