Development of a Modified-Release Formulation of Lovastatin Targeted to Intestinal Methanogens Implicated in Irritable Bowel Syndrome With Constipation

J Pharm Sci. 2018 Feb;107(2):662-671. doi: 10.1016/j.xphs.2017.09.028. Epub 2017 Oct 6.


There is growing evidence that methane production, predominantly by Methanobrevibacter smithii, in the intestines is a cause of constipation, pain, and bloating in irritable bowel syndrome with constipation (IBS-C). M smithii resides primarily in the large intestine but can also colonize the small intestine. In vitro studies found that the prodrug lactone form of lovastatin, found in cholesterol-lowering drugs, inhibited methane production in stool samples from patients with IBS-C. However, the cholesterol-lowering lovastatin β-hydroxyacid was ineffective at inhibiting methane production in this system. A considerable amount of lovastatin is converted to hydroxyacid in the stomach and is absorbed. It was hypothesized that galenic innovations could protect lovastatin from the stomach and allow release in 2 strategic locations, the duodenum and the ileocecal region, to reach M smithii. The desired release profile was achieved by developing an oral dosage form containing lovastatin and coated with 2 different enteric polymers that enabled a pH-dependent "dual pulse" drug release. Combinations of the 2 coated tablets were encapsulated together to deliver the desired amount of lovastatin to the targeted intestinal locations. The capsules have been tested in vitro and in vivo and show promise in treating IBS-C.

Keywords: coating; colon; compression; dissolution; encapsulation; formulation; oral drug delivery; pharmacokinetics; tableting; targeted drug delivery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticholesteremic Agents / chemistry
  • Anticholesteremic Agents / pharmacology
  • Chemistry, Pharmaceutical / methods
  • Constipation / drug therapy*
  • Constipation / microbiology
  • Dogs
  • Drug Delivery Systems / methods
  • Drug Liberation
  • Intestines / microbiology*
  • Irritable Bowel Syndrome / drug therapy*
  • Irritable Bowel Syndrome / microbiology
  • Lovastatin / chemistry*
  • Lovastatin / pharmacology
  • Male
  • Methane / metabolism*
  • Methanobrevibacter / drug effects*
  • Methanobrevibacter / metabolism
  • Polymers / chemistry
  • Tablets / chemistry
  • Tablets / pharmacology


  • Anticholesteremic Agents
  • Polymers
  • Tablets
  • Lovastatin
  • Methane