Clinical Therapeutics/Volume 37, Number 2, 2015
Pharmacokinetic Properties and Tolerability of Low-dose
SoluMatrix Diclofenac
Paul J. Desjardins, DMD, PhD1; Kemi Olugemo, MD2; Daniel Solorio, MS3;
and Clarence L. Young, MD3
1
Desjardins Associates, LLC, Maplewood, New Jersey; 2Parexel International Corporation, Baltimore,
Maryland; and 3Iroko Pharmaceuticals, LLC, Philadelphia, Pennsylvania
ABSTRACT
Purpose: This study compared the pharmacokinetic
properties and safety profile of low-dose (18- and 35-
mg) diclofenac capsules manufactured using SoluMa-
trix Fine Particle Technology (Trademark of iCeutica
Inc. (Philadelphia, Pennsylvania), and the technology
is licensed to Iroko Pharmaceuticals, LLC (Philadel-
phia, Pennsylvania) for exclusive use in NSAIDs),
which produces submicron-sized drug particles with
enhanced dissolution properties, to those of diclofenac
potassium immediate-release (IR) 50-mg tablets.
Methods: This Phase 1, single-center, randomized,
open-label, single-dose crossover study was conducted
in 40 healthy volunteers. Subjects received, in random-
ized order, SoluMatrix diclofenac 18- or 35-mg cap-
sules in the fasting condition, SoluMatrix diclofenac
35-mg capsules under fed conditions, and diclofenac
potassium IR 50-mg tablets under fasting and fed
conditions. Pharmacokinetic parameters (Tmax, Cmax,
AUC0–t, AUC0–1) were calculated from the concen-
trations of diclofenac in the plasma. Absorption, food
effect, and dose proportionality were determined using
a mixed-model ANOVA for Cmax, AUC0–t, and
AUC0–1. Tolerability was assessed by recording ad-
verse events, physical examination findings, vital sign
measurements: clinical laboratory test results.
Findings: Overall, 35 healthy volunteers aged 18 to 52
years completed the study. The mean age of the subjects
was 33.4 years, and approximately half were men
(47.5%). Median Tmax values were similar between the
low-dose SoluMatrix diclofenac 35-mg capsules and the
diclofenac potassium IR 50-mg tablets (both, 1.0 hour).
The mean maximum plasma concentration (Cmax) after
the administration of low-dose SoluMatrix diclofenac
35-mg capsules was 26% lower than that with diclofenac
potassium IR 50-mg tablets under fasting conditions
(868.72 vs 1194.21 ng/mL). The administration of
448
low-dose SoluMatrix diclofenac 35-mg capsules was
associated with a 23% lower overall systemic exposure
compared with that of diclofenac potassium IR 50-mg
tablets under fasting conditions. Food decreased the rate
but not the overall extent of absorption of SoluMatrix
diclofenac. No serious AEs and no clinically significant
abnormalities in physical examination findings, including
vital sign measurements, or clinical laboratory test results,
were noted during this study.
Implications: The pharmacokinetic properties of
low-dose SoluMatrix diclofenac capsules in the healthy
volunteers in this study suggest rapid diclofenac ab-
sorption as measured by Tmax. Low-dose SoluMatrix
diclofenac capsules represent a potential option for the
management of acute and osteoarthritis-related pain.
(Clin Ther. 2015;37:448–461) & 2015 Elsevier HS
Journals, Inc. All rights reserved.
Key words: diclofenac, pain, pharmacokinetics,
SoluMatrix, submicron.
INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are
a well-established analgesic class indicated for the
treatment of acute and chronic pain.1 Systematic
reviews have described dose-dependent adverse events
(AEs) associated with NSAID use, most notably AEs
involving the cardiovascular, renal, and gastrointesti-
nal systems.2–4 The US Food and Drug Administration
(FDA) has required standard labeling that advises
physicians to prescribe NSAIDs for their patients “at
Accepted for publication October 22, 2014.
http://dx.doi.org/10.1016/j.clinthera.2014.10.018
0149-2918/$ - see front matter
& 2015 Elsevier HS Journals, Inc. All rights reserved.
Volume 37 Number 2

the lowest effective dose for the shortest duration,
consistent with individual patient treatment goals.”5
Although minimizing of NSAID dosage could
potentially address tolerability concerns regarding this
drug class, reducing active drug concentrations could
limit the efficacy of these agents. A portfolio of oral
NSAID drug products is being developed to provide
low-dose treatment options for patients who require
these agents. Low-dose SoluMatrix* diclofenac
capsules† are a drug product containing submicron
particles of diclofenac. This product was designed to
provide effective analgesia with lower systemic
exposure compared with that of other diclofenac-
containing drug products.
Diclofenac is the most commonly prescribed NSAID
worldwide and has been available in the United States
since 1988.6 Diclofenac inhibits the activity of
cyclooxygenase (COX)-1, which has been associated
with the gastrointestinal AEs associated with NSAIDs,
and COX-2, the inhibition of which has been associated
with NSAID therapeutic efficacy, but is associated with
an increased risk of cardiovascular AEs.7–9 Diclofenac
has been reported to achieve analgesia at concentrations
associated with clinically relevant inhibition of the
COX-2 enzyme (IC80; the drug concentration that
produces 80% inhibition), with a lesser degree of
COX-1 inhibition.8 However, diclofenac products are
often dosed supratherapeutically. For example, the
commonly used diclofenac dosage of 50 mg three
times daily (TID) achieves 490% inhibition of COX-
2 over 8 hours after dosing, with only partial inhibition
of COX-1 (49.5%).10 Consequently, lowering the dose
would continue to provide analgesia with the potential
of a reduced risk for AEs. SoluMatrix diclofenac
capsules (35 mg) are equivalent to a 20% lower
diclofenac dose compared with diclofenac potassium
immediate-release (IR) 50 mg11 and have reported
analgesia in clinical trials in patients experiencing
acute pain after bunionectomy12 and pain associated
with osteoarthritis.13 In addition, SoluMatrix diclofenac
capsules were recently approved by the FDA for the
management of mild to moderate acute pain and
osteoarthritis-related pain.14
*
SoluMatrix® is a registered trademark of iCeutica Pty Ltd
(Philadelphia, Pennsylvania) and is licensed to Iroko Pharma-
ceuticals, LLC (Philadelphia, Pennsylvania).
†
Trademark: Zorvolexs, Iroko Pharmaceuticals, LLC (Philadel-
phia, Pennsylvania).
February 2015
P.J. Desjardins et al.
SoluMatrix diclofenac capsules consist of submi-
cron drug particles that are 200 to 800 nm in
diameter, which is  20 times smaller than the starting
active pharmaceutical ingredient, diclofenac free
acid.15 The reduced particle size leads to faster
diclofenac dissolution in vitro, with the goal of
improving absorption in vivo (data on file, Iroko
Pharmaceuticals, LLC, [2013]). A possible advantage
of the finely milled diclofenac acid drug product
compared with conventional products containing the
diclofenac potassium salt is that the salt form becomes
protonated to form diclofenac acid when dissolved in
an acidic aqueous medium such as the stomach.16 This
protonation results in an uncontrolled precipitated
solid formation with a particle size distribution that
may vary widely depending on stomach pH and
stomach contents. By selecting the free acid form for
the SoluMatrix formulation and milling it to a
uniform particle size and distribution, the dissolution
and absorption of the drug substance are better
controlled, allowing for more consistent and robust
product performance. Thus, SoluMatrix diclofenac
capsules, which contain diclofenac free acid, are not
interchangeable with other oral diclofenac drug
products that contain diclofenac potassium or
sodium salt, although there is some similarity in the
chemical properties.17,18
A previous Phase 1 study evaluated the pharmaco-
kinetic profile of low-dose SoluMatrix diclofenac
capsules in healthy adults. The administration of
SoluMatrix diclofenac 35-mg capsules was associated
with a 4 19% lower overall systemic exposure com-
pared with that of diclofenac potassium IR 50-mg
tablets.18 The mean (SD) Tmax of SoluMatrix
diclofenac 18 and 35 mg and diclofenac potassium
IR 50-mg tablets was 0.62 [0.35], 0.59 [0.20], 0.80
[0.50] hours, respectively, suggesting rapid absorp-
tion.11 The analgesic efficacy of this low-dose Solu-
Matrix diclofenac drug product was reported in a
Phase 2 study in patients with acute pain after dental
surgery.19
After the completion of the Phase 1 and 2 proof-of-
concept studies, the manufacturing process for low-
dose SoluMatrix diclofenac included a change from a
wet to dry granulation process and additional minor
formulation changes downstream of the milling proc-
ess to enable large-scale production. Although the
dissolution of the SoluMatrix diclofenac drug prod-
uct, based on in vitro profiling, remained unchanged,
449
 Clinical Therapeutics
the possibility that the optimized process may have
altered the biopharmaceutical properties of the drug
product is a potential concern.20 Furthermore, rapid
dissolution of the active drug substance from IR solid
oral dosage formulations (eg, SoluMatrix diclofenac
capsules) makes it difficult to achieve in vitro–in vivo
correlation that would enable the prediction of
biologically relevant changes in the performance of
these drug products.21–23 A precise characterization
of the pharmacokinetic properties of the commercial
low-dose SoluMatrix drug product is critically im-
portant because this formulation has been evaluated
for efficacy and tolerability in 2 Phase 3 studies in
patients with acute pain after bunionectomy surgery12
and in patients with osteoarthritis pain.13 We report
the results from the Phase 1 study conducted to
characterize the pharmacokinetic properties of
commercial low-dose SoluMatrix diclofenac 18- and
35-mg capsules in healthy volunteers and used diclo-
fenac IR 50 mg as a reference to determine whether
the commercial formulation of SoluMatrix diclofenac
35 mg results in lower total systemic exposure
compared to that of a commonly prescribed diclofe-
nac dosage.24
The objectives of this study were to: (1) compare
the pharmacokinetic properties of SoluMatrix diclo-
fenac 35-mg capsules to those of diclofenac potassium
IR 50-mg tablets administered in the fasting condition;
(2) determine the effects of food on the rate and extent
of absorption after single-dose administration of
SoluMatrix diclofenac 35-mg capsules and diclofenac
potassium IR 50-mg tablets administered in the fed
and fasting conditions; and (3) evaluate the dose-
proportionality of SoluMatrix diclofenac 35- and
18-mg capsules in the fasting condition.
SUBJECTS AND METHODS
Study Design
This single-center, randomized, open-label, single-
dose, crossover pharmacokinetic study was conducted
in 40 healthy adults by Parexel International Corpo-
ration (Baltimore, Maryland). A sample size of 40
subjects was selected to replicate the pharmacokinetic
study of the early development formulation of Solu-
Matrix diclofenac capsules. The following treatment
regimens were investigated: SoluMatrix diclofenac
18-mg (treatment A) and 35-mg (treatment B) capsu-
les administered in the fasting condition; SoluMatrix
diclofenac 35-mg capsules administered in the fed
450
condition (treatment C); and diclofenac potassium
IR 50-mg tablets‡ administered in the fasting
(treatment D) and fed (treatment E) conditions.
Eligible subjects were randomly assigned to receive
1 of 5 predetermined treatment sequences: ABCDE,
BDECA, CEBAD, DCAEB, or EADBC. Before ran-
domization, all subjects provided written informed
consent to participate. The study protocol, informed-
consent form, and subject-recruitment materials were
approved by an independent institutional review
board (Aspire IRB, Santee, California). The study
was conducted in compliance with the standards set
forth in the Declaration of Helsinki and the principles
for Good Clinical Practice from the International
Conference on Harmonisation in 1996.25
During treatment period 1, subjects were admitted
to the research center on the evening before drug
administration and underwent Z10 hours of fasting.
The following morning, subjects assigned to receive
treatment in the fasting condition were administered a
single oral dose of study medication with 240 mL of
water. Subjects assigned to undergo study drug ad-
ministration in the fed condition were given a single
oral dose with 240 mL of water 30 minutes after
receiving an FDA-standardized high-fat meal, with a
fat content of 50% of the total caloric content of the
meal (800–1000 calories).26 After the administration
of the study drug, subjects in all treatment groups
were not permitted to eat until 4 hours postdose.
Water was restricted from 1 hour predose until 1 hour
postdose, except the 240 mL of water permitted with
study drug administration. In treatment periods 2 to
5, subjects were administered the study drug
according to their assigned sequence after a 7-day
washout interval between administrations. Because
the apparent terminal elimination half life (t½) of
diclofenac potassium IR 50-mg tablets is  2 hours,24
a 7-day washout period ensured complete elimination
of the drug between treatment periods. Subjects in
each treatment period adhered to the procedures
outlined earlier.
Study Subjects
Eligible subjects included men and women (non-
lactating and nonpregnant) who were in good health,
aged 18 to 55 years, and weighed Z50 kg, with a
‡
Trademark: Cataflams (Novartis Pharmaceuticals Corpora-
tion, East Hanover, New Jersey).
Volume 37 Number 2

body mass index between 18 and 30 kg/m2. Excluded
were subjects who had a known history of allergic
reaction or intolerance to diclofenac, aspirin, acetami-
nophen, or any other NSAID; a history of any
clinically significant unstable disease; a clinically sig-
nificant gastrointestinal event r6 months before
screening; a history of peptic or gastric ulcers or
gastrointestinal bleeding; any prior digestive tract
surgery (except appendectomy); and/or any condition
that could have affected the absorption, metabolism,
or elimination of drugs. Other exclusion criteria
included: enrollment in another clinical study of
low-dose SoluMatrix diclofenac capsules or the use
of any investigational drug or device within 30 days
before screening; the use of any prescribed medication,
except oral contraceptives, within 7 days of study
initiation; and the use of any medication known to
inhibit or induce hepatic metabolism within 30 days
of study initiation.
Analytical Methods
Concentrations of diclofenac in plasma were quan-
tified using a validated liquid chromatography-
tandem mass spectrometry assay.27 Diclofenac acid
C14H11Cl2NO2 (Bioanalytical Services Division ref.
number R326a; Aptuit LLC, Greenwich, Connecticut)
was used as analytical standard, and indomethacin
C19H16ClNO4 (BASD ref. number R019a; Aptuit
LLC) was used as an internal standard. Samples
were assayed in batches; each batch consisted of 11
calibration standard levels within the concentration
range of 2.442 to 2501 ng/mL for diclofenac, with 8
levels of quality-control samples extending over this
range. The calibration curve and quality-control sam-
ples were prepared by diluting the diclofenac reference
standard with normal blank plasma to attain the
desired standard concentrations. Peak area ratios from
the Wagner calibration curve established the accuracy
of this method over the specified diclofenac concen-
tration range. Based on the results from the quality-
control samples in the 44 runs from the production
phase, the percentage of inaccuracy (bias of the
method) for diclofenac ranged from –4.4% to
–2.3%, and the % coefficient of variation (the impre-
cision of the method) ranged from 2.2% to 9.6%.
Pharmacokinetic Analyses
Blood samples for pharmacokinetic analyses were
collected via an indwelling catheter predose (time 0)
February 2015
P.J. Desjardins et al.
and at the following intervals after study drug admin-
istration: 5, 10, 15, 20, 30, 40, 60, 80, 100, 120, 140,
160, 180, 200, 220, 240, and 270 minutes and at 5, 6,
8, 10, and 12 hours. Blood samples were collected in
heparinized test tubes and processed in batches and
centrifuged within 1 hour of collection at 2500g for
10 minutes at 01C to 81C. The blood samples were
handled on ice after collection until placed into the
centrifuge. Thereafter, the supernatant of each sample
was divided into 2 aliquots by transferring at least
750 μL of plasma to 2 labeled polypropylene storage
tubes. Plasma was stored at –201C until shipping.
Samples were shipped on dry ice (with temperature
monitoring) to the bioanalytical laboratory (Parexel
International, Bioanalytical Services Division, Bloem-
fontein, South Africa) for pharmacokinetic analysis.
Upon receipt, the samples were stored at approxi-
mately 20°C until assayed.
All pharmacokinetic parameters were calculated
from the plasma concentration–time profiles using
actual sampling times relative to dosing using Phoenix
WinNonlin 6.2 (Pharsight Corporation, St. Louis,
Missouri). The following pharmacokinetic parameters
were calculated: Cmax, obtained directly from the
concentration–time curve; Tmax; apparent terminal
elimination rate constant (λz), estimated at terminal
phase by linear regression after log-transformation of
the concentrations; and apparent t½, calculated as the
natural log 2/λz ratio. AUC was calculated using the
linear trapezoidal method for all incremental trape-
zoids arising from increasing concentrations, and the
logarithmic trapezoidal method was used for those
arising from decreasing concentrations. AUC0–t was
defined as area under the concentration–time curve
from time 0 to the time of the last sample with a
quantifiable concentration. AUC0–1 was calculated as
the sum of AUC0–t and the last measurable concen-
tration/λz ratio.
Analysis of Absorption, Food Effect,
and Dose Proportionality
For all analyses, subjects within each sequence were
designated as a random effect; sequence, period, and
treatment were modeled as fixed factors. Diclofenac
absorption was determined using a mixed-model
ANOVA for pharmacokinetic parameters (Cmax,
AUC0–t, AUC0–1). Statistical comparisons of the
ratios of geometric means (low-dose SoluMatrix
diclofenac 35-mg capsules, fasting/diclofenac potassium
451
 Clinical Therapeutics
IR 50-mg tablets, fasting) were calculated using SAS
version 9.1.3 (SAS Institute Inc., Cary, North Caro-
lina) by taking the antilogarithm of the difference
between treatment means. SoluMatrix diclofenac
35-mg capsules and diclofenac potassium IR 50-mg
tablets in the fasting condition were considered com-
parable for a specific pharmacokinetic parameter if the
90% confidence interval (CI) of the ratio of the
geometric least squares means of the treatments was
between 0.8 and 1.25.
To determine the effect of food on the rate (Cmax)
and extent (AUC0–t, AUC0–1) of absorption, a mixed-
model ANOVA was used. Treatment ratios for low-
dose SoluMatrix diclofenac 35-mg capsules in the
fasting and fed conditions, and treatment ratios for
diclofenac potassium IR 50-mg tablets in the fasting
and fed conditions were calculated by taking the
antilogarithm of the difference between treatment
means (fasting vs fed). The absence of food effect on
absorption kinetics was concluded if the 90% CI of
the ratio of geometric least square means of all
comparisons was between 0.8 and 1.25. To analyze
the effect of food on Tmax, the Hodges-Lehman
methodology28,29 for paired samples was used to
calculate the difference in the medians (fasting vs
fed) and corresponding 90% CIs of SoluMatrix
diclofenac 35-mg capsules and diclofenac potassium
IR 50-mg tablets.
To assess dose proportionality, low-dose SoluMa-
trix diclofenac 18- and 35-mg capsules dose-
normalized AUC0–t, AUC0–1, and Cmax values were
natural log–transformed and analyzed using a linear
mixed model. Dose proportionality was concluded if
the estimated ratio of the geometric means of Solu-
Matrix diclofenac 35-mg capsules and SoluMatrix
diclofenac 18-mg capsules administered in the fasting
condition was close to 1.0, and if the 90% CI of the
ratio of geometric means was within the range 0.8
to 1.25.
Tolerability Evaluation
All subjects who received Z1 dose of the study
drug were included in the tolerability analysis. All
tolerability data, including AEs, physical examination,
findings including vital sign measurement or clinical
laboratory results were recorded. Subjects could
withdraw from the study due to intolerable or unac-
ceptable AEs; all AEs were medically treated if
necessary.
452
RESULTS
Subject Disposition
Forty subjects met the eligibility criteria and were
randomly assigned to receive the study treatments.
Overall, 35 subjects completed the study, and 5
discontinued—reasons for discontinuation are listed
in Table I. The mean age of the subjects was 33.4
years (range, 1852 years), and approximately half
were men (47.5%). Participantsʼ demographic
characteristics were reflective of a healthy adult
population; the mean body weight and body mass
index were 74.09 kg and 25.02 kg/m2, respectively
(Table I).
Pharmacokinetic Properties in the
Fasting Condition
The diclofenac concentration–time profiles after
single-dose administration of SoluMatrix diclofenac
18- and 35-mg capsules and diclofenac potassium IR
50-mg tablets are shown in Figure 1. The mean (SD)
Cmax was lower with SoluMatrix diclofenac 35-mg
capsules compared with diclofenac potassium IR 50-
mg tablets in the fasting condition (868.7 [352.83] vs
1194.2 [543.15] ng/mL, respectively) (Table II and
Figure 2A). The ratio of the geometric means for the
Cmax of SoluMatrix diclofenac 35 mg/diclofenac
potassium IR 50 mg was 0.744, indicating a 26%
lower Cmax (Table III). The upper limit of the 90% CI
(0.628–0.881) of the ratio of geometric means was
within the range of 0.8 to 1.25 (Table III).
The median (range) Tmax values (in hours) were
similar between low-dose SoluMatrix diclofenac
18- and 35-mg capsules and diclofenac potassium IR
50-mg tablets administered in the fasting condition
(1.0 [0.5–4.5] and 1.0 [0.5-4.0] vs 1.0 [0.3–4.5],
respectively) (Table II). The mean t½ values were
similar between low-dose SoluMatrix diclofenac 35-
mg capsules and diclofenac potassium IR 50-mg
tablets administered in the fasting condition. The
mean λz values were comparable across all treatments
(Table II).
The administration of low-dose SoluMatrix diclo-
fenac 18- and 35-mg capsules in the fasting condition
was associated with lower AUC0–1 compared with
that of diclofenac potassium IR 50-mg tablets (mean
[SD], 499.2 [105.51] and 1001.1 [229.74] vs 1334.1
[312.51] ng  h/mL, respectively). The 90% CIs of the
geometric mean ratios of AUC0–t and AUC0–1 with
SoluMatrix diclofenac 35-mg capsules and diclofenac
Volume 37 Number 2
February 2015

Table I. Disposition and demographic characteristics of the subjects in this study of the bioavailability of SoluMatrix* diclofenac capsules. Data
are given as number (%) of patients unless otherwise noted.
Treatment Sequence

ABCDE BDECA CEBAD DCAEB EADBC

Characteristic (n ¼ 8) (n ¼ 8) (n ¼ 8) (n ¼ 8) (n ¼ 8) Overall (N ¼ 40)

Disposition
Completed study 6 (75.0) 7 (87.5) 8 (100) 7 (87.5) 7 (87.5) 35 (87.5)
Discontinued 2 (25.0) 1 (12.5) 0 1 (12.5) 1 (12.5) 5 (12.5)
Reason for discontinuation
Protocol violation 2 (25.0) 0 0 0 0 2 (5.0)
Consent withdrawn 0 1 (12.5) 0 0 0 1 (2.5)
Other 0 0 0 1 (12.5)† 1 (12.5)‡ 2 (5.0)
Demographic
Age, y
Mean (SD) 37.9 (12.47) 30.0 (6.46) 33.8 (6.78) 28.4 (8.90) 36.9 (8.56) 33.4 (9.23)
Median (range) 41.0 (21–52) 29.0 (23–39) 30.0 (26–44) 27.0 (18–42) 37.5 (26–50) 30.0 (18–52)
Sex
Female 4 (50.0) 4 (50.0) 4 (50.0) 4 (50.0) 5 (62.5) 21 (52.5)
Male 4 (50.0) 4 (50.0) 4 (50.0) 4 (50.0) 3 (37.5) 19 (47.5)
Ethnicity
Not Hispanic or Latino 7 (87.5) 8 (100) 8 (100) 8 (100) 6 (75.0) 37 (92.5)
Hispanic or Latino 1 (12.5) 0 0 0 2 (25.0) 3 (7.5)
Race
Black or African American 5 (62.5) 5 (62.5) 5 (62.5) 8 (100) 7 (87.5) 30 (75.0)
White 3 (37.5) 3 (37.5) 3 (37.5) 0 1 (12.5) 10 (25.0)
Clinical
Weight, kg
Mean (SD) 73.6 (10.51) 76.4 (11.29) 78.9 (12.86) 71.0 (14.06) 70.5 (11.73) 74.09 (11.96)
Median (range) 76.6 (55.2–85.6) 81.8 (55.6–88.0) 81.7 (55.4–95.2) 67.2 (55.0–96.4) 69.7 (53.4–90.8) 75.60 (53.4–96.4)
BMI, kg/m2
Mean (SD) 24.9 (2.90) 25.5 (2.68) 26.3 (2.92) 23.5 (2.85) 24.9 (3.21) 25.02 (2.92)
Median (range) 24.2 (21.8–29.4) 25.8 (20.7–28.2) 26.55 (21.6–30.0) 22.2 (21.0–28.3) 24.7 (20.6–30.0) 25.15 (20.6–30.0)

P.J. Desjardins et al.

A ¼ SoluMatrix diclofenac 18-mg capsules, fasting; BMI ¼ body mass index; B ¼ SoluMatrix diclofenac 35-mg capsules, fasting; C ¼ SoluMatrix diclofenac 35-mg
capsules, fed; D ¼ diclofenac potassium immediate-release 50-mg tablets, fasting; E ¼ diclofenac potassium immediate-release 50-mg tablets, fed.
*
SoluMatrix® is a registered trademark of iCeutica Pty Ltd (Philadelphia, Pennsylvania) and is licensed to Iroko Pharmaceuticals, LLC (Philadelphia, Pennsylvania).
†
Transportation problems.
‡
Family emergency.
453
 Clinical Therapeutics
800
Diclofenac Plasma Concentration (ng/mL)
700
600
500
400
300
200
100
0
0 2
Scheduled Protocol Time-Point (h)
Figure 1. Concentration–time curve of low-dose SoluMatrix* diclofenac 18- and 35-mg capsules compared
with diclofenac potassium immediate-release (IR) 50-mg tablets in the fasting and fed conditions
over 12 hours. Inset represents the same concentration time–curve over 3 hours. *SoluMatrix® is a
registered trademark of iCeutica Pty Ltd (Philadelphia, Pennsylvania) and is licensed to Iroko
Pharmaceuticals, LLC (Philadelphia, Pennsylvania).
potassium IR 50-mg tablets administered in the fasting
condition were outside of the range of 0.8 to 1.25
(0.735–0.799 and 0.738–0.800, respectively), which
was consistent with a 23% lower overall systemic
exposure with SoluMatrix diclofenac 35-mg capsules
(Table III).
Low-dose SoluMatrix diclofenac 18- and 35-mg
capsules demonstrated dose-proportional AUC0–t and
AUC0–1 in the fasting condition (dose-normalized,
geometric mean ratios [90% CIs], 1.041 [0.995–
1.089] and 1.031 [0.987–1.077], respectively). There
was some evidence of dose proportionality for Cmax,
with a dose-normalized geometric mean ratio of 0.904;
however, the lower bound of the 90% CI (0.777–
1.050) fell outside of the specified lower limit of the
range of 0.80 to 1.25 for dose-proportionality accept-
ance (Table IV).
Pharmacokinetic Parameters
in the Fed Condition
The diclofenac concentration–time profiles after
single-dose administration of SoluMatrix diclofenac 35-
mg capsules and diclofenac potassium IR 50-mg tablets
454
SoluMatrix Diclofenac 18-mg Capsules (n = 39)
SoluMatrix Diclofenac 35-mg Capsules (n = 37)
Diclofenac Potassium IR 50-mg Tablets (n = 37)
SoluMatrix Diclofenac 35-mg Capsules, Fed (n = 38)
Diclofenac Potassium IR 50-mg Tablets, Fed (n = 38)
800
700
600
500
400
300
200
100
0
0 1 2 3
4 6 8 10 12
after a high-fat meal are shown in Figure 1. The mean
(SD) Cmax attained after the administration of low-dose
SoluMatrix diclofenac 35-mg capsules after a high-fat
meal was lower compared with that in the fasting
condition (354.8 [169.91] vs 868.7 [352.83] ng/mL,
respectively) (Table II). The ratio of natural log–
transformed Cmax geometric means of SoluMatrix
diclofenac 35-mg capsules fed/fasting administration
(0.399) suggested that food decreased the Cmax by
60%; the 90% CI (0.337–0.473) fell outside of the
range of 0.8 to 1.25, supporting an effect of food on
Cmax (Table V). The Cmax for diclofenac potassium IR
50-mg tablets in the fed condition was reduced by 43%
compared with that in the fasting condition (Table V).
The diclofenac Cmax range after low-dose SoluMatrix
diclofenac 35-mg capsule administration overlapped
the range with diclofenac potassium IR 50-mg tablets
in the fed condition (139.6–885.6 and 208.9–1710.0
ng/mL, respectively) (Figures 2A and 2B, Table V).
Tmax was prolonged for both SoluMatrix diclofenac
35-mg capsules and diclofenac potassium IR 50-mg
tablets after administration in the fed condition
(median [range] [in hours], 3.3 [0.5–10.0] and 2.3
Volume 37 Number 2
 P.J. Desjardins et al.

Table II. Pharmacokinetic properties of low-dose SoluMatrix* diclofenac capsules and diclofenac potassium
immediate-release (IR) tablets administered in the fasting and fed conditions.
Fasting Fed

SoluMatrix SoluMatrix Diclofenac SoluMatrix Diclofenac

Diclofenac 18-mg Diclofenac 35-mg Potassium IR Diclofenac 35-mg Potassium IR
Parameter Capsules Capsules 50-mg Tablets Capsules 50-mg Tablets

Cmax, ng/mL
No. of subjects 39 37 37 38 38
Mean (SD) 495.8 (202.93) 868.7 (352.83) 1194.2 (543.15) 354.8 (169.91) 712.5 (392.82)
Tmax, h
No. of subjects 39 37 37 38 38
Median (range) 1.0 (0.5–4.5) 1.0 (0.5–4.0) 1.0 (0.3–4.5) 3.3 (0.5–10.0) 2.3 (0.5–4.5)
t ½, h
No. of subjects 39 36 37 32 38
Mean (SD) 1.9 (0.50) 2.1 (0.49) 2.3 (0.60) 2.2 (0.82) 2.3 (0.64)
AUC0–t, ng  h/mL
No. of subjects 39 37 37 38 38
Mean (SD) 490.2 (105.09) 1004.7 (242.75) 1318.8 (307.85) 861.2 (209.92) 1178.0 (271.35)
AUC0–1, ng 
h/mL
No. of subjects 39 36 37 32 38
Mean (SD) 499.2 (105.51) 1001.1 (229.74) 1334.1 (312.51) 876.1 (211.45) 1204.0 (275.68)
λz, h–1
No. of subjects 39 36 37 32 38
Mean (SD) 0.4 (0.12) 0.3 (0.09) 0.3 (0.12) 0.4 (0.25) 0.3 (0.11)

λz ¼ terminal elimination rate constant; AUC0-t ¼ area under the concentration-time curve from time 0 to the time of the
last quantifiable concentration; AUC0-∞ ¼ area under the concentration-time curve from time 0 extrapolated to infinity; Cmax ¼
peak plasma level; IR ¼ immediate release; SD ¼ standard deviation; t½ ¼ apparent terminal elimination half-life; tmax ¼
time to peak plasma level.
*
SoluMatrix® is a registered trademark of iCeutica Pty Ltd (Philadelphia, Pennsylvania) and is licensed to Iroko
Pharmaceuticals, LLC (Philadelphia, Pennsylvania).

[0.5–4.5]) (Table II). Food had no apparent effect on λz Tolerability

or t½ (Table II).
The administration of low-dose SoluMatrix
diclofenac 35-mg capsules or diclofenac potassium
IR 50-mg tablets after a high-fat meal did not affect
the overall extent of systemic absorption (AUC0–t
and AUC0–1) (Table V; Figures 2C and 2D). The
mean AUC0–t and AUC0–1 values with SoluMatrix
diclofenac 35-mg capsules administered with food
were reduced by 14% and 11%, respectively, com-
pared with the fasting condition (Table V). The
90% CIs of the geometric mean ratios of both
AUC0–t and AUC0–1 were within the range of 0.8
to 1.25.
All of the subjects were included in the tolerability
analysis, and there were no discontinuations due to
AEs or serious AEs. Six subjects each reported 1 AE
during the study; all were considered by the inves-
tigator as mild and unrelated to the study medication.
One subject reported penile discharge and another
subject reported menstrual cramps before the first
dosing session. The remaining 4 AEs were tension
headache (SoluMatrix diclofenac 18-mg capsules,
fasting); migraine without aura (diclofenac potassium
IR 50-mg tablets, fed); nasal congestion (diclofenac
potassium IR 50-mg tablets, fasting), and a forearm
hematoma (SoluMatrix diclofenac 35-mg capsules, fed).

February 2015 455

 Clinical Therapeutics

A B
2000 2000
Mean (SD) Cmax
(ng.h/mL) 1500 1500

1000 1000

500 500

0 0
SoluMatrix SoluMatrix Diclofenac SoluMatrix Diclofenac
Diclofenac Diclofenac Potassium IR Diclofenac Potassium IR
18-mg Capsules 35-mg Capsules 50-mg Tablets 35-mg Capsules 50-mg Tablets
(n = 39) (n = 37) (n = 37) (n = 38) (n = 38)

C D
2000 2000
Mean (SD) AUC0-∝

1500 1500
(ng.h/mL)

1000 1000

500 500

0 0
SoluMatrix SoluMatrix Diclofenac SoluMatrix Diclofenac
Diclofenac Diclofenac Potassium IR Diclofenac Potassium IR
18-mg Capsules 35-mg Capsules 50-mg Tablets 35-mg Capsules 50-mg Tablets
(n = 39) (n = 36) (n = 37) (n = 32) (n = 38)

Figure 2. Mean Cmax (A) and overall systemic exposure (C) of low-dose (18 and 35 mg) SoluMatrix*
diclofenac capsules and diclofenac potassium immediate-release (IR) 50-mg tablets in the fasting
condition. Mean Cmax (B) and overall systemic exposure (D) of low-dose (35 mg) SoluMatrix
diclofenac capsules and diclofenac potassium IR 50-mg tablets in the fed condition. *SoluMatrix®
is a registered trademark of iCeutica Pty Ltd (Philadelphia, Pennsylvania) and is licensed to Iroko
Pharmaceuticals, LLC (Philadelphia, Pennsylvania).

There were no clinically significant abnormalities in
physical examination findings, including vital sign
measurements, or clinical laboratory test results (data
not shown).
DISCUSSION
The finding of a 23% lower overall systemic exposure
with the administration of SoluMatrix diclofenac 35-mg
capsules compared with diclofenac potassium IR 50-mg
tablets in the fasting condition was as expected after the
administration of a lower dose. The reduction in overall
systemic exposure after the administration of SoluMa-
trix diclofenac 18-mg capsules was substantial (62%)
compared with diclofenac potassium IR 50-mg tablets.
The similar median Tmax values between SoluMatrix
diclofenac 35-mg capsules and diclofenac potassium IR
50-mg tablets (both, 1.0 hour) achieved the stated goal
of developing a drug product that provides rapid
absorption at a low dose. The mean Cmax was 26%
lower after the administration of low-dose SoluMatrix
diclofenac 35-mg capsules compared with diclofenac
potassium 50-mg IR tablets in the fasting condition
(868.7 vs 1194.2 ng/mL, respectively).
Similar to that of other NSAIDs,30–32 the absorp-
tion of diclofenac was decreased with food. Mean
Cmax was reduced by  60% in fed subjects after the
administration of SoluMatrix diclofenac 35-mg cap-
sules and by 43% after the administration of diclofe-
nac potassium IR 50-mg tablets. The administration
of food had no apparent effect on the overall extent of
diclofenac absorption from either drug product. Low-
dose SoluMatrix diclofenac 35- and 18-mg capsules
demonstrated dose-proportional changes in AUC0–t
and AUC0–1 in the fasting condition. The 90% CI for
Cmax fell outside of the specified lower limit of the
range of 0.8 to 1.25 for dose proportionality.
The pharmacokinetic properties of the early devel-
opment low-dose SoluMatrix diclofenac drug product

456 Volume 37 Number 2

 P.J. Desjardins et al.

Table III. Comparison of pharmacokinetic properties of low-dose SoluMatrix* diclofenac 35-mg capsules and
diclofenac potassium immediate-release (IR) 50-mg tablets in the fasting condition.

SoluMatrix Diclofenac Diclofenac Potassium IR Treatment Ratio

Parameter 35-mg Capsules 50-mg Tablets (90% CI†)

Cmax, ng/mL
No. of subjects
Geometric LSM (95% CI)
AUC0–t, ng  h/mL
No. of subjects
Geometric LSM (95% CI)
AUC0–1, ng  h/mL
No. of subjects
Geometric LSM (95% CI)
37 37
808.35 (700.03–933.44) 1086.53 (940.71–1254.94) 0.744 (0.628–0.881)
37 37
976.99 (907.95–1051.27) 1274.22 (1184.14–1371.16) 0.767 (0.735–0.799)
36 37
989.65 (919.22–1065.48) 1288.35 (1196.92–1386.76) 0.768 (0.738–0.800)

LSM ¼ least squares mean.

*
SoluMatrix® is a registered trademark of iCeutica Pty Ltd (Philadelphia, Pennsylvania) and is licensed to Iroko
Pharmaceuticals, LLC (Philadelphia, Pennsylvania).
†
Absorption kinetic property was considered similar between treatments if the 90% CI of the treatment ratio was between 0.8
and 1.25.

were previously described in a Phase 1 study in potassium IR 50-mg tablets.11 In contrast to that in
healthy volunteers.11 That study reported 419% the present study, the Cmax of the early development
reduced overall systemic exposure of SoluMatrix SoluMatrix diclofenac drug product was comparable
diclofenac 35-mg capsules compared with diclofenac to that of diclofenac potassium IR 50-mg tablets

Table IV. Analysis of dose proportionality with dose-normalized low-dose SoluMatrix* diclofenac 35-mg
capsules versus 18-mg capsules administered in the fasting condition.

SoluMatrix Diclofenac SoluMatrix Diclofenac Treatment Ratio

Parameter 18-mg Capsules 35-mg Capsules (90% CI†)

Cmax, ng/mL
No. of subjects 39 37
Geometric LSM (95% CI) 25.41 (22.18–29.12) 22.96 (19.96–26.41) 0.904 (0.777–1.050)
AUC0–t, ng  h/mL
No. of subjects 39 37
Geometric LSM (95% CI) 26.80 (24.82–28.93) 27.90 (25.82–30.15) 1.041 (0.995–1.089)
AUC0–1, ng  h/mL
No. of subjects 39 36
Geometric LSM (95% CI) 27.06 (25.13–29.15) 27.90 (25.88–30.09) 1.031 (0.987–1.077)

LSM ¼ least squares mean.

*
SoluMatrix® is a registered trademark of iCeutica Pty Ltd (Philadelphia, Pennsylvania) and is licensed to Iroko
Pharmaceuticals, LLC (Philadelphia, Pennsylvania).
†
Treatments were considered dose proportional if the 90% CI of the treatment ratio was between 0.8 and 1.25.

February 2015 457

Clinical Therapeutics

(1347 vs 1316 ng/mL, respectively). Furthermore, the

SoluMatrix® is a registered trademark of iCeutica Pty Ltd (Philadelphia, Pennsylvania) and is licensed to Iroko Pharmaceuticals, LLC (Philadelphia, Pennsylvania).
Table V. Analysis of food effect for low-dose SoluMatrix* diclofenac 35-mg capsules versus diclofenac potassium immediate-release (IR) 50-mg

Treatment Ratio (90% CI )

†
mean Tmax occurred earlier after the administration of

0.894 (0.858–0.932)
0.573 (0.484–0.678)

0.904 (0.869–0.941)
the early development SoluMatrix diclofenac 35-mg
capsules compared with that of diclofenac potassium
IR 50-mg tablets (0.59 vs 0.80 hour).11 These results
are consistent with the well-documented pharmacoki-
netic variability of diclofenac.33–35
Diclofenac Potassium IR 50-mg Tablets

The early development SoluMatrix diclofenac drug

1274.22 (1184.14–1371.16) 1139.46 (1059.26–1225.74)

1288.35 (1196.92–1386.76) 1164.76 (1082.42–1253.35)

622.07 (539.62–717.12)

product was manufactured before a change from a

wet to dry granulation process, which was imple-
mented to enable automated capsule filling to support
Fed

38

38

38

manufacture at a commercial scale. The formulation

and process development of the commercial formulation
ensured that the performance (ie, extent and rate of
in vitro dissolution) of the drug product was main-
1086.53 (940.71–1254.94)

tained during all stages of development. The median

particle size of both the early formulation and the
Fasting

commercial formulation of the SoluMatrix diclofenac

37

37

37

drug product is o0.400 mm, and the in vitro

Food effect was considered absent if the 90% CI of the treatment ratio was between 0.8 and 1.25.

dissolution profiles of the 2 formulations were com-

parable (data on file, Iroko Pharmaceuticals, LLC,
[2013]). The differences in the pharmacokinetic prop-
Treatment Ratio (90% CI )
†

erties of the early development and commercial low-

0.858 (0.824–0.895)

0.892 (0.855–0.931)
0.399 (0.337–0.473)

dose SoluMatrix diclofenac drug products may reflect

the variability of the pharmacokinetic properties of
diclofenac previously reported in studies in healthy
volunteers.36–39 Possible explanations for the differ-
SoluMatrix Diclofenac 35-mg Capsules

ences in diclofenac absorption from the low-dose

SoluMatrix diclofenac drug products include differ-
Geometric LSM (95% CI) 808.35 (700.03–933.44) 322.79 (280.07–372.03)

Geometric LSM (95% CI) 976.99 (907.95–1051.27) 838.63 (779.59–902.14)

Geometric LSM (95% CI) 989.65 (919.22–1065.48) 883.03 (819.14–951.89)

ences in gastrointestinal pH; variability in gastric-

emptying kinetics affecting absorption in the stomach;
Fed

38

38

32

and small intestine and enterohepatic recirculation of

the drug, which can result in multiple absorption
peaks.33–35 Further evidence of variability among sub-
jects is provided by differences in the median (range)
diclofenac Tmax in the present study (1.0 hours [0.3-4.5
hours]) from diclofenac potassium IR 50-mg tablets
Fasting

compared with the previous study (0.67 hours [0.3–2.0

36
37

37

hours]) (data on file, Iroko Pharmaceuticals, LLC,

2009).
LSM ¼ least squares mean.

Diclofenac was developed before the role of COX-2

was identified and is commonly referred to as a non-
selective NSAID.6,40 However, evidence suggests that
tablets.

AUC0–1, ng ∙ h/mL

the ratio of the concentrations required to achieve 80%

AUC0–t, ng ∙ h/mL
No. of subjects

No. of subjects
No. of subjects

inhibition of COX-2 and COX-1 (IC80 ratio) differs

Cmax, ng/mL

among many NSAIDs generally considered to be non-

Parameter

selective. Furthermore, the degree of selectivity for

COX-2 inhibition at IC80 compared with COX-1
*
†

inhibition for diclofenac is greater than that of other

458 Volume 37 Number 2


nonselective NSAIDs and is more similar to that of
celecoxib.7,8 Because diclofenac administered at 50 mg
TID results in greater COX-2 inhibition than is
necessary for therapeutic efficacy, the low-dose Solu-
Matrix diclofenac drug is expected to be efficacious.
The expected decrease in dose-dependent COX-1 and
COX-2 inhibition at the lower diclofenac doses may
reduce the risk for AEs related to COX inhibition while
maintaining efficacy. To further investigate the safety
profile of SoluMatrix diclofenac 35 mg, an open-label
tolerability study in 601 patients with osteoarthritis
was conducted and reported that SoluMatrix diclofe-
nac was generally well tolerated over 12 months.13 The
full results of this study have been presented at the
2014 meeting of the American College of
Rheumatology41 and have not yet been published
(data on file, Iroko Pharmaceuticals, LLC, 2013).
Further study will be needed to support the link
between the differential inhibition of COX-1 and -2
isozymes and the efficacy and tolerability of SoluMa-
trix diclofenac.
The early development low-dose SoluMatrix diclo-
fenac drug product had reported analgesia in a Phase 2
study in patients with acute pain after oral surgery.19
The efficacy and tolerability of the commercial
SoluMatrix diclofenac drug product was subsequently
evaluated in patients experiencing moderate to severe
acute pain after bunionectomy. The use of SoluMatrix
diclofenac 18 and 35 mg TID was associated with
significantly reduced pain intensity over 0 to 48 hours
compared with placebo (P ¼ 0.010 and P o 0.001,
respectively).12 SoluMatrix diclofenac 35 mg TID also
had reported efficacy in a Phase 3, 12-week, placebo-
controlled study in patients with osteoarthritis pain
(P ¼ 0.0024).13 The 35-mg twice daily regimen was
considered marginally significant (P ¼ 0.079). SoluMa-
trix diclofenac capsules were generally well tolerated
across these clinical studies.12,13 The results of these
studies suggest that SoluMatrix diclofenac provides
effective analgesia at low doses.
The pharmacokinetic properties of low-dose Solu-
Matrix diclofenac capsules are consistent with a rapid
rate of diclofenac absorption (Tmax) in vivo. Results
from clinical studies in patients with acute and osteo-
arthritis pain suggest that the pharmacokinetic proper-
ties of low-dose SoluMatrix diclofenac—specifically
rapid Tmax—correlate with clinically meaningful anal-
gesia.42–44 Commercial low-dose SoluMatrix diclofe-
nac capsules demonstrated efficacy in Phase 3 studies in
February 2015
P.J. Desjardins et al.
patients with acute pain after bunionectomy surgery23
and in patients diagnosed with osteoarthritis of the hip
or knee.25 These results suggest that low-dose SoluMa-
trix diclofenac capsules represent a potential alternative
therapeutic option for these patients.
CONCLUSIONS
The pharmacokinetic properties of low-dose SoluMa-
trix diclofenac capsules in the healthy subjects in the
present study suggest rapid diclofenac absorption as
measured by Tmax associated with a reduction in
overall systemic exposure. Low-dose SoluMatrix di-
clofenac represents a new option for the management
of acute and osteoarthritis-related pain.
ACKNOWLEDGMENTS
The authors thank Dave Dickason, Claire Sheridan,
PhD, and Melanie Funke, PhD, of Iroko Pharmaceut-
icals, LLC (Philadelphia, Pennsylvania); Ewa Wand-
zioch, PhD, and Colville Brown, MD, of
AlphaBioCom (King of Prussia, Pennsylvania) for
editorial support. All authors participated in the
preparation of the manuscript and approved its final
version.
CONFLICTS OF INTEREST
Funding for this research and editorial support
was provided by Iroko Pharmaceuticals, LLC.
Dr. Olugemo is an employee of Parexel, which was
contracted to perform this study. Dr. Desjardins is an
independent clinical consultant and serves in an
advisory capacity to Iroko Pharmaceuticals, LLC.
Drs. Solorio and Young are employees of Iroko
Pharmaceuticals, LLC. The authors have indicated
that they have no other conflicts of interest with
regard to the content of this article.
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