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Novel ileocolonic release peppermint oil 123 6 Introduction Irritable bowel syndrome (IBS) is a complex functional bowel disorder affecting up to 10-20% of the population in developed countries. 1,2 It is characterized by recurrent abdominal pain associated with changes in bowel habits. 1 Of the currently available treatment entities, peppermint oil released in the upper small intestine has been shown to be effective in reducing complaints of abdominal pain and inducing global symptom improvement 3,4 with a reported Number Needed to Treat (NNT) of 2-3. 5,6 The main constituent of peppermint oil is L-menthol, which is rapidly metabolized to menthol-glucuronide and excreted in urine when taken orally. The exact mechanism of how peppermint oil acts remains to be elucidated, but is most likely multifactorial. 7 What is known however, is its dose-related relaxational effect of intestinal smooth muscle through the inhibition of calcium influx into the sarcolemma of smooth muscle cells 8-10 and thereby potentially decreasing abdominal cramps. Furthermore, there are indications that peppermint oil has a direct local anti-nociceptive effect in the colon through an interaction of L-menthol with transient receptor potential (TRPM8 and/or TRPA1) channels, channels known to play a role in visceral hypersensitivity and pain generation. 11-14 Other studies have reported inhibition of serotonin type 3 receptors (5HT 3 ) in the human colon 15 , antimicrobial 16,17 , and carminative effects. 18 Capsules containing peppermint oil are available as an over the counter drug on the European market 19 and capsules containing peppermint oil microspheres are available as a medical food product in the USA and Canada. 20 All these formulations release peppermint oil in the small intestine. The use of small-intestinal release peppermint oil is associated with upper gastro- intestinal side effects, such as an altered sensation in the mouth in up to 11% and dyspeptic symptoms including heartburn, reflux and belching in up to 24% of patients. 21- 24 These burdensome symptoms negatively affect therapy adherence. To decrease these side effects, it could be argued that an ileocolonic release of peppermint oil is beneficial. In addition, a colonic release may increase efficacy in IBS patients by enhancing local colonic relaxation and TRP stimulation. Therefore, a new peppermint oil soft capsule formulation with a predominant distal ileocolonic release has been developed using a previously described ileocolonic delivery technology to coat existing peppermint oil capsules. 25-27 This study aimed to determine the pharmacokinetic differences and safety of both the small-intestinal release peppermint oil and the ileocolonic release peppermint oil in an in