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Novel ileocolonic release peppermint oil 125 6 disease (as assessed by screening in which medical history, physical examination, and vital signs were checked). Participants were recruited via local advertisements and a national recruitment website. Exclusion criteria included high intake of alcohol (>15 consumptions per week) or caffeine (>8 cups coffee a day). Women of fertile age underwent a standard pregnancy test and were instructed to continue their contraception throughout the study. Medication use (except for contraception) was prohibited in the 14 days prior to the test period and volunteers were instructed to abstain from alcohol, caffeine, grapefruit, and menthol- or peppermint oil containing products such as toothpaste, candy, and mouthwash for 48 h before each test day. Menthol-free toothpaste was provided beforehand. Study design This study is designed according to US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines for bioequivalence studies 30,31 ; a randomized, double blind, two-treatment, single dose, crossover pharmacokinetic study with a wash-out period of at least 14, but no longer than 21 days ( Figure 6.1 ). Figure 6.1 Study design; after screening, participants (healthy volunteers) were randomized and received small-intestinal release peppermint oil (PO) or ileocolonic release PO in a crossover design with a wash-out period of <21 days but >14 days. The study consisted of two identical test periods of 24 hours in which all participants received 182 mg of ileocolonic and small-intestinal release peppermint oil capsules. In line with the European Pharmacopoeia entry for peppermint oil 32 , both 182 mg formulations contained between 51 mg and 105 mg of L-menthol (normal variance between capsules, no differences between small-intestinal versus ileocolonic release). As the estimated half-life of menthol-glucuronide in both preparations was between 3 and Screening 8 healthy volunteers N=4 ƃ N=4 Ƃ Small�intestinal release peppermint oil N=4 Ileocolonic release peppermint oil N=4 W A S H O U T Small�intestinal release peppermint oil N=4 Ileocolonic release peppermint oil N=4