Assessment of the bioavailability of phenolics from an orange peel extract

Against the background of numerous detrimental effects of reduced sleep and
sleep quality in the developed world, substances that are capable of improving
sleep have been of growing interest. Especially natural products, e.g. for
functional foods and nutritional supplements, such as valerian extracts have
been of interest. Valerian roots contain several polyphenolic compounds, some
of which are identical to polyphenols found in citrus fruits, specifically
hesperidin, linarin and apigenin. The present study focuses on hesperidin
extracted from the peel of sweet oranges. Published studies have indicated that
hesperidin, when administered intraperitoneally acutely prolonged sleep in
rodents, while it exhibited anxiolytic effects when administered chronically
over a four week time period orally. The positive effects of hesperidin on
sleep are exerted by the intact molecule, while the main metabolite, hesperitin
does not seem to exhibit potent effects. Hence the need to develop and test
novel dosage forms that make hesperidin bioavailable by avoiding premature
metabolization in the gut and liver, such as lozenges. Lozenges are absorbed in
the mouth while capsules are ingested and absorbed in the gastrointestinal
tract, which might lead to an improved absorption of the intact hesperidin
molecule by administering it in the form of a lozenge. Furthermore, different
types of hesperidin extract could influence the bioavailability.

The present study aims to determine the bioavailability of hesperidin when
micronized and non-micronized, when S-enantiomeric enriched and racemic, and
when incorporated in a lozenge compared to a capsule, such that the appropriate
dosage form can be chosen.

The cross-over study will be performed in 8 non-smoking adults. The
intervention comprises oral intake of three different 500mg dosages: (1) HE
with S:R ratio 1,5:1 in a capsule, (2) micronized HE with S:R ratio 4:1 in a
capsule, and (3) micronized HE with S:R ratio 4:1 in a lozenge. Each subject
will receive each dosage form on three separate days that are at least one week
apart.

The study will consist of 3 study days in which each subject will consume in
randomized order one of the three dosage forms containing the orange peel
extract at the beginning of the test day.

After an overnight fasting, a catheter is placed in the arm of each subject for
repeated blood collection. Per study day, 11 times 8 mL blood sample will be
taken. Each individual is instructed to collect his/her urine during the stay
at the facility. The participants are asked to collect their urine for 24 hours
after intake of the orange peel extract and deliver it the next day at the
facility. Furthermore, one more blood sample of 8 mL will be taken the next day
at t=24h. The participants are asked not to change their normal dietary habits
before the study period, except that they are instructed to avoid any citric
fruits and other polyphenol-rich foods and dietary supplements, all sorts of
alcohol, tea and vinegars as much as realistically possible for a period
starting 3 days prior to the start of the study day. Participants will not
benefit directly from participation.