A Novel Ileocolonic Release Peppermint Oil Capsule for Treatment of Irritable Bowel Syndrome: A Phase I Study in Healthy Volunteers
Peppermint oil (PO) has been shown to reduce abdominal pain in patients with irritable bowel syndrome (IBS). PO is assumed to induce intestinal smooth muscle relaxation and desensitization of nociceptive nerve afferents. To increase colonic PO concentration, an ileocolonic release peppermint oil (IC-PO) capsule has been developed. The aim of this study was to compare pharmacokinetic parameters of the currently available small intestinal release PO (SI-PO) and the novel IC-PO.
In this randomized, double-blind, crossover study, subjects received 182 mg of either SI-PO or IC-PO in a crossover design with a washout period of more than 14 days. Blood samples were collected to determine menthol glucuronide concentrations.
Eight healthy volunteers (50% female, median age 22) were included. The time to reach the maximum concentration (Tmax) of IC-PO was significantly longer compared to SI-PO with a median (IQR) of 360 (360–405) versus 180 (120–180) min. The lag time (Tlag) was significantly longer with a median (IQR) of 225 (204–284) for IC-PO compared to 37 (6–65) min for SI-PO. The areas under the menthol glucuronide plasma concentration–time curves were significantly smaller with a median (IQR) of 2331 μg h/L (2006–2510) for IC-PO compared to 2623 μg h/L (2471–2920) for SI-PO. No significant differences were found in peak concentrations and elimination half-lives.
IC-PO has a significantly delayed peak menthol glucuronide concentration and Tlag, both pointing to the release of PO in the more distal part of the intestine. This may enhance therapeutic efficacy as it results in increased exposure of colonic mucosal afferents to the PO. A randomized controlled trial investigating the efficacy of SI and IC-PO in IBS is currently ongoing.
ClinicalTrials.gov identifier, NCT02291445, EudraCT database 2014-004195-32.
KeywordsAbdominal pain Irritable bowel syndrome Gastroenterology Peppermint oil Pharmacokinetics Phase I Targeted therapeutics
The authors acknowledge Dr. Stein and colleagues, Mönchengladbach, Germany, for performing the pharmacokinetic analysis (PK) (GC/MS) and work-up. In addition, the authors thank the participants of the study.
The authors state that the capsules for this study have been provided in kind by Will Pharma B.V., Wavre, Belgium. Will Pharma had no role in the study design, data collection, and analysis or preparation of the manuscript. Further funding regarding research with the ileocolonic release peppermint oil in IBS was provided by a received ZonMw, The Netherlands Organisation for Health Research and Development (Dutch governmental), grant. The funding did not specifically include the journal’s article processing charges, although funding was received from ZonMw for purposes of dissemination of study results.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for the version to be published. The authors had full access to the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
These data were previously presented, in part, as an oral presentation at the GENIEUR Final Conference, held from March 14, 2016, to March 15, 2016, in Heidelberg, Germany. The data were also presented in abstract and poster form at the Federation of Neurogastroenterology and Motility 2016 Joint International Meeting, hosted by the American Neurogastroenterology and Motility society, held from August 26, 2016, to August 28, 2016, in San Francisco, CA, USA.
Daniel Keszthelyi has received an unrestricted research grant from Will Pharma B.V., Wavre, Belgium. Daniel Keszthelyi has received a ZonMw, The Netherlands Organisation for Health Research and Development (Dutch governmental), health care efficiency grant for research with peppermint oil in IBS. Jacobus R.B.J. Brouwers has received a consultancy fee from Will Pharma B.V., Wavre, Belgium, which was unrelated to this manuscript. The employer of Henderik W. Frijlink has a license agreement with Will Pharma B.V., Wavre, Belgium, regarding the ColoPulse technology. The findings of this study could lead to further development of ileocolonic release peppermint oil capsules, which could lead to financial gain for Will Pharma B.V., Wavre, Belgium. Ad A.M. Masclee has received a ZonMw, The Netherlands Organisation for Health Research and Development (Dutch governmental), health care efficiency grant for research with peppermint oil in IBS. Zsa Zsa R.M. Weerts, Lisa Vork, Nic C.P. Aendekerk, Cees Neef and Daisy M.A.E. Jonkers have nothing to disclose.
Compliance with Ethics Guidelines
All procedures performed in in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All participants gave a written informed consent prior to participation.
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
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