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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1965–1978
Number of pages14
JournalAdvances in Therapy
Volume35
Issue number11
DOIs
Publication statusPublished - Nov 2018

Keywords

  • Abdominal pain
  • Irritable bowel syndrome
  • Gastroenterology
  • Peppermint oil
  • Pharmacokinetics
  • Phase I
  • Targeted therapeutics
  • RANDOMIZED-TRIAL
  • DRUG-DELIVERY
  • COLONIC SPASM
  • L-MENTHOL
  • PHARMACOKINETICS
  • VARIABILITY
  • EFFICACY
  • TRPM8
  • PAIN
  • COLONOSCOPY

Cite this

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title = "A Novel Ileocolonic Release Peppermint Oil Capsule for Treatment of Irritable Bowel Syndrome: A Phase I Study in Healthy Volunteers",
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, RANDOMIZED-TRIAL, DRUG-DELIVERY, COLONIC SPASM, L-MENTHOL, PHARMACOKINETICS, VARIABILITY, EFFICACY, TRPM8, PAIN, COLONOSCOPY",
author = "Weerts, {Zsa Zsa R M} and Daniel Keszthelyi and Lisa Vork and Aendekerk, {Nic C P} and Frijlink, {Henderik W} and Brouwers, {Jacobus R B J} and Cees Neef and Jonkers, {Daisy M A E} and Masclee, {Ad A M}",
year = "2018",
month = "11",
doi = "10.1007/s12325-018-0802-1",
language = "English",
volume = "35",
pages = "1965–1978",
journal = "Advances in Therapy",
issn = "0741-238X",
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number = "11",

}

A Novel Ileocolonic Release Peppermint Oil Capsule for Treatment of Irritable Bowel Syndrome : A Phase I Study in Healthy Volunteers. / Weerts, Zsa Zsa R M; Keszthelyi, Daniel; Vork, Lisa; Aendekerk, Nic C P; Frijlink, Henderik W; Brouwers, Jacobus R B J; Neef, Cees; Jonkers, Daisy M A E; Masclee, Ad A M.

In: Advances in Therapy, Vol. 35, No. 11, 11.2018, p. 1965–1978 .

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A Novel Ileocolonic Release Peppermint Oil Capsule for Treatment of Irritable Bowel Syndrome

T2 - A Phase I Study in Healthy Volunteers

AU - Weerts, Zsa Zsa R M

AU - Keszthelyi, Daniel

AU - Vork, Lisa

AU - Aendekerk, Nic C P

AU - Frijlink, Henderik W

AU - Brouwers, Jacobus R B J

AU - Neef, Cees

AU - Jonkers, Daisy M A E

AU - Masclee, Ad A M

PY - 2018/11

Y1 - 2018/11

N2 - 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.

AB - 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.

KW - Abdominal pain

KW - Irritable bowel syndrome

KW - Gastroenterology

KW - Peppermint oil

KW - Pharmacokinetics

KW - Phase I

KW - Targeted therapeutics

KW - RANDOMIZED-TRIAL

KW - DRUG-DELIVERY

KW - COLONIC SPASM

KW - L-MENTHOL

KW - PHARMACOKINETICS

KW - VARIABILITY

KW - EFFICACY

KW - TRPM8

KW - PAIN

KW - COLONOSCOPY

U2 - 10.1007/s12325-018-0802-1

DO - 10.1007/s12325-018-0802-1

M3 - Article

C2 - 30284674

VL - 35

SP - 1965

EP - 1978

JO - Advances in Therapy

JF - Advances in Therapy

SN - 0741-238X

IS - 11

ER -