A SINGLE-CENTER, SINGLE-DOSE, OPEN-LABEL, FOUR-WAY-CROSSOVER STUDY TO EVALUATE THE PHARMACOKINETIC PROFILE OF THE HP-5000 PATCH (DICLOFENAC SODIUM TRANSDERMAL DRUG DELIVERY SYSTEM) FOLLOWING 24-HOUR APPLICATION COMPARED TO FLECTOR® AND VOLTAREN® 100 MG IN HEALTHY ADULT MALE AND FEMALE SUBJECTS UNDER FASTING CONDITIONS

The drug to be given is an existing compound, diclophenac, in a new application
form (transdermal patches). Diclophenac is an anti-inflammatory drug.
In this study a new administration method of diclophenac, the HP-5000
transdermal patch, will be tested. This is the first time diclophenac will be
administrated to humans in this form of transdermal patches. In addition to
diclophenac in the new application form (transdermal patches), the volunteers
will receive single dose of registered Voltaren® (a tablet that contains
diclophenac) in the form of a tablet and two Flector® transdermal patches
(containing diclophenac epolamine).

The purpose of the study is to investigate how quickly and to what extent
diclophenac is absorbed and eliminated from the body (this is called
pharmacokinetics) when it is administrated by using a HP-5000 transdermal
patch. Furthermore, the pharmacokinetic profile of HP-5000 transdermal patches
will be compared to oral administration of Voltaren® and Flector® patches. In
addition, the safety and tolerability of the HP-5000 transdermal patch will be
investigated.

This is a single-center, single-dose, open-label, 6-sequence, 4-period
crossover study in 18 healthy adult male and female subjects. All subjects in
the study will take a single oral Voltaren® XR tablet (containing 100 mg
diclofenac sodium) in the first period (Treatment A). For the next 3 periods,
all subjects will be randomly assigned to 1 of the 6 sequences of 3 single dose
transdermal patch treatments (Treatments B, C and D), each with a total
application time of 24 hours: once-a-day HP-5000-75A patch, once-a-day
HP-5000-75B patch, and twice-a-day Flector® patch

Procedures and assessments:
Screening and follow-up: demographics, physical examination, height, weight,
vital signs, 12-lead electrocardiogram (ECG), clinical laboratory (including
clinical chemistry, hematology and urinalysis), pregnancy test (females only),
drug and alcohol screen, serology (hepatitis B surface antigen [HBsAg],
hepatitis C virus antibody [anti HCV] and human immunodeficiency virus type 1
and 2 antibody [anti-HIV-1/2]), adverse events and previous and concomitant
medication
Upon each admission: clinical laboratory (including clinical chemistry,
hematology and urinalysis), pregnancy test (females only), drug and alcohol
screen, adverse events and previous and concomitant medication

Blood sampling for PK of diclofenac in plasma:
Treatment A: before dosing untill 24 hours after dosing
Treatments B, C and D: before application untill 48 hours after application

Residual drug: used patches will be collected in the labeled vials following
the procedures provided by the Sponsor and shipped back to the Sponsor for
analysis of residual diclofenac (Treatments B, C, D)

Dermal assessments:
skin irritation: immediately before application untill 24 hours after (first)
application (Treatments B, C, D)
discomfort: untill 24 hours after (first) application (Treatments B, C, D)
patch adhesion: untill 24 hours after (first) application (Treatments B, C, D)
adhesive residue at application site: immediately after patch removal
(Treatments B, C, D)

Safety assessments:
AEs: recorded from the first admission until completion of the follow up visit
clinical laboratory assessments (including clinical chemistry, hematology and
urinalysis): prior to discharge on Day 2 (treatment A) or Day 3 (treatments B,
C, D)
vital signs (including sitting systolic and diastolic blood pressure and
sitting pulse rate) and ECG: pre-doseuntill 48 hours post-dose/after patch
application
physical examination (including body weight)

Treatment A: one Voltaren® XR oral tablet (containing 100 mg diclofenac sodium)
under fasting conditions
Treatment B: one HP-5000-75A transdermal patch applied vertically on the back
for 24 hours under fasting conditions
Treatment C: one HP-5000-75B transdermal patch applied vertically on the back
for 24 hours under fasting conditions
Treatment D: one Flector® patch applied on the back for 12 hours, under fasting
conditions, followed by a second Flector® transdermal patch of the same
strength applied on the same area of the back for the next 12 hours

As the HP-5000 transdermal patch will be administered to man for the first time
in this study, adverse effects in man have not been reported up to now. As with
other transdermal system products, the use of the patches may occasionally lead
to symptoms of contact dermatitis such as redness, rash, eruption, flare,
itching, pigmentation, skin irritation and loss of hair at the site of
application.

Flector® and Voltaren® are registered drugs, both containing diclophenac as
active ingredient. The most reported adverse effects after administration with
tablets include headache, dizziness, vertigo, nausea, vomiting, diarrhea,
dyspepsia, abdominal pain/cramps, flatulence, anorexia, and rashes.

With the dose used in this study no serious adverse effects are expected. The
occurrence of known or other effects cannot be excluded. All potential drugs
cause adverse events to some extent.

Registration af adverse effects: During the entire investigation all adverse
effects reported will be documented.

Blood draw, indwelling canula: During this study less then 500 ml of blood will
be drawn. In period 1, blood will be drawn until 24 hours after administration
of Voltaren® (thus until Day 2). In period 2, 3 and 4 blood will be drawn until
48 hours (thus until Day 3) after patch application.
It is anticipated that on Day -1 an indwelling canula will be inserted for most
of the blood sampling on Day 1. On the other days during this study, blood will
be drawn by direct puncture of the vein.

Heart trace (ECG*s): ECG*s will be made regularly: specifically on Day 1.