A randomized, phase I, double-blind, crossover study on pharmacokinetics of peppermint oil capsules in healthy volunteers: Enteric-coating versus colon-targeted-delivery

Z.Z.R.M. Weerts, D. Keszthelyi, H.W. Frijlink, J.R.B.J. Brouwers, L. Vork, D.M.A.E. Jonkers, A.A.M. Masclee

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Abstract

Peppermint oil (PO) has been shown to reduce abdominal pain in patients with Irritable Bowel Syndrome (IBS). Menthol, the main constituent of PO, induces intestinal smooth muscle relaxation and desensitizes nociceptive nerve afferents. Enteric-coated (EC PO) capsules that release PO mainly in the small intestine are commercially available. In order to increase local, colonic anti-nociception, a colon-targeted-delivery peppermint oil (CTD PO) capsule has been developed. The aim of this study was to compare pharmacokinetic parameters of both formulations and to evaluate safety and tolerability. In this randomized, double blind, placebo-controlled study, subjects received 182 mg of either EC PO or CTD PO in a crossover design with ≥14 days washout period in between. After baseline measurements and drug administration, blood samples to determine menthol-glucuronide (menthol is rapidly metabolized to menthol-glucuronide), blood pressure and heart rate measurements were collected at several time points. Side effects were evaluated using questionnaires. The primary outcome was Tmax: time to reach peak menthol-glucuronide concentration in plasma. Eight healthy volunteers (50% female), aged between 20 and 65 years (median 22.2, IQR 20.8-28.8) were included. The Tmax of CTD PO was significantly longer (in all volunteers) compared to EC PO with a median (IQR) of 360 (360-405) vs 180 (120-180) min, respectively, p <0.05. The Area Under the menthol-glucuronide plasma concentration time Curves were smaller with a median (IQR) of 2331 μg∗h/L (2006-2510) for CTD compared to 2623 μg∗h/L (2471-2920) for EC capsules, p <0.05. No significant differences were found in peak concentrations and elimination half-lives. No differences in vital signs or side effects were observed between both regimens. Remarkably, subjects noticed alterations in fecal odor after CTD PO but not after EC PO, again pointing to more distal delivery with CTD PO. In conclusion, the CTD PO has a significantly delayed peak menthol-glucuronide concentration, and is thereby assumed to release peppermint oil in the more distal part of the intestine. This may enhance therapeutic efficacy of PO as the application of the CTD results in increased exposure to the colonic mucosal afferents. These results encourage our randomized controlled trial with CTD PO in IBS patients.
Original languageEnglish
Pages (from-to)101
Number of pages1
JournalNeurogastroenterology and motility
Volume28
DOIs
Publication statusPublished - 1-Aug-2016

Keywords

  • peppermint oil
  • placebo
  • adult
  • aged
  • antinociception
  • blood pressure monitoring
  • clinical article
  • clinical trial
  • controlled clinical trial
  • controlled study
  • crossover procedure
  • double blind procedure
  • elimination half-life
  • enteric coated tablet
  • exposure
  • female
  • heart rate
  • human
  • human tissue
  • irritable colon
  • male
  • microcapsule
  • odor
  • pharmacokinetics
  • plasma concentration-time curve
  • questionnaire
  • randomized controlled trial
  • safety
  • side effect
  • visually impaired person
  • vital sign
  • volunteer

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