Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs
Determination of the Transdermal
Bioavailability of a Newly Developed
Diclofenac Sodium Patch in Comparison
with a Reference Preparation
Michael H. Gschwenda, Wolfgang Martin a, Peter Arnolda, Marie-Odile Verdun b, Nathalie Cambon b,
Adrian Frentzelb, and Werner Scheiweb
Pharmakin GmbH, Gesellschaft für Pharmakokinetika, Ulm (Germany), and Mepha AGb, Aesch (Switzerland)
Summary
Two different transdermal diclofenac
(CAS 15307-86-5) formulations (Olfen
Patch 140 mg diclofenac sodium as test
preparation and 180 mg diclofenac epol-
amine plaster, equivalent to 140 mg diclo-
fenac sodium, as reference preparation)
were investigated in 24 healthy male and
female volunteers in order to compare
the transdermal bioavailability between
both treatments following topical mul-
tiple dose administration. Subjects were
applied 2 plasters of test and reference
formulation at a dose interval of 12 h for
4 consecutive days. Test and reference
preparation were administered in ran-
domised sequence at a marked spot at
the left upper arm under non-fasting con-
ditions. For determination of diclofenac
concentrations, pre-dose (trough) values
were taken during steady-state build-up
and during the period of switch-over be-
tween both preparations on days 1−3 and
5−7. Blood samples for pharmacokinetic
profiling were taken on days 4 and 8 at
pre-defined time points up to 24 h follow-
ing drug administration (after the 7th
resp. 15th dose). Treatments were not se-
parated by a wash-out phase. Consider-
ing the short half-life of diclofenac, it
was appropriate that a switch-over de-
sign was chosen without wash-out
periods between treatments. Diclofenac
plasma concentrations were determined
by means of a validated LC-MS/MS
method (limit of detection: 0.06 ng/ml;
lower limit of quantification: 0.15 ng/ml).
For the test preparation, maximum
plasma concentrations of 3.36 ng/ml
Arzneim.-Forsch./Drug Res. 55, No. 7, 403−413 (2005)
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(Cmax, 0-12), 3.73 ng/ml (Cmax, 12-24) and
3.84 ng/ml (Cmax, 0-24) as well as areas un-
der the plasma concentration-time curve
(AUC) of 31.11 ng·h/ml (AUC0-12), 34.83
ng·h/ml (AUC12-24) and 65.94 ng·h/ml
(AUC0-24) were determined. For the refer-
ence preparation, these values were 1.55
ng/ml (Cmax, 0-12), 1.45 ng/ml (Cmax, 12-24)
and 1.57 ng/ml (Cmax, 0-24) as well as
13.28 ng·h/ml (AUC0-12), 12.68 ng·h/ml
(AUC12-24) and 25.96 ng·h/ml (AUC0-24).
For the test preparation, peak-to-trough
fluctuations (% PTF) of 34.78 % (% PTF0-12),
38.50 % (% PTF12-24) and 43.68 % (%
PTF0-24) were observed. Corresponding
values for the reference preparation were
35.82 % (% PTF0-12), 31.36 % (% PTF12-24)
and 40.55 % (% PTF0-24). In order to
evaluate comparable bioavailability of Key words
both preparations, 90 % confidence inter-
vals of the test/reference ratios were de- 䊏 Anti-inflammatory drug,
termined. Thereby, for all dose intervals non-steroidal
considered and all AUC parameters calcu- 䊏 CAS 15307-86-5
lated, the extent of diclofenac absorption 䊏 Diclofenac epolamine, plas-
from the test preparation markedly ex-
ter, topical administration,
ceeds those values obtained for the refer-
ence preparation. Likewise, maximum
transdermal bioavailability
plasma concentrations, as a measure for 䊏 Diclofenac sodium, plaster,
the rate of absorption, were higher after topical administration,
the test preparation. With respect to transdermal bioavailability
peak-to-trough fluctuation of plasma di- 䊏 Olfen Patch
clofenac levels, both plaster preparations
were comparable for the morning dose Arzneim.-Forsch./Drug Res.
interval 0−12 h as well as for the 0−24 h 55, No. 7, 403−413 (2005)
period.
Gschwend et al. − Diclofenac 403
Analgetika · Antiphlogistika · Antirheumatika · Entzündungshemmer

Zusammenfassung

Bestimmung der transdermalen Biover-
fügbarkeit eines neu entwickelten Diclo-
fenac-Natrium-Pflasters im Vergleich zu
einem Referenzpräparat
Zwei verschiedene transdermale Diclo-
fenac (CAS 15307-86-5)-Formulierungen
(Olfen Patch 140 mg Diclofenac-Na-
trium als Testpräparat und 180 mg Diclo-
fenac-Epolamin Pflaster, äquivalent zu
140 mg Diclofenac-Natrium, als Referenz-
präparat) wurden an 24 gesunden männ-
lichen und weiblichen Probanden unter-
sucht, um die transdermale Bioverfügbar-
keit beider Behandlungen nach topischer
Mehrfachgabe miteinander zu verglei-
chen. Die Probanden erhielten je 2 Pfla-
ster des Test- und Referenzpräparates in
einem Dosierungsintervall von 12 h an 4
nierten Zeitpunkten bis zu 24 h nach der
siebten bzw. fünfzehnten Dosierung abge-
nommen. Die Behandlungen waren nicht
von einer Auswaschphase voneinander
getrennt. Aufgrund der kurzen Halbwerts-
zeit von Diclofenac galt ein switch-over-
Design ohne Auswaschphase zwischen
den Behandlungsphasen als geeignet.
Diclofenac-Plasmakonzentrationen wur-
den mit Hilfe einer validierten LC-MS/
MS-Methode bestimmt (analytische Nach-
weisgrenze: 0.06 ng/ml; untere analyti-
sche Bestimmungsgrenze: 0.15 ng/ml).
Für das Testpräparat ergaben sich maxi-
male Plasmakonzentrationen von 3.36
ng/ml (Cmax, 0-12), 3.73 ng/ml (Cmax, 12-24)
und 3.84 ng/ml (Cmax, 0-24) sowie Flächen
unter der Plasmakonzentrations-Zeit-
Kurve („area under the curve“; AUC) von
bei 35.82 % (% PTF0-12), 31.36 % (% PTF12-24)
und 40.55 % (% PTF0-24). Für einen Ver-
gleich der Bioverfügbarkeit beider For-
mulierungen wurden 90 %-Konfidenz-
intervalle der Test/Referenz-Quotienten
bestimmt. Dabei ergaben sich für alle Do-
sierungsintervalle in den entsprechenden
AUC-Parameter ein deutlich höheres Aus-
maß der Wirkstoff-Absorption für das
Testpräparat im Vergleich zum Referenz-
präparat. Auch waren die maximalen
Plasmakonzentrationen (als Maß für die
Geschwindigkeit der Absorption) für das
Testpräparat deutlich höher. Bezüglich
der Peak/Trough-Fluktuation der Diclofe-
nac-Plasmaspiegel waren beide Pflaster-
Präparate für das morgendliche Intervall
von 0−12 h sowie für die Periode 0−24 h
miteinander vergleichbar.

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aufeinanderfolgenden Tagen. Die Ver-
abreichung von Test- und Referenzpräpa-
rat erfolgte randomisiert an einer mar-
kierten Stelle des linken Oberarms unter
non-fasting-Bedingungen. Zur Bestim-
mung von Diclofenac-Konzentrationen
wurden pre-dose (trough)-Werte wäh-
rend der Aufsättigungsphase und der
switch-over-Phase zwischen beiden Prä-
paraten an den Tagen 1−3 und 5−7 ge-
wonnen. Blutproben zur Bestimmung
der pharmakokinetischen Profile wurden
an den Tagen 4 und 8 an jeweils vordefi-
31.11 ng·h/ml (AUC0-12), 34.83 ng·h/ml
(AUC12-24) und 65.94 ng·h/ml (AUC0-24).
Für das Referenzpräparat wurden Cmax-
Werte von 1.55 ng/ml (Cmax, 0-12), 1.45
ng/ml (Cmax, 12-24) und 1.57 ng/ml
(Cmax, 0-24) sowie AUC-Werte von 13.28 ng ·
h/ml (AUC0-12), 12.68 ng · h/ml (AUC12-24)
und 25.96 ng·h/ml (AUC0-24) bestimmt.
Für das Testpräparat ergaben sich „peak-
to-trough“ Fluktuationen (% PTF) von
34.78 % (% PTF0-12), 38.50 % (% PTF12-24)
und 43.68 % (% PTF0-24). Entsprechend
lagen die Werte für das Referenzpräparat

1. Introduction The anti-inflammatory activity of diclofenac and

Diclofenac (2-(2,6-dichloroanilino)phenyl acetic acid,
CAS 15307-86-5) belongs to the group of ortho-
phenylacetic acids and is a non-steroidal anti-inflam-
matory drug (NSAID) with anti-phlogistic, analgesic,
antipyretic and anti-rheumatic activities. Diclofenac ex-
hibits potent analgesic effects and is widely used for
treatment of inflammatory and degenerative joint dis-
eases, acute gout and rheumatoid arthritis, osteoar-
thritis, ankylosing spondylitis, soft-tissue inflamma-
tions/injuries, short-term alleviation of post-operative
pain and painful dysmenorrhoea [1−4]. The molecular
structure of diclofenac is depicted below.
Cl
NH
Cl
CO2H
Molecular structure of diclofenac
most of its other pharmacological effects are generally
thought to be related to the inhibition of cyclo-oxy-
genase, the crucial enzyme for prostaglandin biosyn-
thesis [2]. Diclofenac is a potent inhibitor of the cyclo-
oxygenase in vitro and in vivo [2]. In addition, in com-
mon with other NSAIDs, diclofenac is a potent revers-
ible inhibitor of the secondary phase of induced platelet
aggregation [2]. Inhibition of collagen-induced aggrega-
tion of platelets has been proven by in-vitro tests and
is reported after rectal and also after intravenous ad-
ministration of 75 mg of the drug [5]. However diclo-
fenac at usual therapeutic dosages has little effect on
bleeding time in humans [2].
Diclofenac 75 to 150 mg daily administered either
orally or rectally has been well studied in controlled
clinical trials in patients with rheumatoid arthritis, os-
teoarthritis and ankylosing spondylitis, showing similar
analgesic and anti-inflammatory efficacy to usual
therapeutic dosages of other NSAIDs [2]. The tolerabil-
ity profile of diclofenac is well established, as wide ex-
perience has been gained with the drug in clinical prac-
tice [2]. Diclofenac is well tolerated compared with
other NSAIDs and no other agent of this class appears

Arzneim.-Forsch./Drug Res. 55, No. 7, 403−413 (2005)

404 Gschwend et al. − Diclofenac
 Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs
to have a side effect profile which is clearly superior to
diclofenac [2]. As with other NSAIDs, gastrointestinal
problems are the most frequent effects, followed by mi-
nor CNS symptoms and allergic or local reactions [2].
However, side effects are usually mild and transient and
safety and tolerability of diclofenac is evident [2, 6].
Diclofenac is most often administered orally, but it
has also been administered topically, intravenously, in-
tramuscularly, intracolonically and rectally [1]. Conven-
tional immediate release tablets and capsules, enteric-
coated tablets, sustained release preparations, suspen-
sions, gels, suppositories, ampoules and optic drops are
commercially available [1].
The pharmacokinetics of diclofenac has been thor-
oughly investigated employing different routes of drug
administration. The systemic absorption of diclofenac
is directly proportional to the dose within the range of
25 to 150 mg [1]. Administration of multiple doses
yields absorption characteristics which are similar to
those seen following single doses [1]. Following oral or
rectal administration the drug is rapidly and completely
absorbed from the gastro-intestinal tract. Absolute
bioavailability is reported to be 90 ± 11.6 % following
the oral administration of a single dose of 50 mg [1].
However, diclofenac undergoes significant “first-pass”
metabolism with about 60 % of the drug reaching sys-
temic circulation in an unchanged form [2]. Similar to
other NSAIDs, diclofenac is highly bound to human
serum proteins (ⱖ 99.5 %), mostly to albumin [2]. In
humans a total volume of distribution between 0.12 and
0.17 L/kg was calculated [2]. Diclofenac penetrates into
the synovial fluid of patients with osteoarthritis and
rheumatoid arthritis and is eliminated less rapidly from
this site than from plasma [2]. During steady-state
pharmacokinetics, achieved by once daily administra-
tion of a 100 mg diclofenac sodium slow release formu-
lation, maximum concentrations in plasma (c = 222 ng/
ml) and in synovial fluid (c = 181 ng/ml) were achieved
4 h after drug administration [7].
Diclofenac is extensively metabolised and eliminated
principally by metabolism and subsequent urinary and
biliary excretion of glucuronide and sulphate conjug-
ates of the metabolites. The principal metabolite in hu-
man is 4’-hydroxydiclofenac (most likely catalysed by
CYP2C9). The amount of 4’-hydroxydiclofenac excreted
in the urine accounts for 20 to 30 % and that in the bile
for 10 to 20 % of the dose. Three other metabolites each
account for 10 to 20 % of the dose excreted in the urine
and small amounts of the dose excreted in the bile.
Conjugates of unchanged diclofenac account for 5 to
10 % of the dose recovered in urine and less than 5 % of
that excreted in bile [1, 2]. All hydroxy- and di-hydroxy
derivatives of diclofenac are at least 50 times less potent
in inhibiting prostaglandin E2 synthesis [8].
Transdermal delivery systems have recently attracted
much interest as an alternative to the traditional routes
of dosing, by ensuring the required therapeutic efficacy
with reduced unwanted side effects [9]. Different top-
Arzneim.-Forsch./Drug Res. 55, No. 7, 403−413 (2005)
ical diclofenac formulations are available in the market.
Various pharmacokinetic studies have reported that di-
clofenac, when applied topically, penetrates the skin
barrier to reach joints, muscles and synovial fluids in
sufficiently high concentration to exert local thera-
peutic activity [1, 3, 4, 10, 11]. E.g. thrice daily adminis-
tration of 2.5 g diclofenac sodium cream (1 % Voltaren
cream; corresponding to 25 mg diclofenac sodium) for 9
days under non-occlusive conditions resulted in steady-
state drug levels of 5−10 ng/ml [10]. Sioufi et al. re-
ported on steady-state levels of 3−15 ng/ml after twice
daily administration of 1.16 % Voltaren Emulgel (1.16 %
diclofenac diethylammonium salt; equivalent to 1 % di-
clofenac sodium) [11]. In another study, multiple epicu-
taneous administration of diclofenac hydroxyethylpyr-
rolidine (DHEP) gel (1 % diclofenac) resulted in max-
imum plasma concentrations of 28.1 ± 13.2 ng/ml [9,
12].
In contrast to conventional topical formulations
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such as creams or gels, plasters or patches permit a
constant and continuous transdermal delivery of the
active ingredient into the affected area by means of an
occlusive bandage and controlled, slow release of the
drug [3, 9, 13]. The skin acts as an efficient barrier to
the passage of materials into and out of the body. The
ideal drug candidate for transdermal delivery would
have a low molecular weight, be highly potent, and have
both hydrophobic and hydrophilic properties [12]. In
addition, the best delivery system would release the
drug to the skin at a rate lower than the maximum rate
of skin transport [12]. Such a formulation will control
for variability in skin permeability between individuals
and ensure a constant release rate [12].
The usual therapeutic practice consists in the twice
daily administration of plasters at the painful site, thus
considering the relatively short half-life of diclofenac in
plasma. Administration of a diclofenac hydroxy-
ethylpyrrolidine (DHEP) plaster, resulted in steady-state
plasma levels of 17.4 ± 13.5 ng/ml [9,12]. These plasma
levels were about 100 times lower compared to those
achieved after systemic dosing (about 1,500 ng/ml after
50 mg enteric coated Voltaren) [9]. Comparable results
with about 100 times lower Cmax-values as compared
with an oral dose were obtained for diclofenac sodium
cream [10].
The present study was conducted to investigate the
transdermal pharmacokinetics and bioavailability of di-
clofenac released from a newly developed patch in
healthy volunteers following topical multiple dose ad-
ministration. Clinical data on efficacy and safety assess-
ment were obtained and reported separately [3, 14].
2. Subjects, materials and methods
2.1. Ethical considerations
The study was performed at the clinical facilities of Cross Re-
search s.a., Phase I unit (Arzo, Switzerland) according to the
principles of the Declaration of Helsinki and the recommenda-
Gschwend et al. − Diclofenac 405
Analgetika · Antiphlogistika · Antirheumatika · Entzündungshemmer
Table 1: Mean demographic data of subjects.
Age Body weight Height
[Year] [kg] [cm]
Mean 28.17 68.55 169.54
SD 5.49 11.34 8.36
CV [%] 19.52 16.55 4.93
Min 21.0 52.0 156.0
Max 39.0 96.0 187.0
tions of Good Clinical Practice. The study protocol was ap-
proved by the relevant local (Canton Ticino) Research Ethics
Committee before the start of the study and the Federal Au-
thorities were informed of the study. The trial was carried out
according to the general principles of “Note for Guidance on
Good Clinical Practice”, Topic E6, CPMP − ICH/135/95 [15].
2.2. Subjects
A total of 26 healthy Caucasian subjects were screened (13
males and 13 females). Two of them were not enrolled (one
male and one female) because of personal reasons. All 24 re-
cruited subjects completed the trial as per protocol. Subjects
were included into the study following a thorough physical ex-
amination. Furthermore, clinical laboratory tests were per-
formed and compliance with pre-defined inclusion and exclu-
sion criteria was checked before study start. All subjects who
participated in this clinical trial signed the informed consent.
Information about the study was given in writing and orally.
Individual mean demographic data of subjects are listed in
Table 1.
2.3. Materials
Test preparation: Olfen Patch (hereinafter called “test”)
plaster, containing 140 mg diclofenac
sodium, size 140 cm2 (multiple dose, 8
plasters, b.i.d), batch number N00101,
distributed by Mepha Pharma AG,
Aesch (Switzerland).
Reference preparation: diclofenac epolamine plaster (herein-
after called “reference”) plaster, con-
taining 180 mg diclofenac epolamine,
equivalent to 140 mg diclofenac so-
dium (multiple dose, 8 plasters, b.i.d),
batch number 000801 (marketed in
Switzerland).
2.4. Study design
The study was conducted as a mono-centric open, random-
ised, two-way cross-over, multiple dose pharmacokinetic study
in 24 healthy male (12) and female (12) Caucasian subjects.
For reasons of safety and in order to minimise the inter-
subject variability of diclofenac pharmacokinetics a series of
inclusion and exclusion criteria were defined and checked dur-
ing pre-study examination. Volunteers must fulfil following in-
clusion criteria: healthy male or female Caucasians aged 18 to
45 years inclusive and body weight within ± 15 % of the normal
body weight according to the Metropolitan Life Insurance
Tables 1983; vital signs: normal values of BP (100−139 mmHg
systolic and 50−89 mmHg diastolic) and of HR (50-90 bpm),
measured after 5 min of rest in the sitting position; ECG (12
leads), physical examination and laboratory analysis: no clinic-
406 Gschwend et al. − Diclofenac
ally relevant abnormal findings which could interfere with the
objectives of the study and no positive result of pregnancy test.
Exclusion criteria were as follows: presence of clinically rele-
vant abnormal values; allergic reactions in general; participa-
tion in the evaluation of any drug during the 3 months before
the start of the study; any clinically significant organ dysfunc-
tion; any relevant history of diseases; skin abnormalities likely
to be aggravated by the study product; medications including
OTC products except oral contraceptives during 2 weeks before
study start, in particular use of NSAIDs; blood donations within
3 month preceding the beginning of the study; history of drug,
tobacco, alcohol or caffeine abuse; inability to comprehend the
full nature and purpose of the study; no signed prior to inclu-
sion in the study; presence of excessive hairgrowth, large scars
or skin disease on both upper arms; for women: no reliable
contraception or positive result of pregnancy test (at screening
and at discharge examination).
Subjects received each of 8 plasters of test formulation and
reference formulation b.i.d. at a dose interval of 12 h at the
same spot of the left upper arm. Removal / replacement of
plasters on study days 1−3 and 5−7 was performed under su-
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pervised conditions on an ambulatory basis. Subjects were
hospitalized during the 1st treatment period from the evening
before the 7th plaster administration on day 3 until after the 9th
plaster administration on day 5 (i.e., until 1st administration of
the 2nd treatment period). For the 2nd treatment period con-
finement started from the evening before the 15th plaster ad-
ministration on day 7 until 12 h after the 16th plaster adminis-
tration on day 9. The duration of hospitalization was approxim-
ately 36 h in each treatment period. Plaster administration no.
1−6 and no. 9−14 were used for achieving steady-state. Treat-
ments were not separated by a wash-out phase.
Drug profiling occurred by pre-dose blood sampling for
monitoring steady-state conditions and switch-over period as
well as on study days 4 and 8 over a 24-hour period for
pharmacokinetic profiling (i.e., until after the 7th resp. 15th
dose). The doses administered were 8 × 140 mg diclofenac so-
dium (test preparation) and 8 × 180 mg diclofenac epolamine
(reference preparation), equivalent to 8 × 140 mg of diclofenac
sodium. Plasters were administered under non-fasting condi-
tions.
For evaluation of diclofenac plasma concentrations, pre-
dose (trough) values were taken at days 1−3 and 5−7 (i.e., at 1
d 0 h, 1 d 12 h, 2 d 0 h, 2 d 12 h, 3 d 0 h, 3 d 12 h, 5 d 12 h, 6
d 0 h, 6 d 12 h, 7 d 0 h and 7 d 12 h). Blood samples for
pharmacokinetic profiling were taken on days 4 and 8 at 0h
(pre-7th/15th dose), 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h,
8 h, 10 h, 12 h (pre-8th/16th dose), 12.5 h, 13 h, 13.5 h, 14 h,
14.5 h, 15 h, 16 h, 18 h, 20 h, 22 h and 24 h after the 7th/
15th dose.
Approximately 8 ml of blood were withdrawn by an indwell-
ing catheter with switch valve into Li-heparinised monovettes.
After centrifugation [4 °C, 1,750 g (3000 rpm), 10 min] the su-
pernatant plasma was transferred into labelled polypropylene
tubes. The tubes were stored at ⱕ −20 °C until analysed.
2.5. Analytical method
Diclofenac plasma concentrations were determined by a valid-
ated liquid chromatography-tandem mass spectrometry (LC-
MS/MS) method with electrospray (positive ion mode) ionis-
ation (ESI+). Analyte determination was based on multiple re-
action monitoring (MRM) of product ions generated from pre-
cursor ions [M+H]+ by collision-induced dissociation (CID). Ac-
Arzneim.-Forsch./Drug Res. 55, No. 7, 403−413 (2005)
 Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs
ceptance criteria for method validation and analytical perform-
ance met internationally accepted standards [16].
2.5.1. Sample preparation
Frozen plasma samples were thawed in a water bath at 20 °C
and 1 ml aliquots were given into a 12 ml reaction vial. To 1 ml
of plasma 50 µl of internal standard (ISTD; [2H6]-diclofenac)
and 500 µl 0.1 mol/l HCl were added, followed by homogenis-
ation.
Afterwards the mixture was extracted with 6 ml of cyclohex-
ane: tert. butylmethyl ether = 1 : 2 (v/v) by turning samples
upside down for 30 min. After centrifugation (5 min, 3500
rpm), the upper organic phase was recovered, placed into an-
other reaction vial and evaporated to dryness under a stream
of nitrogen (40 °C, 15−20 min).
The dry residue was dissolved in 250 µl of the LC-eluent
(methanol: 5 mmol/l ammonium carbaminate = 8 : 2 (v/v), ad-
justed to pH 4 with formic acid), mixed for 10 s, given in an
ultrasonic bath for 5 min, again mixed for 10 s and transferred
into microvials. Thereafter extracts were once more centrifuged
for 5 min at 12,000 rpm and 50 µl of the solution were used for
subsequent LC-MS/MS analysis.
2.5.2. Apparatus
For LC-MS/MS investigations a triple stage quadrupole mass
spectrometer arrangement (micromass Quattro II; micromass,
Altrincham, UK) together with a liquid chromatograph (Jasco
HPLC pump PU 980; Jasco, Groβ-Umstadt, Germany) was used.
Chromatographic separation was carried out in the isocratic
mode on a Purospher RP18 column with 5 µm particle size and
75 × 4 mm i.d. (precolumn: Purospher RP18 column with 5 µm
particle size and 4 × 4 mm i.d.) with the eluent methanol: 5
mmol/l ammonium carbaminate = 8 : 2 (v/v), adjusted to pH
4 with formic acid. The injection volume was 50 µl, the flow
rate 0.8 ml/min (split after the column with a T-device: approx-
imately 90 µl/min into MS).
MS/MS conditions were as follows: ionisation was per-
formed by electrospray ionisation in the positive ion mode
(ESI+), source temperature: 90 °C, desolvation temperature:
250 °C, desolvation gas (nitrogen): 350 l/h, ESI nebulising gas
(nitrogen): 20 l/h. Collision induced dissociation with helium
as collision gas and a collision energy of 125 eV was employed
for an increased sensitivity and an enhanced selectivity. Pairs
of precursor/product ions were detected by multiple reaction
monitoring.
2.5.3. Calibration
A primary calibration curve using deuterated diclofenac as in-
ternal standard was established after linear regression and 1/x
weighting of the peak area ratio analyte/ISTD versus concen-
tration relationship in the range of 0.15 ng/ml to 100.00 ng/ml
diclofenac. The calibration curve was generated by threefold
determination of 8 calibration standards which covered the
calibration range mentioned above.
2.5.4. Specificity
Specificity of the method was tested by measurement of six
blank plasma samples of different origin. Specificity was veri-
fied by the fact that MRM detected unambiguously pairs of
signals of product ions [M + H]+ at m/z 213.9 for diclofenac
and m/z 218.9 for [2H6]-diclofenac from precursor ions m/z
296.1 (diclofenac) and m/z 302.1 ([2H6]-diclofenac).
Arzneim.-Forsch./Drug Res. 55, No. 7, 403−413 (2005)
2.5.5. Daily recalibration
Study samples were measured batchwise, with daily analysed
batches usually comprising all samples of one volunteer. For
each batch, a calibration curve for diclofenac based on the
analysis of 8 calibration standards was established.
2.5.6. Precision and accuracy
Quality control (QC) samples with concentrations in the high,
intermediate and low concentration range were included in
duplicate into each run and represented nominal concentra-
tions of 79.71 ng/ml, 7.97 ng/ml and 0.20 ng/ml for diclofenac.
QC samples were considered acceptable if they met the follow-
ing criteria: at least four out of six QC samples deviated by less
than ± 15 % from their respective nominal concentrations. Two
out of six QC samples (not at the same concentration) were
allowed to be outside of this range. For the lowest QC a devi-
ation of ± 20 % was accepted.
2.5.7. Stability
As a part of the validation of the analytical method, stability of
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the analyte in plasma was investigated during repeated freez-
ing and thawing (3 cycles). Additionally, stability of extracts in
the autosampler at 9 °C during a 72 h stay as well as in the
freezer at < −20 °C for 72 h was demonstrated.
Furthermore, the stability investigations conducted in the
course of this study consisted in the analysis of four study
samples of two subjects each at study termination, which had
already been analysed at study start in pertaining batches. Fi-
nally, analyte stability in plasma stored at < −20 °C throughout
the duration of the analytical period was assessed.
2.5.8. Recovery
Individual peak area ratios, obtained after triple analysis of
three different recovery reference samples representing the low,
intermediate and high concentration range were related to
mean peak area ratios of threefold analysed, ISTD-spiked blank
plasma samples, containing defined amounts of diclofenac ad-
ded after sample clean-up.
2.6. Pharmacokinetic evaluation
Pharmacokinetic evaluation was performed using the validated
inhouse software PRODA (Pharmakin GmbH, Ulm, Germany).
Determination of the pharmacokinetic parameters was per-
formed by using model-independent methods. The concentra-
tion-time profiles were used to determine the maximum
plasma concentrations (Cmax) of diclofenac for specified obser-
vation periods (0−12 h, 12−24 h, 0−24 h) and the time required
to attain these maximum concentrations (tmax). Furthermore,
minimum plasma concentrations (Cmin, 1; Cmin, 2) at the begin-
ning and the end of a dosing interval were determined. The
area under the plasma concentration time curve (AUC) was
calculated by the linear trapezoidal rule, based on plasma con-
centrations of two different dose intervals of 12 h (0−12 h, 12−
24 h) as well as following two dose intervals of 12 h each (0−
24 h). Finally, percentage peak-trough fluctuation [% PTF =
(Cmax − Cmin) / Cav · 100] was determined for specified observa-
tion periods (0−12 h, 12−24 h, 0−24 h). Cav was determined as
the average concentration of a dosing interval (AUC/τ).
2.7. Statistical evaluation
For statistical analysis the computer program BIOQV2.10 (De-
partment of Biometry, Byk Gulden Pharmaceuticals, Konstanz,
Gschwend et al. − Diclofenac 407
Analgetika · Antiphlogistika · Antirheumatika · Entzündungshemmer
Germany) was used. Pharmacokinetic parameters AUC0-12,
AUC12-24, AUC0-24, Cmax, 0-12, Cmax, 12-24 and Cmax, 0-24 (primary
parameters) as well as % PTF0-12, % PTF12-24, % PTF0-24 (sec-
ondary parameters) were tested for comparable bioavailability
by means of analysis of variance (ANOVA). In order to achieve
a better approximation to a normal distribution, data were log-
arithmically transformed before analysis and tested paramet-
rically for statistically significant differences by analysis of vari-
ance. From the result of this procedure, the two one-sided hy-
pothesis at the α = 0.05 level of significance was tested by con-
structing the 90 % confidence interval for the ratios test versus
reference preparation. The 90 % confidence intervals were cal-
culated by retransformation of the shortest confidence interval
for the difference of the ln-transformed data. Comparable
bioavailability was concluded if the 90 % confidence interval of
the two-one-sided t-tests procedure for the geometric ratios of
the test / reference was within the acceptance range of 80 %−
125 % for the AUC − ratio and 70 %−143 % for the Cmax − ratio.
For Cmax a wider range of acceptance was defined due to the
fact that single concentrations like Cmax generally exhibit larger
variations than integrated characteristics like AUC [17].
Also for % PTF the two-one-sided t-tests procedure was ap-
plied, however, results of % PTF were established for explorat-
ory purposes only and presented as supportive data. Addition-
ally, tmax − values were evaluated on a descriptive basis. In or-
der to estimate achievement and maintenance of steady-state
characteristics for the study preparations, descriptive statistics
for trough values were applied.
3. Results
3.1. Clinical observations
All 24 subjects included into the study participated in
the entire trial, so that 24 completed cases for each
treatment were available for analysis of diclofenac
plasma concentrations. Their age ranged between 21
and 39 years, their height between 156 and 187 cm and
DI-PE-02 Sm (Mn, 2x3)
100
0
DI-PE-02 Sm (Mn, 2x3)
100
0 Time
0.00 0.20 0.40 0.60 0.80 1.00 1.20
Fig. 1: MRM of selectivity sample representing blank plasma with ISTD spike (upper MRM chromatogram with signal at tR = 2.18 min).
408 Gschwend et al. − Diclofenac
their weight between 52 and 96 kg, in any case included
in ± 15 % of normal body weight according to the Met-
ropolitan Life Insurance Tables 1983.
12 out of 24 subjects experienced a total number of
15 adverse events during the course of the study. All
adverse events were of mild or moderate intensity and
recovered without sequelae; severe or serious adverse
events did not occur. One subject had to be treated with
5 mg heparinoidum gel b.i.d. for 4 consecutive days be-
cause of a hematoma on the left arm, which was judged
to be not drug-related. 8 adverse events were judged to
be probably related to the study drug [(5) sensation of
irritation, (2) itching, (1) sensation of burning] and 7
adverse events were judged to have no causal relation-
ship to the study drug [(2) dizziness, (1) haematoma left
arm, (1) abdominal pain, (1) vomiting, (1) headache,
(1) tussis)].
From the results of the precautionary observations it
was concluded that the test and reference preparation
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were tolerated well. A clinically relevant difference in
both tolerability and safety of the treatments was not
detected.
3.2. Analytical results
A primary calibration function using [2H6]-diclofenac as
ISTD for diclofenac was established after 1/x weighting
of the peak area ratio analyte/ISTD versus concentra-
tion relationship in the range of 0.15 ng/ml − 100.00
ng/ml (diclofenac). The calibration demonstrated the
linearity of the obtained functions and characteristics
of the sensitivity of the method were calculated to be
0.06 ng/ml for the limit of detection and 0.10 ng/ml
for the limit of quantification. For practical laboratory
purposes a lower limit of quantification of 0.15 ng/ml
for diclofenac was used during measurement of study
plasma samples.
MRM of 2 Channels ES+
2.18 302.10 > 218.90
16552 9.19e4
Area
MRMof 2 Channels ES+
296.10 > 213.90
234
Area
1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 4.00
Arzneim.-Forsch./Drug Res. 55, No. 7, 403−413 (2005)
 Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs

#1-46_V1_02 Sm (Mn, 2x3) MRM of 2 Channels ES+

100 2.02 302.10 > 218.90
14781 8.03e4
Area

0
#1-46_V1_02 Sm (Mn, 2x3) MRM of 2 Channels ES+
100 2.04 296.10 > 213.90
104 731
Area

0 Time
0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 4.00

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Fig. 2: MRM of selectivity sample representing ISTD-spiked standard sample E-H (c = 0.15 ng/ml); analyte and ISTD signals are given
in the lower and upper mass chromatogram with signals at tR = 2.04 min and tR = 2.02 min.

A mean day-to-day precision for diclofenac of 0.44 %,
1.29 % and 4.76 % were calculated for QC samples with
nominal diclofenac concentrations of 79.71 ng/ml (QC-
1), 7.97 ng/ml (QC-2) and 0.20 ng/ml (QC-3).
A comparison of measured arithmetic QC means for
deviations between nominal and measured values
served for assessment of analytical accuracy. From the
mean relative deviations of 0.31 %, −2.88 % and 2.88 %
for nominal QC concentrations of 79.71 ng/ml (QC-1),
7.97 ng/ml (QC-2) and 0.20 ng/ml (QC-3) an acceptable
level of between-day accuracy could be deduced for the
present investigation.
These results demonstrated the validity of the
method and underlined the reliability of analytical re-
sults.
Specifity was ensured by MRM which allows selective
determination of product ions of m/z 213.9 for diclo-
fenac and m/z 218.9 for [2H6]-diclofenac, generated by
collision induced dissociation (CID) of precursor ions
with m/z 296.1 (diclofenac) and m/z 302.1 ([2H6]-diclo-
fenac).
Examples of two-channel-MRM chromatograms of
plasma samples are given in Fig. 1−4. These mass chro-
matograms illustrate the level of selectivity achieved

#1-46_V1_08 Sm (Mn, 2x3) MRM of 2 Channels ES+

100 2.02 302.10 > 218.90
11384 6.27e4
Area

0
#1-46_V1_08 Sm (Mn, 2x3) MRM of 2 Channels ES+
100 2.04 296.10 > 213.90
55030 3.05e5
Area

0 Time
0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 4.00

Fig. 3: MRM of selectivity sample representing ISTD-spiked standard sample E-A (c = 100.0 ng/ml); analyte and ISTD signals are given
in the lower and upper mass chromatograms with signals at tR = 2.04 min and tR = 2.02 min.

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Gschwend et al. − Diclofenac 409
Analgetika · Antiphlogistika · Antirheumatika · Entzündungshemmer

#1-34_V1_05 Sm (Mn, 2x3) MRM of 2 Channels ES+

2.27 302.10 > 218.90
100
11661 6.25e4
Area

0
#1-34_V1_05 Sm (Mn, 2x3) MRM of 2 Channels ES+
100 2.30 296.10 > 213.90
193 1.22e3
Area

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0 Time
0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 4.00

Fig. 4: MRM of plasma sample taken from study volunteer no. 1, period I, test preparation, day 1, pre-dose value (evening dose), c =
0.37 ng/ml diclofenac; analyte and ISTD signals are given in the lower and upper mass chromatograms with signals at tR = 2.30 min
and tR = 2.27 min.

and confirmed a selective determination of the analyte the analyte in plasma was demonstrated at < −20 °C for
under investigation. 7 weeks. The differences between determined concen-
For each batch, a calibration curve based on the trations remained within the accepted range of accu-
analysis of 8 calibration standards was established. racy of the method. Stability tests performed during
Slopes of recalibration lines varied from 0.4492 · 10-1 − method validation indicate a sufficient stability of the
0.4745 · 10-1 for diclofenac and were well comparable analyte in plasma during freeze-thaw cycles, of extracts
with that of the primary calibration line (0.4555 · 10-1). in the autosampler at 9 °C during a 72 h stay as well as
Furthermore, mean deviations of back-calculated val- of extracts in the freezer at < −20 °C for 72 h.
ues from nominal values of all recalibrations did not Recovery of analyte was 84.31 %, 81.45 % and
exceed 3.04 % (given as CV [%]). 84.14 % for the low, intermediate and high concentra-
The stability of the analyte in plasma throughout the tion range. Recovery of internal standard was deter-
whole study period was confirmed by repeated analysis mined to be 85 %.
of individual plasma samples. Furthermore, stability of

3
concentration [ng/ml]

0
0 3 6 9 12 15 18 21 24
time [h]

Fig. 5: Mean plasma concentration/time profiles (± SEM) of diclofenac after transdermal administration of two different patch formula-
tions (test preparation, open symbols, and reference preparation, closed symbols).

Arzneim.-Forsch./Drug Res. 55, No. 7, 403−413 (2005)

410 Gschwend et al. − Diclofenac
 Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs

3.3. Pharmacokinetic results 3.4. Statistical results

Mean plasma concentration/time profiles (± SEM) of
both test and reference preparation assessed on days
of pharmacokinetic profiling and determined for two
consecutive dose intervals (0−12 h, 12−24 h) are de-
picted in Fig. 5. Resulting pharmacokinetic parameters
of different dose intervals (0−12 h, 12−24 h, 0−24 h) are
summarised in Tables 2−4.
For the test preparation, maximum plasma concen-
trations of 3.36 ng/ml (Cmax, 0-12), 3.73 ng/ml (Cmax, 12-24)
and 3.84 ng/ml (Cmax, 0-24) as well as areas under the
plasma concentration-time curve (AUC) of 31.11 ng·h/
ml (AUC0-12), 34.83 ng·h/ml (AUC12-24) and 65.94 ng·h/
ml (AUC0-24) were determined. For the reference pre-
paration, these values were 1.55 ng/ml (Cmax, 0-12), 1.45
ng/ml (Cmax, 12-24) and 1.57 ng/ml (Cmax, 0-24) as well as
13.28 ng·h/ml (AUC0-12), 12.68 ng·h/ml (AUC12-24) and
25.96 ng·h/ml (AUC0-24). Additionally, minimum plasma
concentrations Cmin,1 and Cmin,2 at the beginning and
The 90 % confidence intervals of the test/reference −
ratios were determined. Results are summarised in
Tables 5−7. Thereby, for all dose intervals considered
and all AUC parameters calculated, the extent of diclo-
fenac absorption from the test preparation markedly
exceeds those values obtained for the reference pre-
paration. Likewise, maximum plasma concentrations,
as a measure for the rate of absorption, were higher
after the test preparation. With respect to peak-to-
trough fluctuation of plasma diclofenac levels, both
plaster preparations were comparable for the morning
dose interval 0−12 h as well as for the 0−24 h period.
Intra-subject-coefficients of variation (ANOVA-cv) of
AUC were 31.0 % (AUC0-12), 34.3 % (AUC12-24) and
32.0 % (AUC0-24). Those data reflect the normal range of
variation generally expected for topically administered
drug formulations.

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the end of a dose interval are compiled in Tables 2−4.
As supportive data, peak-to-trough fluctuations (%
PTF) of 34.78 % (% PTF0-12), 38.50 % (% PTF12-24) and
43.68 % (% PTF0-24) were observed for the test prepara- Table 5: Statistical results of diclofenac (test vs reference; dose
tion. Corresponding values for the reference prepara- interval 0−12 h; parameters are described in chapter 2.6.).

tion were 35.82 % (% PTF0-12), 31.36 % (% PTF12-24) and AUC0-12: 90 % confidence interval of
two one-sided t-tests: 2.065−2.787
40.55 % (% PTF0-24). point estimator: 2.40

Cmax, 0-12: 90 % confidence interval of

two one-sided t-tests: 1.876−2.595
point estimator: 2.21

% PTF0-12: 90 % confidence interval of

Table 2: Pharmacokinetic results (arithmetic means ± SD) of di- two one-sided t-tests: 0.829−1.457
clofenac (dose interval 0-12 h). point estimator: 1.10

Prepara- AUC0-12 Cmax, 0-12 % PTF0-12 Cmin, 1 Cmin, 2

tion [ng·h/ml] [ng/ml] [%] [ng/ml] [ng/ml]

Test 31.11 3.36 34.78 2.48 2.39

± 11.11 ± 1.24 ± 14.12 ± 0.96 ± 0.82 Table 6: Statistical results of diclofenac (test vs reference; dose
Reference 13.28 1.55 35.82 1.16 1.17 interval 12-24 h; parameters are described in chapter 2.6.).
± 5.07 ± 0.59 ± 27.97 ± 0.45 ± 0.55
AUC12-24: 90 % confidence interval of
two one-sided t-tests: 2.403−3.346
point estimator: 2.84

Cmax,12-24: 90 % confidence interval of

Table 3: Pharmacokinetic results (arithmetic mean ± SD) of diclo- two one-sided t-tests: 2.262−3.110
fenac (dose interval 12−24 h). point estimator: 2.65

Prepara- AUC12-24 Cmax, 12-24 % PTF12-24 Cmin, 1 Cmin, 2 % PTF12-24: 90 % confidence interval of
tion [ng·h/ml] [ng/ml] [%] [ng/ml] [ng/ml] two one-sided t-tests: 1.175−2.495
point estimator: 1.71
Test 34.83 3.73 38.50 2.39 2.82
± 10.92 ± 1.23 ± 17.95 ± 0.82 ± 0.87
Reference 12.68 1.45 31.36 1.17 1.13
± 4.83 ± 0.57 ± 28.31 ± 0.55 ± 0.51

Table 7: Statistical results of diclofenac (test vs reference; dose

interval 0−24 h; parameters are described in chapter 2.6.).
AUC0-24: 90 % confidence interval of
Table 4: Pharmacokinetic results (arithmetic mean ± SD) of diclo- two one-sided t-tests: 2.239−3.051
fenac (dose interval 0−24 h). point estimator: 2.61

Prepara- AUC 0-24 Cmax, 0-24 % PTF 0-24 Cmin, 1 Cmin, 2 Cmax, 0-24: 90 % confidence interval of
tion [ng·h/ml] [ng/ml] [%] [ng/ml] [ng/ml] two one-sided t-tests: 2.143−2.951
point estimator: 2.51
Test 65.94 3.84 43.68 2.48 2.82
± 21.65 ± 1.27 ± 18.41 ± 0.96 ± 0.87 % PTF0-24: 90 % confidence interval of
Reference 25.96 1.57 40.55 1.16 1.13 two one-sided t-tests: 0.925−1.528
± 9.78 ± 0.59 ± 29.14 ± 0.45 ± 0.51 point estimator: 1.19

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Gschwend et al. − Diclofenac 411
Analgetika · Antiphlogistika · Antirheumatika · Entzündungshemmer

4. Discussion parable for the morning dose interval 0−12 h and the
0−24 h period. On average, trough diclofenac concen-
The aim of the present study was to investigate the
trations were higher after administration of the test pre-
transdermal pharmacokinetics and bioavailability of di-
paration, as compared with data from the reference pre-
clofenac released from a newly developed patch in
paration.
healthy volunteers following topical multiple dose ad-
Transdermal bioavailability of diclofenac from the
ministration. This open-label study was conducted to
new test patch was significantly higher in terms of rate
compare the transdermal bioavailability between the
(Cmax) and extent (AUC) of drug absorption in compar-
test and a reference preparation. It was of adequate size
ison with the reference preparation, irrespective of the
and design to provide information about the steady-
dose interval considered. Hence, diclofenac when ad-
state kinetics of the test preparation in comparison with
ministered as the test patch penetrates the skin to a
the reference and to differentiate between day and
significantly greater extent than the reference, as asses-
night kinetics. The study showed that diclofenac penet-
sed by systemic diclofenac concentrations. However,
rates the skin well when administered via the test patch.
the diclofenac plasma levels over the 24 h sampling
There is a continued release of diclofenac during day
period were still lower by several orders of magnitude
and nighttime thereby assuring plasma levels inde-
compared with standard oral treatment. In terms of
pendent from a diurnal rhythm. Nevertheless, mean ab-
safety, the test patch was well tolerated. Adverse events
solute diclofenac values in plasma were very low and
were generally mild or moderate in nature. No clinically
approximately 200 times lower compared to mean Cmax
relevant differences in the local tolerability and safety
values seen with standard oral treatments.

Downloaded by: University of Liverpool. Copyrighted material.

of both treatments were detected.
Generally, bioavailability is defined as the rate and
To summarise pharmacokinetic results of the present
extent to which the active drug or therapeutic moiety
study, a b.i.d treatment regimen of the topical adminis-
thereof is absorbed from a medicinal product and be-
tration was sufficient to achieve steady-state condi-
comes available at the site of drug action [17, 18].
tions. The test patch offers the advantage of an appro-
According to the CPMP-note for guidance III/54/89-
priate skin penetration, showing a nearly constant
EN, Final December 1991 “Investigation of Bioavailabil-
steady-state profile for a round the clock duration of
ity and Bioequivalence” [19] two medicinal products are
24 h.
bioequivalent if their bioavailabilities (rate and extent
Topical administration of NSAIDs offers the advant-
of absorption) after administration in the same molar
age of local, enhanced drug delivery to affected tissues
dose are similar to such degree that their effects with
with a lower incidence of systemic adverse effects, such
respect to both efficacy and safety will be essentially
as peptic ulcer disease and gastrointestinal haemor-
the same.
rhage, due to reduced plasma concentrations [12]. In
The requirement for a comparable bioavailability is
contrast to other topical dosage forms, plasters or
fulfilled, if the 90 % confidence interval of the geometric
patches permit a constant and continuous delivery of
AUC-ratio test / reference is lying within a range of
the active ingredient to the affected area by means of
80 %−125 %. For Cmax a wider range of acceptance from
an occlusive bandage and slow release of the drug [13].
70 % to 143 % was defined due to the fact that single
Supporting the clinical relevance of patches contain-
concentrations, in particular extreme values like Cmax,
ing an NSAID, these findings were confirmed recently
generally have larger variations than integrated charac-
in a randomised, placebo controlled, double blind, mul-
teristics like AUC [17]. Due to the generally broad thera-
ticentre study in patients with acute sport (blunt) im-
peutic range of diclofenac, acceptance of a wider range
pact injuries resulting in significant reductions in pain
was justified.
scores compared to placebo [3, 14]. The diclofenac
Pharmacokinetic parameters AUC and Cmax, asses-
patch was significantly more effective than placebo (p <
sed for different dose intervals (morning dose interval:
0.0001) with a significantly faster pain relief [3, 14].
0−12 h; evening dose interval: 12−24 h; two consecutive
Thus, the test patch was effective and safe in the treat-
dose intervals: 0−24 h), were determined and statisti-
ment of blunt injuries and complements the pharma-
cally compared between test and reference preparation
ceutical armamentarium for treating inflammatory re-
as primary end points. Additionally, peak trough fluctu-
actions caused by sports impact injuries and might be
ations (% PTF) served as secondary endpoints, in order
used in indications with similar pathomechanisms [3,
to describe steady-state characteristics of diclofenac
14].
after release from the patch.
For all dose intervals considered and all AUC para-
meters calculated, the extent of diclofenac absorption
from the test preparation exceeded those values ob-
tained for the reference preparation. Maximum plasma
concentrations for all dose intervals were higher after
test preparation.
With respect to peak-to-trough fluctuation of plasma
diclofenac levels, both plaster preparations were com-

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412 Gschwend et al. − Diclofenac
 Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs

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Gschwend et al. − Diclofenac 413