A single-center, randomized, open-label, 3 way crossover study to evaluate the single and multiple dose pharmacokinetic profile of HP-5000 compared to PENNSAID® 2% in healthy volunteers

The drug to be given is an existing compound, diclofenac, in a new application
form, transdermal patches (transdermal means: patch for administration via the
skin). Diclofenac is an anti inflammatory drug and is available in the market
under several dosages and formulations.

In this study a new administration method of diclofenac, the HP-5000
transdermal patch, will be tested. This form of diclofenac-containing
transdermal patches is not registered but similar formulations with a lower
dose of diclofenac have been given to humans before.

In addition to diclofenac in the new application form (transdermal patches),
the volunteer will receive PENNSAID® 2%. This is a diclofenac-containing
solution that will be applied to the skin. This is a registered medication.

To investigate how quickly and to what extent diclofenac is absorbed and
eliminated from the body (this is called pharmacokinetics) when it is
administrated by using a HP 5000 transdermal patch. Furthermore, the
pharmacokinetics of HP-5000 transdermal patches will be compared to the
pharmacokinetics of PENNSAID® 2% diclofenac solution. In addition, the safety
and tolerability of the HP-5000 transdermal patch will be investigated.

The actual study will consist of 3 periods during which the volunteer will stay
in the clinical research center in Zuidlaren for 18 days (17 nights) in each
period. The time interval between the different periods is at least 16 full
days (between the last blood sample in one period and the first medication
administration in the next period).

During the study, in each period HP 5000 75, HP 5000 DRS400, or PENNSAID® 2%
solution will be applied to the skin in the morning of Day 1, and the mornings
of Day 3 up to and including Day 16. Thereafter you will receive breakfast. The
administration of PENNSAID® 2% solution will be repeated after 12 hours on Days
3 through 16.

During this study the volunteer will receive in random order 3 treatments in 3
periods. The volunteer will thus receive each treatment once and will receive
only 1 treatment in each period. The order in which the volunteer will receive
these treatments will be determined by chance.

Treatment A: HP-5000-75* transdermal patches, containing 150 mg diclofenac
sodium per 140 cm2;
on Day 1 and from Day 3 up to and including Day 16 once daily (every 24 hours)
a new patch will be applied to the upper part of the back.
Treatment B: HP-5000-DRS400 transdermal patches, containing 150 mg diclofenac
sodium per 140 cm2;
on Day 1 and from Day 3 up to and including Day 16 once daily (every 24 hours)
a new patch will be applied to the upper part of the back.
Treatment C: PENNSAID® 2% solution, containing 40 mg diclofenac sodium per 2 mL;
once on Day 1 and twice daily from Day 3 up to and including Day 16, 2 mL will
be applied to an area of 140 cm2 on the upper part of the back

In every period, Day 1 is the day of first study medication application.

The HP-5000 transdermal patches were tested in earlier studies. The most
frequently reported adverse events were application site reactions, such as
itch (pruritus). As with other transdermal system products, the use of the
patches may occasionally lead to symptoms of contact dermatitis (this is a skin
reaction or eczema caused by contact with irritating substances or substances
that a person is allergic to) such as redness, rash, eruption, flare, itching,
pigmentation, skin irritation and loss of hair at the site of application. The
active ingredient, diclofenac, also has known adverse effects as described
below.

PENNSAID® 2% solution for application on the skin is a registered drug
containing diclofenac as active ingredient. It is available in the United
States since February 2014. Since 2009, PENNSAID® 1.5% solution has been
registered as a drug and is used in the United States. The most frequently
reported adverse events after application of diclofenac in the form of
PENNSAID® 1.5% are skin reactions at the application site, such as dryness,
redness, and contact dermatitis (skin reaction/eczema) with redness and
hardening of the skin or with blisters and itching. Other frequently reported
adverse effects of PENNSAID® are stomach upset (dyspepsia: symptoms are upper
abdominal pain or fullness, burping, nausea, vomiting and heartburn), stomach
pain, gas, diarrhea and nausea. The reported adverse effects after application
of PENNSAID® 2% solution are comparable to those reported for PENNSAID® 1.5%.

Other frequently reported adverse effects of diclofenac in general include
headache, dizziness, vertigo, anorexia (lack of appetite), and rashes.

Procedures: pain, minor bleeding, bruising, possible infection.