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Chapter 6 124 vitro model and in healthy volunteers. Because the ileocolonic release formulation will release the peppermint oil in the ileocolonic region as opposed to the upper small intestine, we hypothesized that this will result in a delayed and possibly lower peak menthol-glucuronide concentration in the plasma compared to plasma concentrations found after administration of small-intestinal release capsules. Materials and methods In vitro GISS experiment The novel ileocolonic release capsules were tested in the gastro-intestinal simulation system (GISS). The GISS is an in vitro model based on the pharmacopoeial dissolution test and has been described in detail elsewhere. 28 In summary, the model simulates pH and transit times through the human gastro-intestinal tract and enables variation of these and other parameters such as osmolality and agitation. 28,29 Table 6.1 shows the four GISS test phases. Phase I human trial The research protocol was approved by the Maastricht University Medical Center+ Committee of Ethics and all study procedures were performed in compliance with Good Clinical Practice Guidelines and according to the revised Declaration of Helsinki. The study has been registered in the US National Library of Medicine ( NCT 02291445 ) and the EudraCT database (2014-004195-32) and all subjects gave a written informed consent prior to participation. Table 6.1 Specifications of the four phases of the dissolution test (GISS). Phase Gastrointestinal Segment Volume (mL) Residence time (h) pH Osmolality (modmol/kg) I Stomach 500 2.0 1.2 ± 0.10 150 ± 25 II Jejunum 629 2.0 6.8 ± 0.20 250 ± 50 III Ileum (distal) 940 0.5 7.5 ± 0.25 250 ± 50 IV Colon (proximal) 1000 1.5 6.0 ± 0.25 250 ± 60 GISS; gastro-intestinal simulation system. Adapted from Schellekens et al. , 2007. 28 Subjects All subjects were healthy, non-smoking volunteers between 18 and 65 years old, with a BMI between 18 and 25 kg/m 2 and no history of gastrointestinal or other chronic