Controlled Delivery of Bile Acids to the Colon
Name
Controlled_Delivery_of_Bile_Acids_to_the_Colon.9.pdf
Description
Published version
Size
870.99 KB
Format
Adobe PDF
Checksum (MD5)
6972596ec8e9b7c38444efc3a1c73fbd
Author(s)
Steiger, Christoph
Phan, Nhi V
Sun, Haoying
Huang, Hen-Wei
Hess, Kaitlyn
Lopes, Aaron
Korzenik, Joshua
Langer, Robert
Traverso, Giovanni
Date Issued
2020
Journal
Clinical and Translational Gastroenterology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Version
Final published version
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Mechanical Engineering
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.14309/ctg.0000000000000229
