Advertisement

A Novel Ileocolonic Release Peppermint Oil Capsule for Treatment of Irritable Bowel Syndrome: A Phase I Study in Healthy Volunteers

  • Zsa Zsa R. M. Weerts
  • Daniel Keszthelyi
  • Lisa Vork
  • Nic C. P. Aendekerk
  • Henderik W. Frijlink
  • Jacobus R. B. J. Brouwers
  • Cees Neef
  • Daisy M. A. E. Jonkers
  • Ad A. M. Masclee
Original Research

Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusion

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.

Trial registration

ClinicalTrials.gov identifier, NCT02291445, EudraCT database 2014-004195-32.

Keywords

Abdominal pain Irritable bowel syndrome Gastroenterology Peppermint oil Pharmacokinetics Phase I Targeted therapeutics 

Notes

Acknowledgements

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.

Funding

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.

Authorship

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.

Prior Presentation

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.

Disclosures

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.

Data Availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Supplementary material

12325_2018_802_MOESM1_ESM.pdf (2.5 mb)
Supplementary material 1 (PDF 2598 kb)

References

  1. 1.
    Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl J Med. 2012;367(17):1626–35.  https://doi.org/10.1056/NEJMra1207068.CrossRefPubMedGoogle Scholar
  2. 2.
    Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology. 1997;112(6):2120–37.CrossRefGoogle Scholar
  3. 3.
    Khanna R, MacDonald JK, Levesque BG. Peppermint oil for the treatment of irritable bowel syndrome: a systematic review and meta-analysis. J Clin Gastroenterol. 2014;48(6):505–12.  https://doi.org/10.1097/MCG.0b013e3182a88357.CrossRefPubMedGoogle Scholar
  4. 4.
    Ruepert L, Quartero AO, de Wit NJ, van der Heijden GJ, Rubin G, Muris JW. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2011;8:CD003460.  https://doi.org/10.1002/14651858.cd003460.pub3.CrossRefGoogle Scholar
  5. 5.
    Enck P, Junne F, Klosterhalfen S, Zipfel S, Martens U. Therapy options in irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2010;22(12):1402–11.  https://doi.org/10.1097/MEG.0b013e3283405a17.CrossRefPubMedGoogle Scholar
  6. 6.
    Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(Suppl 1):S2–26.  https://doi.org/10.1038/ajg.2014.187 (quiz S7).CrossRefPubMedGoogle Scholar
  7. 7.
    Chumpitazi BP, Kearns GL, Shulman RJ. Review article: the physiological effects and safety of peppermint oil and its efficacy in irritable bowel syndrome and other functional disorders. Aliment Pharmacol Ther. 2018.  https://doi.org/10.1111/apt.14519.CrossRefPubMedGoogle Scholar
  8. 8.
    Hawthorn M, Ferrante J, Luchowski E, Rutledge A, Wei XY, Triggle DJ. The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations. Aliment Pharmacol Ther. 1988;2(2):101–18.CrossRefGoogle Scholar
  9. 9.
    Grigoleit HG, Grigoleit P. Pharmacology and preclinical pharmacokinetics of peppermint oil. Phytomedicine. 2005;12(8):612–6.  https://doi.org/10.1016/j.phymed.2004.10.007.CrossRefPubMedGoogle Scholar
  10. 10.
    Talley NJ. Evaluation of drug treatment in irritable bowel syndrome. Br J Clin Pharmacol. 2003;56(4):362–9.CrossRefGoogle Scholar
  11. 11.
    Harrington AM, Hughes PA, Martin CM, et al. A novel role for TRPM8 in visceral afferent function. Pain. 2011;152(7):1459–68.  https://doi.org/10.1016/j.pain.2011.01.027.CrossRefPubMedGoogle Scholar
  12. 12.
    Blackshaw LA. Transient receptor potential cation channels in visceral sensory pathways. Br J Pharmacol. 2014;171(10):2528–36.  https://doi.org/10.1111/bph.12641.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Akbar A, Yiangou Y, Facer P, Walters JR, Anand P, Ghosh S. Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut. 2008;57(7):923–9.  https://doi.org/10.1136/gut.2007.138982.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhou Q, Yang L, Larson S, et al. Decreased miR-199 augments visceral pain in patients with IBS through translational upregulation of TRPV1. Gut. 2016;65(5):797–805.  https://doi.org/10.1136/gutjnl-2013-306464.CrossRefPubMedGoogle Scholar
  15. 15.
    Walstab J, Wohlfarth C, Hovius R, Schmitteckert S, Roth R, Lasitschka F, et al. Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: implications for treating gastrointestinal disorders. Neurogastroenterol Motil. 2014;26:810–20.CrossRefGoogle Scholar
  16. 16.
    Trombetta D, Castelli F, Sarpietro MG, et al. Mechanisms of antibacterial action of three monoterpenes. Antimicrob Agents Chemother. 2005;49(6):2474–8.  https://doi.org/10.1128/AAC.49.6.2474-2478.2005.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hawrelak JA, Cattley T, Myers SP. Essential oils in the treatment of intestinal dysbiosis: a preliminary in vitro study. Altern Med Rev. 2009;14(4):380–4.PubMedGoogle Scholar
  18. 18.
    Harries N, James KC, Pugh WK. Antifoaming and carminative actions of volatile oils. J Clin Pharm Ther. 1977;2(3):171–7.  https://doi.org/10.1111/j.1365-2710.1977.tb00087.x.CrossRefGoogle Scholar
  19. 19.
    White DA, Thompson SP, Wilson CG, Bell GD. A pharmacokinetic comparison of two delayed-release peppermint oil preparations, Colpermin and Mintec, for treatment of the irritable bowel syndrome. Int J Pharm. 1987;40(1–2):151–5.  https://doi.org/10.1016/0378-5173(87)90060-3.CrossRefGoogle Scholar
  20. 20.
    Cash BD, Epstein MS, Shah SM. A novel delivery system of peppermint oil is an effective therapy for irritable bowel syndrome symptoms. Dig Dis Sci. 2016;61(2):560–71.  https://doi.org/10.1007/s10620-015-3858-7.CrossRefPubMedGoogle Scholar
  21. 21.
    Mosaffa-Jahromi M, Lankarani KB, Pasalar M, Afsharypuor S, Tamaddon AM. Efficacy and safety of enteric coated capsules of anise oil to treat irritable bowel syndrome. J Ethnopharmacol. 2016;194:937–46.  https://doi.org/10.1016/j.jep.2016.10.083.CrossRefPubMedGoogle Scholar
  22. 22.
    Merat S, Khalili S, Mostajabi P, Ghorbani A, Ansari R, Malekzadeh R. The effect of enteric-coated, delayed-release peppermint oil on irritable bowel syndrome. Dig Dis Sci. 2010;55(5):1385–90.  https://doi.org/10.1007/s10620-009-0854-9.CrossRefPubMedGoogle Scholar
  23. 23.
    Cappello G, Spezzaferro M, Grossi L, Manzoli L, Marzio L. Peppermint oil (Mintoil) in the treatment of irritable bowel syndrome: a prospective double blind placebo-controlled randomized trial. Dig Liver Dis. 2007;39(6):530–6.  https://doi.org/10.1016/j.dld.2007.02.006.CrossRefPubMedGoogle Scholar
  24. 24.
    Liu JH, Chen GH, Yeh HZ, Huang CK, Poon SK. Enteric-coated peppermint-oil capsules in the treatment of irritable bowel syndrome: a prospective, randomized trial. J Gastroenterol. 1997;32(6):765–8.CrossRefGoogle Scholar
  25. 25.
    Schellekens RC, Stellaard F, Olsder GG, Woerdenbag HJ, Frijlink HW, Kosterink JG. Oral ileocolonic drug delivery by the colopulse-system: a bioavailability study in healthy volunteers. J Control Release. 2010;146(3):334–40.  https://doi.org/10.1016/j.jconrel.2010.05.028.CrossRefPubMedGoogle Scholar
  26. 26.
    Maurer JM, Schellekens RC, van Rieke HM, et al. ColoPulse tablets perform comparably in healthy volunteers and Crohn’s patients and show no influence of food and time of food intake on bioavailability. J Control Release. 2013;172(3):618–24.  https://doi.org/10.1016/j.jconrel.2013.09.021.CrossRefPubMedGoogle Scholar
  27. 27.
    Schellekens RC, Stellaard F, Mitrovic D, Stuurman FE, Kosterink JG, Frijlink HW. Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings. J Control Release. 2008;132(2):91–8.  https://doi.org/10.1016/j.jconrel.2008.08.008.CrossRefPubMedGoogle Scholar
  28. 28.
    Schellekens RC, Stuurman FE, van der Weert FH, Kosterink JG, Frijlink HW. A novel dissolution method relevant to intestinal release behaviour and its application in the evaluation of modified release mesalazine products. Eur J Pharm Sci. 2007;30(1):15–20.  https://doi.org/10.1016/j.ejps.2006.09.004.CrossRefPubMedGoogle Scholar
  29. 29.
    Maurer MJ, Schellekens RC, Wutzke KD, Stellaard F. Isotope-labelled urea to test colon drug delivery devices in vivo: principles, calculations and interpretations. Isot Environ Health Stud. 2013;49(4):473–91.  https://doi.org/10.1080/10256016.2013.803099.CrossRefGoogle Scholar
  30. 30.
    European Medicines Agency (EMA), Committee for medicinal products for human use (CHMP). Guideline on the investigation of bioequivalence. 2010.Google Scholar
  31. 31.
    US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry. Bioavailability and bioequivalence studies for orally administered drug products—general considerations. 2002.Google Scholar
  32. 32.
    The European Directorate for the Quality of Medicines & HealthCare (EDQM), European Pharmacopoeia (Ph.Eur.) Monograph Peppermint oil. 8.2-1353.2014Google Scholar
  33. 33.
    Mascher H, Kikuta C, Schiel H. Pharmacokinetics of menthol and carvone after administration of an enteric coated formulation containing peppermint oil and caraway oil. Arzneimittelforschung. 2001;51(6):465–9.  https://doi.org/10.1055/s-0031-1300064.CrossRefPubMedGoogle Scholar
  34. 34.
    Hiki N, Kaminishi M, Hasunuma T, et al. A phase I study evaluating tolerability, pharmacokinetics, and preliminary efficacy of l-menthol in upper gastrointestinal endoscopy. Clin Pharmacol Ther. 2011;90(2):221–8.  https://doi.org/10.1038/Clpt.2011.110.CrossRefPubMedGoogle Scholar
  35. 35.
    Gelal A, Jacob P 3rd, Yu L, Benowitz NL. Disposition kinetics and effects of menthol. Clin Pharmacol Ther. 1999;66(2):128–35.  https://doi.org/10.1053/cp.1999.v66.100455001.CrossRefPubMedGoogle Scholar
  36. 36.
    Degen LP, Phillips SF. Variability of gastrointestinal transit in healthy women and men. Gut. 1996;39(2):299–305.CrossRefGoogle Scholar
  37. 37.
    Abuhelwa AY, Foster DJ, Upton RN. A quantitative review and meta-models of the variability and factors affecting oral drug absorption-part II: gastrointestinal transit time. AAPS J. 2016;18(5):1322–33.  https://doi.org/10.1208/s12248-016-9953-7.CrossRefPubMedGoogle Scholar
  38. 38.
    Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138:103–41.CrossRefGoogle Scholar
  39. 39.
    Tracy TS, Chaudhry AS, Prasad B, et al. Interindividual variability in cytochrome P450-mediated drug metabolism. Drug Metab Dispos. 2016;44(3):343–51.  https://doi.org/10.1124/dmd.115.067900.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Alam MS, Roy PK, Miah AR, et al. Efficacy of peppermint oil in diarrhea predominant IBS—a double blind randomized placebo-controlled study. Mymensingh Med J. 2013;22(1):27–30.PubMedGoogle Scholar
  41. 41.
    Bautista DM, Siemens J, Glazer JM, et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature. 2007;448(7150):204–8.  https://doi.org/10.1038/nature05910.CrossRefPubMedGoogle Scholar
  42. 42.
    Keszthelyi D, Troost FJ, Jonkers DM, et al. Alterations in mucosal neuropeptides in patients with irritable bowel syndrome and ulcerative colitis in remission: a role in pain symptom generation? Eur J Pain. 2013;17(9):1299–306.  https://doi.org/10.1002/j.1532-2149.2013.00309.x.CrossRefPubMedGoogle Scholar
  43. 43.
    Ramachandran R, Hyun E, Zhao L, et al. TRPM8 activation attenuates inflammatory responses in mouse models of colitis. Proc Natl Acad Sci USA. 2013;110(18):7476–81.  https://doi.org/10.1073/pnas.1217431110.CrossRefPubMedGoogle Scholar
  44. 44.
    Karashima Y, Damann N, Prenen J, et al. Bimodal action of menthol on the transient receptor potential channel TRPA1. J Neurosci. 2007;27(37):9874–84.  https://doi.org/10.1523/JNEUROSCI.2221-07.2007.CrossRefPubMedGoogle Scholar
  45. 45.
    Yoshida N, Naito Y, Hirose R, et al. Prevention of colonic spasm using l-menthol in colonoscopic examination. Int J Colorectal Dis. 2014;29(5):579–83.  https://doi.org/10.1007/s00384-014-1844-8.CrossRefPubMedGoogle Scholar
  46. 46.
    Asao T, Mochiki E, Suzuki H, et al. An easy method for the intraluminal administration of peppermint oil before colonoscopy and its effectiveness in reducing colonic spasm. Gastrointest Endosc. 2001;53(2):172–7.CrossRefGoogle Scholar
  47. 47.
    Inoue K, Dohi O, Gen Y, et al. l-Menthol improves adenoma detection rate during colonoscopy: a randomized trial. Endoscopy. 2014;46(3):196–202.  https://doi.org/10.1055/s-0034-1365035.CrossRefPubMedGoogle Scholar
  48. 48.
    Nair B. Final report on the safety assessment of Mentha piperita (peppermint) oil, Mentha piperita (peppermint) leaf extract, Mentha piperita (peppermint) leaf, and Mentha piperita (peppermint) leaf water. Int J Toxicol. 2001;20(Suppl 3):61–73.PubMedGoogle Scholar
  49. 49.
    Heimes K, Hauk F, Verspohl EJ. Mode of action of peppermint oil and (−)-menthol with respect to 5-HT3 receptor subtypes: binding studies, cation uptake by receptor channels and contraction of isolated rat ileum. Phytother Res. 2011;25(5):702–8.  https://doi.org/10.1002/ptr.3316.CrossRefPubMedGoogle Scholar
  50. 50.
    European Medicines Agency (EMA), Committee on herbal medicinal products (HMPC). Public statement on the use of herbal medicinal products containing pulegone and menthofuran. 2005.Google Scholar
  51. 51.
    European Medicines Agency (EMA), Committee on herbal medicinal products (HMPC). Community herbal monograph on Mentha x Piperita L. Aetheroleum. 2007.Google Scholar
  52. 52.
    Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012;10(7):712–21.  https://doi.org/10.1016/j.cgh.2012.02.029 (e4).CrossRefPubMedGoogle Scholar
  53. 53.
    Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet. 2003;42(2):107–21.  https://doi.org/10.2165/00003088-200342020-00001.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Healthcare Ltd., part of Springer Nature 2018

Authors and Affiliations

  • Zsa Zsa R. M. Weerts
    • 1
  • Daniel Keszthelyi
    • 1
  • Lisa Vork
    • 1
  • Nic C. P. Aendekerk
    • 1
  • Henderik W. Frijlink
    • 2
  • Jacobus R. B. J. Brouwers
    • 3
  • Cees Neef
    • 4
  • Daisy M. A. E. Jonkers
    • 1
  • Ad A. M. Masclee
    • 1
  1. 1.Division of Gastroenterology-Hepatology, NUTRIM School for Nutrition and Translational Research in MetabolismMaastricht University Medical CenterMaastrichtThe Netherlands
  2. 2.Department of Pharmaceutical Technology and BiopharmacyUniversity of Groningen, Groningen Research Institute of PharmacyGroningenThe Netherlands
  3. 3.Unit of Pharmacotherapy, Pharmacoepidemiology and PharmacoeconomicsUniversity of Groningen, Groningen Research Institute of PharmacyGroningenThe Netherlands
  4. 4.Department of Clinical Pharmacy and Toxicology, CAPHRI School for Public Health and Primary CareMaastricht University Medical CenterMaastrichtThe Netherlands

Personalised recommendations