A single-center, open-label, randomized, 3-way crossover study to evaluate the pharmacokinetic profile and tolerability of Flurbiprofen following administration of two Flurbiprofen transdermal formulations compared to Yakuban Tape® in healthy subjects

Flurbiprofen Transdermal System (FTS) is a new transdermal formulation (a patch
for administration via the skin) of the registered anti-inflammatory drug
flurbiprofen. FTS is being developed and is not registered as a drug but has
been given to humans before in a similar formulation. Flurbiprofen is not a new
drug; it is already available in the market under several dosages and
formulations. In addition to the two formulations of the FTS applied for 24
hours, you will receive 2 Yakuban Tape® transdermal patches that also contain
flurbiprofen and will be applied twice for 12 hours (24 hours in total). These
Yakuban Tape® transdermal patches are not registered in the European Union but
are registered in Asia.

The purpose of the study is to investigate to what extent the FTS patches are
tolerated. It will also be investigated how quickly and to what extent
flurbiprofen from the FTS patch is absorbed and eliminated from the body (this
is called pharmacokinetics).

The actual study will consist of 3 periods during which the volunteer will stay
in the clinical research center in Zuidlaren for 5 days (4 nights). The time
interval between the different periods is between 6 and 8 days.
For each period, the volunteer is expected at the clinical research center at
14:00 h in the afternoon prior to the day of (first) administration of study
medication. The volunteer will leave the clinical research center on Day 4 (Day
1 is the day of administration of study medication). Between 7 and 10 days
after you have left the clinic after Period 3 the volunteer will be called for
a short follow-up.

During the study, the flurbiprofen patches will be applied to the lower back
for 24 hours (FTS-A2 and FTS-B2) or 2 times 12 hours (Yakuban Tape®). Study
personnel will apply the patches and will press the patches firmly in place,
using the palm of the hand for at least 30 seconds to assure good adhesion.
From 10 hours before until 4 hours after the application of the (first) patch
the volunteer is not allowed to eat or drink anything except for water. The
volunteer will receive a lunch 4 hours after application of the study
medication in each period.

Other transdermal formulations that contain flurbiprofen have been administered
in humans and were shown to be safe and tolerable. Some of the documented side
effects with Yakuban Tape® include: itching, redness, rash, and tingling at the
site of patch application.
This is the first time that these particular transdermal systems of
flurbiprofen, FTS, will be tested in humans. Though local tolerability was good
in animal experiments, local skin irritation may be a side effect of FTS. An
earlier version of the FTS patches did not have unexpected adverse effects.
Flurbiprofen administered through a tablet has well-documented side effects of
which the most important are: edema (swelling caused by fluid retention),
abdominal pain, constipation, diarrhea, indigestion/heartburn, elevated liver
enzymes, flatulence, gastrointestinal bleeding, nausea, vomiting, body weight
changes, headache, nervousness, anxiety, insomnia, increased reflexes, tremor,
amnesia, fatigue, depression, malaise (feeling sick), somnolence, rhinitis,
rash, changes in vision, dizziness, tendinitis and tinnitus.

Procedures: pain, minor bleeding, bruising, possible infection