Diclofenac sodium and diclofenac potassium

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1
Biowaiver Monographs for Immediate Release Solid
Oral Dosage Forms: Diclofenac Sodium and
Diclofenac Potassium
B. CHUASUWAN,1,2 V. BINJESOH,1,3 J.E. POLLI,1 H. ZHANG,4 G.L. AMIDON,5 H.E. JUNGINGER,6 K.K. MIDHA,7
V.P. SHAH,9 S. STAVCHANSKY,9 J.B. DRESSMAN,10 D.M. BARENDS11
1
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland
2
Research and Development Institute, The Government Pharmaceutical Organization, Bangkok, Thailand
3
Faculty of Pharmacy, Rangsit University, Pathumtani, Thailand
4
AstraZeneca Pharmaceuticals LP, Wilmington, Delaware
5
College of Pharmacy, University of Michigan, Ann Arbor, Michigan
6
Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
7
University of Saskatchewan, Saskatoon, Saskatchewan, Canada
8
International Pharmaceutical Federation FIP, The Hague, The Netherlands
9
Pharmaceutical Division, College of Pharmacy, University of Texas at Austin, Austin, Texas
10
Institute of Pharmaceutical Technology, J.W. Goethe University, Frankfurt, Germany
11
RIVM—National Institute for Public Health and the Environment, Bilthoven, The Netherlands
Received 23 May 2008; accepted 3 July 2008
Published online 27 August 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21525
ABSTRACT: Literature data are reviewed regarding the scientific advisability of allowing a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release
(IR) solid oral dosage forms containing either diclofenac potassium and diclofenac
sodium. Within the biopharmaceutics classification system (BCS), diclofenac potassium
and diclofenac sodium are each BCS class II active pharmaceutical ingredients (APIs).
However, a biowaiver can be recommended for IR drug products of each salt form, due to
their therapeutic use, therapeutic index, pharmacokinetic properties, potential for
excipient interactions, and performance in reported BE/bioavailability (BA) studies,
provided: (a) test and comparator contain the same diclofenac salt; (b) the dosage form of
the test and comparator is identical; (c) the test product contains only excipients present
in diclofenac drug products approved in ICH or associated countries in the same dosage
form, for instance as presented in this paper; (d) test drug product and comparator
dissolve 85% in 30 min or less in 900 mL buffer pH 6.8, using the paddle apparatus at
75 rpm or the basket apparatus at 100 rpm; and (e) test product and comparator show
dissolution profile similarity in pH 1.2, 4.5, and 6.8. ß 2008 Wiley-Liss, Inc. and the American
Pharmacists Association J Pharm Sci 98:1206–1219, 2009
A project of the International Pharmaceutical Federation
FIP, Groupe BCS, www.fip.org/bcs. This article reflects the
scientific opinion of the authors and not the policies of regulating agencies, the International Pharmaceutical Federation
(FIP) and the World Health Organization (WHO).
1206
Correspondence to: D.M. Barends (Telephone: 31-302744209; Fax: 31-30-2744462; E-mail: [email protected])
Journal of Pharmaceutical Sciences, Vol. 98, 1206–1219 (2009)
ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
BIOWAIVER MONOGRAPH FOR DICLOFENAC
1207
Keywords: absorption; bioequivalence; biopharmaceutics classification system
(BCS); diclofenac; permeability; solubility; regulatory science
INTRODUCTION
A biowaiver monograph of diclofenac is presented based on literature data and new experimental
data. Risks are evaluated in basing a BE assessment on in vitro study results (i.e., ‘‘biowaiving’’), rather than in vivo study results, for the
approval of new IR solid oral dosage forms
containing diclofenac sodium and diclofenac
potassium, for example, plain IR tablets, dispersable tablets and powders for oral solutions. This
risk evaluation considers diclofenac sodium and
diclofenac potassium biopharmaceutical and clinical properties, as they pertain to reformulated
products and new multisource products. This
evaluation concerns drug products containing
diclofenac as the only API and does not concern
combination drug products. This evaluation does
not concern delayed release products or any other
modified release formulations of diclofenac.
The purpose and scope of this series of monographs have been previously discussed.1 Briefly,
the aim is to evaluate all pertinent data available
from literature sources for a given API to assess
the risks associated with a biowaiver. For these
purposes, risk is defined as the probability of
making an incorrect biowaiver decision, as well as
the resulting consequences of such a decision in
terms of public health and individual patient
risks. On the basis of these considerations, a
recommendation can be made as to whether a
biowaiver is advisable or not. This systematic
approach to recommend for or to advise against a
biowaiver is described in the recently published
World Health Organization (WHO) Guideline.2
These monographs do not intend to simply apply
the WHO, FDA3 and/or EMEA Guidance,4 but aim
to apply these guidances and further serve as a
critical validation of these regulatory documents.
Biowaiver monographs have already been published for acetaminophen (INN: paracetamol),5
acetazolamide,6 aciclovir,7 amitriptyline,8 atenolol,1 chloroquine,9 cimetidine,10 ethambutol,11
ibuprofen,12 isoniazid,13 metoclopramide, prednisolone,14 prednisone,15 pyrazinamide,16 propranolol,1 ranitidine,17 and verapamil.1 They are also
available on-line at www.fip.org/bcs. Although
diclofenac is not on the present WHO List of
DOI 10.1002/jps
Essential Medicines,18 it was considered appropriate to include this widely used and important
API in this series.
Literature Review
Published information was obtained from PubMed
up to November 2007. Key words used were:
diclofenac potassium, diclofenac sodium, NSAID,
indication, therapeutic index, solubility, polymorphism, partition coefficient, pKa, absorption,
permeability, distribution, metabolism, excretion,
excipients, bioequivalence and dissolution.
GENERAL CHARACTERISTICS
Name and Structure
The chemical name of diclofenac is 2-[(2,6dichlorophenyl)amino]-benzeneacetic acid. Its
structure is shown in Figure 1.
Therapeutic Indication, Side Effect and
Therapeutic Index
Diclofenac is a well-known nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory,
analgesic and antipyretic properties, comparable or
superior to other NSAIDs.19 Diclofenac shows
preferential inhibition of the cyclooxygenase-2
Figure 1. Structure of diclofenac, where M ¼ Kþ
or Naþ for potassium or sodium salt, respectively.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
1208
CHUASUWAN ET AL.
(COX-2) enzyme.20 Diclofenac sodium is mainly
indicated in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Diclofenac potassium is claimed to dissolve faster, and
hence absorbed faster, than the sodium salt and is
recommended for the treatments that need short
onset of action, mainly for its analgesic properties.
Diclofenac potassium is also indicated for the
treatment of primary dysmenorrheal and mild to
moderate pain.21,22 As with other NSAIDs, diclofenac
is known to increase the risk of gastrointestinal
bleeding and cardiovascular side effects.21,22 However, diclofenac has a relatively high therapeutic
index in comparison to other NSAIDs.23
PHYSICOCHEMICAL PROPERTIES
Salts, Esters, Polymorphs, Hydrates
Diclofenac is usually formulated as the sodium or
potassium salt, but other salts are also used, such
as hydroxyethylpyrrolidine salt for oral preparations, and diethylammonium and diethylamine
for topical preparation.24 This monograph refers
to drug products containing the sodium or
potassium salt of diclofenac only. Most ‘‘plain’’
tablets contain the potassium salt, whereas most
dispersable dosage forms contain diclofenac
sodium, see Tables 1 and 2. In this monograph,
the term diclofenac without indicating the salt
form refers to the sodium and potassium salts.
Trihydrates and tetrahydrates exist for both of
diclofenac potassium and diclofenac sodium,25,26
but in pharmacopoeial drug products only the
anhydrate is used.27,28
Solubility
Solubility values for diclofenac sodium taken from
the literature29 are shown in Table 3 and
experimentally determined solubilities of diclofenac potassium are show in Table 4, respectively,
together with the dose to solubility ratios (D/S) for
several tablet strengths.
Polymorphism
Reports of diclofenac potassium or diclofenac
sodium polymorphs were not found in the
literature.
Partition Coefficient
Partition coefficient in n-octanol/aqueous buffer
(log D) are reported to be 1.4 and 1.1 for pH 6.8 and
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
7.4, respectively.30–32 The experimental log P
(n-octanol/water) and C log P values of diclofenac
are 4.40 and 4.71, respectively,33,34 which are
larger than the corresponding values of 1.72 and
1.35 for the highly permeable marker drug
metoprolol.35
pKa
The pKa of diclofenac is about 3.80 at 258C.36,37
Strengths of Marketed Drug Products
Dosage form strength is expressed in mg of salt
present, not equivalent of the free acid. In the
United States (US) and in the EU, Marketing
Authorizations (MAs), that is, registrations, exist
for IR solid oral dosage forms for 12.5, 25, and
50 mg diclofenac salt, see Tables 1 and 2. Higher
strengths of these drugs have been marketed, but
only as delayed release solid forms or combination
oral products; however, such products are outside
the scope of this monograph.
PHARMACOKINETIC PROPERTIES
The majority of pharmacokinetic data concerns
diclofenac sodium. Literature reports indicate that
diclofenac sodium and diclofenac potassium are
similar in terms of extent of oral absorption, pattern
of distribution, metabolism, and elimination.38
Absorption and Permeability
Diclofenac is 100% absorbed after oral administration, compared to intravenous administration,
based on urine recovery studies.21,22 Only about
60% of drug reaches the systemic circulation
due to first pass metabolism.39,40 In some fasting
volunteers, measurable plasma levels are observed within 10 min of dosing with diclofenac
potassium, although peak plasma levels are
generally achieved after 0.33–2 h.21 For entericcoated diclofenac sodium tablets, drug is released
once the tablet reaches the duodenum, with
subsequent rapid absorption.30,41,42 Absorption
of diclofenac occurs throughout the intestinal
tract.43–46 Diclofenac shows linear pharmacokinetics. The absolute BA of diclofenac potassium
after oral administration did not differ significantly when 1 12.5- and 2 12.5-mg were dose
in a randomized, three-way, crossover study in
DOI 10.1002/jps
BIOWAIVER MONOGRAPH FOR DICLOFENAC
1209
Table 1. Excipientsa Present in Diclofenacb IR Solid Oral Drug Productsc With a Marketing Authorization (MA) in
Germany (DE), Denmark (DK), Finland (FI), France (FR), The Netherlands (NL), Norway (NO), Spain (ES), Sweden
(SE), United Kingdom (UK) and the United States (US)d, and the Minimal and Maximal Amount of that Excipient
Present Pro Dosage Unit in Solid Oral Drug Products With an MA in the USAe
Excipient
Benzoic acid
Calcium hydrogen phosphate
Calcium phosphate
Carmellose sodium
Cellulose
Drug Products Containing that
Excipient With an MA Granted by
the Named Country
DK(1) NO(2) SE(3)
DE(4) DK(5–12) FI(13,14) NO(15,16) SE (17,18) UK(19)
DE(20) DK(21) FI(22) NL(23) NO(24) SE (25,26) US(27,28)
DK(29) FI(30) NO(31) SE (32)
DE(20,33–36) DK(1,29,37) ES(38,39) FI(30,40)
FR (41) NL(23,42,43) NO(2,31,44,45) SE
(3,25,26,32,46,47) US(27,28,48,49)
Croscarmellose sodium
FI(40) US (48)
Crospovidone
DE(50,51)
dimeticone
DE(33)
Glycerol
DK(29) FI(30,40) NO(31) SE (32)
Glycerol dibehenate
DE(50,51)
Hypromellose
DE(34–36,50,51) DK(1,29,37) ES(38) FI(30,40) FR
(41) NO(2,31) SE (3,32) US (28,48)
Lactose
DE(34–36) DK(1,29,37) ES(38,39) FI(30,40) FR (41)
NL(42,43) NO(2,31,44,45) SE (3,32,46,47) US (28,48,49)
Lecithin
DE(4) DK(5–12) FI(13,14) NO(15,16) SE (17,18)
Macrogol
DE(20,33–36,50,51) DK(1,37) ES(38) FR (41) NL(23) NO(2)
SE (3,25,26) US (27,28,48)
Macrogol stearate
DK(1) NO(2) SE (3)
Magnesium stearate
DE(4,20,33–36,50,51) DK(1,5–12,21,29,37) ES(38,39)
FI(13,14,22,30,40) FR (41) NL(23,42,43) NO(2,15,16,
24,31,44,45) SE (3,17,18,25,26,32,46,47) UK(19) US
(27,28,48,49)
Maltodextrin
DE(35,36) DK(37) FR (41)
Mannitol
DE(50,51)
Octamethylcyclotetrasiloxane DK(1) NO(2) SE (3)
Polydextrose
US (48)
Polysorbateg
DK(37)
Polysorbate 80
DE(35,36) FR (41)
Poly(vinylalcohol)
DE(4) DK(5–8) FI(13,14) NO(15,16) SE (17,18)
Potassium hydrogen
DE(50,51)
carbonate
Povidone
DE(4,20,33–36) DK(5–12,21,37) ES(38,39) FI(13,14,22) FR (41)
NL(23,42,43) NO(15,16,24,44,45) SE(17,18,25,26,46,47)
UK (19) US (27,28)
Silica
DE(4,20,34–36) DK(5–12,21,29,37) ES(38,39) FI(13,
14,22,30,40) FR (41) NL(23,42,43) NO(15,16,24,31,44,45) SE
(17,18,25,26,32,46,47) UK (19) US (27,28,48)
Simethicone
DK(1) NO(2) SE (3)
Sodium hydroxide
DE(33)
Sodium lauryl sulphate
DE(50,51) US (48)
Sodium starch glycolate
DE(4,20,33,35,36) DK(1,5–12,21,37) ES(38,39) FI(13,14,22)
FR (41) NL(23,42,43) NO(2,15,16,24,44,45) SE
(3,17,18,25,26,46,47) UK (19) US (27,28)
Sorbic acid
DK(1) NO(2) SE (3)
Range Present in
Solid Oral Dosage
Forms With an MA
in the USA (mg)
No data
104–850
21–362
2.2–160
4.6–1385f
2–180
4.4–792f
3.7
0.14–198f
5.7–14
0.8–86
23–1020f
5–15
0.12–500f
0.15–401f
0.16–80
33–454
No data
3.8–8.1
No data
2.2–418f
0.7–20
12
0.17–75
0.65–99
0.0004–5.7
0.74–6.7
0.65–50
2–876f
0.94
(Continued)
DOI 10.1002/jps
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
1210
CHUASUWAN ET AL.
Table 1. (Continued )
Excipient
Starch
Drug Products Containing that
Excipient With an MA Granted by
the Named Country
Range Present in
Solid Oral Dosage
Forms With an MA
in the USA (mg)
0.44–1135f
Triacetin
Xanthan gum
DE(4,20,33–36) DK(1,5–12,21,29,37) ES(38,39)
FI(13,14,22,30,40) FR (41) NL(23,42,43)
NO(2,15,16,24,31,44,45) SE (3,17,18,25,26,32,46,47)
UK(19) US (27,28)
US (49)
DE(20,33) NL(23) SE (25,26) US (27)
DE(4,20,33,34) DK(1,5–12) ES(38) FI(13,14) NL(23)
NO(2,15,16) SE (3,17,18,25,26)
US (48)
DE(4) DK(5–12) FI(13,14) NO(15,16) SE (17,18)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
Eeze, filmovertrukne tabletter
Ezze 25 mg filmdrasjerte tabletter
Eeze 25/50 mg, filmdragerade tabletter
Diclac1 Dolo 12.5 mg Filmtabletten (Mono)
Diclofenac Rapid ‘‘Actavis’’, filmovertrukne tabletter
Diclofenac Rapid ‘‘Copyfarm’’, filmovertrukne tabletter
Diclon Rapid, filmovertrukne tabletter
Diclopax, filmovertrukne tabletter
Fenaclo, filmovertrukne tabletter
Dictavis, filmovertrukne tabletter
Diclium, filmovertrukne tabletter
Fenacta, filmovertrukne tabletter
Diclofenac Rapid Actavis 25/50 mg tabletti, kalvopäällysteinen
Diclofenac Rapid Copyfarm 25/50 mg tabletti, kalvopäällysteinen
Diclofenackalium Actavis 25/50 mg tabletter, filmdrasjerte
Diclofenackalium Copyfarm 25/50 mg filmdrasjerte tabletter
Diklofenak T Actavis 25/50 mg filmdragerade tabletter
Diklofenak T Copyfarm 25 mg och 50 mg filmdragerade tabletter
Diclofenac potassium 12.5 mg tablets
Voltaren1 K Migräne 50 mg überzogene Tabletten (Mono)
Voltaren Rapid, overtrukne tabletter
Voltaren Rapid 25/50 mg tabletti, päällystetty
Cataflam 25/50, omhulde tabletten 25/50 mg
CATAFLAM 50 mg drasjerte tabletter
Diklofenak T Sandoz 25/50 mg, tabletter
Voltaren T 25/50 mg, dragerade tabletter
Cataflam1 tablet 50 mg, sugar-coated [Novartis Pharmaceuticals Corporation]
Diclofenac potassium tablets 50 mg, film-coated [TEVA Pharmaceuticals USA]
Diclofenac ratiopharm Rapid, filmovertrukne tabletter
Diclomex Rapid 25/50 mg tabletti, kalvopäällysteinen
DiclofenacKalium ratiopharm tabletter, filmdrasjert
Diclofenac T ratiopharm 25/50 mf filmdragerade tabletter
Diclofenac PB 50 mg Tabletten (Mono)h
Diclodoc1 50 Tabletten (Mono)h
Optalidon1 Zahnschmerz mit Diclofenac Filmtabletten (Mono)
Voltaren1 Dolo 12. mg Filmtabletten (Mono)
Voltaren Dolo, filmovertrukne tabletter
DICLOFENACO PENSA 50 mg comprimidos EFGh
Voltalgial 12.5 mg comprimidos
Starch, pregelatinized
Sucrose
Talc
6.6–600
12–900
0.26–220f
0.72–15
14
(Continued)
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
DOI 10.1002/jps
BIOWAIVER MONOGRAPH FOR DICLOFENAC
1211
Table 1. (Continued)
Excipient
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
Drug Products Containing that
Excipient With an MA Granted by
the Named Country
Range Present in
Solid Oral Dosage
Forms With an MA
in the USA (mg)
Diclofenac Rapid ratiopharm 25/50 mg tabletti, kalvopäällysteinen
VOLTARENDOLO 12.5 mg cp enr
Voltaren K, omhulde tabletten 12.5 mg
Otriflu, omhulde tabletten 12.5 mg
CATAFLAM 12.5 mg tabletter, filmdrasjerte
Otriflu 12.5 mg tabletter, filmdrasjerte
Otriflu 12.5 mg filmdragerade tabletter
Voltaren T 12.5 mg filmdragerade tabletter
Diclofenac potassium tablets USP, 50 mg film-coated [Mylan Pharmaceuticals Inc.]
Diclofenac potassium tablets 50 mg, film-coated [Sandoz Inc.]
Diclo-CT akut 12.5 mg Filmtabletten (Mono)
Diclofenac-ratiopharm1 Schmerztabletten 12.5 mg Filmtabletten (Mono)
a
Colourants, flavors and ingredients present in the printing ink are not included. Coating substances are excluded if in the SmPC
the constituents of core and coating are stated separately.
b
Diclofenac potassium and diclofenac sodium. Unless otherwise indicated the reported drug products contain diclofenac
potassium.
ac
Drug products containing more than one API are excluded. Soluble tablets, dispersible tablets and powders and tablets to
prepare an oral solution are reported in Table 2.
d
Sources of data: DE, www.rote-liste.de (assessed September 25, 2007); DK, www.dkma.dk (assessed September 20, 2007); FI,
www.nam.fi (assessed September 25, 2007); FR, www.vidal.fr (assessed September 24, 2007); NL, www.cbg-meb.nl. (assessed
September 20, 2007); NO, www.legemiddelverket.no (assessed September 24, 2007); ES, www.agemed.es (assessed September 21,
2007); SE, www. lakemedelsverket.se (assessed September 25, 2007); UK, www.mhra.gov.uk (assessed February 7, 2008); USA,
http://dailymed.nlm.nih.gov (assessed February 6, 2008).
fe
FDA’s Inactive Ingredient Database: http://www.fda.gov/cder/iig/iigfaqweb.htm#purpose (version date November 1, 2007).
f
The reported upper range value is unusually high. The authors doubt its correctness.
g
Without specified grade.
h
Contains diclofenac sodium.
10 subjects.39 The systemic absorption of diclofenac as a function of the dose is proportional within
the range 25–150 mg,39,44 which suggests that the
low drug solubility at low pH is not limiting
absorption.
Administration with food can extend the lag
time (tlag) of drug absorption, thereby increasing
the time to maximum concentration (tmax) and
decreasing the maximum concentration (Cmax).
Food does not have a significant effect on the
extent of oral absorption of diclofenac sodium or
diclofenac potassium.22,38,47,48 Diclofenac’s rapid
and complete absorption suggests a high permeability through the intestinal membrane.43,44 This
observation of high permeability throughout the
intestinal tract is also supported by reports of
rapid absorption of diclofenac from effervescent
tablets45 and the high permeability of diclofenac
in the colon after administration of the drug as a
suppository.46
In a Caco-2 cell monolayer experiment, the
permeability of diclofenac from apical-to-basolateral ( PA–B) and basolateral-to-apical ( PB–A) direcDOI 10.1002/jps
tions were 20.2 106 and 21.3 106 cm/s,
respectively, while metoprolol permeability was
43.4 0.7 106 and 34.1 0.6 106 cm/s in the
two directions, respectively.49 Metoprolol is
90–95% absorbed from the intestinal tract and
is often used as a reference for the lower limit of a
highly permeable drug.3,35,50 In an artificial
membrane model, Pam of diclofenac, metoprolol
and propanolol were 53.3 106, 5.67 106, and
13.7 106 cm/s, respectively.51
Distribution
The apparent volume of distribution is 1.3 L/kg for
diclofenac potassium21 and 1.4 L/kg for diclofenac
sodium.22 Circulating diclofenac is known to be
greater than 99% bound to human serum protein,
primarily to albumin.30,52 However, this binding
has been described as pharmacokinetically insignificant due to the rapid association–dissociation
of diclofenac to albumin, such that the drug
readily dissociates and permeates across the
vascular membrane to the tissues.38
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
1212
CHUASUWAN ET AL.
Table 2. Excipientsa Present in Diclofenac b IR Soluble Tablets, Dispersable Tablets and Powders for Oral Solutionc
With a Marketing Authorization (MA) in Germany (DE), Denmark (DK), Norway (NO), Spain (ES), Sweden (SE) and
United Kingdom (UK)d , and the Minimal and Maximal Amount of that Excipient Present Pro Dosage Unit in Solid
Oral Drug Products With an MA in the USAe
Excipient
Castor oil hydrogenated
Cellulose
Citric acid
Croscarmellose sodium
Crospovidone
Glycerol dibehenate
Lactose
Magnesium stearate
Mannitol
Potassium hydrogen carbonate
Povidone
Silica
Sodium starch glycolate
Starch
Talc
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Drug Products
Containing that Excipient
With an MA Granted by
the Named Country
Range Present in
Solid Oral Dosage Forms
With an MA in the USA (mg)
DE(1–4) DK(5) ES(6) UK (7)
DE(1–4,8,9) DK(5) ES(6) UK (7)
DE(8,9)
DE(1–4) DK(5) ES(6) UK (7)
DE(8,9) ES(10)
DK(11) NO(12) SE (13)
DE(8,9)
DE(8,9) ES(10)
DK(11) NO(12) SE (13)
DK(11) NO(12) SE (13)
DE(1–3) ES(6)
DE(1–4,8,9) DK(5) ES(6) UK (7)
DE(1–4) DK(5) ES(6) UK (7)
DE(8,9)
DE(1–4) DK(5) ES(6) UK (7)
0.93–37.6f
4.6–1385f
2.6–78
2–180
4.4–792f
5.7–14
23–1020f
0.15–401f
33–454
12
0.17–75
0.65–99
2–876f
0.44–1135f
0.26–220f
Diclofenac AbZ 50 mg Trinktabletten (Mono)g
Diclofenac-CT 50 mg Trinktabletten (Mono)g
Diclofenac-ratiopharm1 50 mg Disperstabletten Tabletten zur Herstellung einer
Suspension zum Einnehmen (Mono)g
Voltaren1 Dispers Tabletten (Mono)g
Voltaren, opløselige tabletterg
DICLOFENACO RCA 50 mg comprimidos dispersables EFGg
Voltarol Dispersible Tablets 50 mgg
Diclac1 Dispers Tabletten (Mono)g
Diclo dispers1 Tabletten zur Herstellung einer Suspension zum Einnehmen (Mono)g
DICLOFENACO NORMON 50 mg Comprimidos Dispersables EFGg
Voltaren Rapid, pulver til oral opløsningh
CATAFLAM 50 mg dosepulver til mikstur, oppløsningh
Voltaren 50 mg pulver till oral lösning, dospåseh
a
Colourants, flavors and ingredients present in the printing ink only are not included.
Diclofenac potassium and diclofenac sodium. The salt form present is indicated for each product.
Drug products containing more than one API are excluded.
d
Sources of data: DE, www.rote-liste.de (assessed October 24, 2007); DK, www.dkma.dk (assessed October 24, 2007); NO,
www.legemiddelverket.no (assessed September 20, 2007); ES, www.agemed.es (assessed October 24, 2007); SE, www. lakemedelsverket.se (assessed October 24, 2007); UK, www.medicines.org.uk (assessed February 7, 2008).
e
FDA’s Inactive Ingredient Database, http://www.fda.gov/cder/iig/iigfaqweb.htm#purpose (version date November 1, 2007).
f
The reported upper range value is unusually high. The authors doubt its correctness.
g
Contains diclofenac sodium.
h
Contains diclofenac potassium.
b
c
Metabolism
Excretion
Diclofenac undergoes extensively hepatic biotransformation involving aromatic hydroxylations and conjugations.53,54 Five diclofenac
metabolites have been identified.22,41,54 One
metabolite has a very weak pharmacological
activity.22
Approximately 65% of diclofenac is excreted in the
urine, largely as metabolites, and 35% in bile as
conjugates of unchanged diclofenac and metabolites.22 Very little drug is eliminated in the
unchanged form in urine.44 The terminal half-life
of unchanged diclofenac is approximately 2 h.22,30
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
DOI 10.1002/jps
BIOWAIVER MONOGRAPH FOR DICLOFENAC
1213
Table 3. Solubility of Diclofenac Sodium from Literature Data19 and the Corresponding Dose/Solubility (D/S)
Ratio’s for Three Tablet Strengths
D/Sa (mL)
pH
Medium
Solubility (mg/mL) (23 28C)
12.5 mg
25 mg
50 mgb
1.2
2.0
3.0
4.1
4.5
5.5
5.8
6.0
6.8
7.0
7.4
7.8
8.0
0.1 N HCl
0.01 N HCl
0.001 N HCl
Acetate buffer
Acetate buffer
Acetate buffer
Phosphate buffer
Phosphate buffer
Phosphate buffer
Phosphate buffer
Phosphate buffer
Phosphate buffer
Phosphate buffer
0.0012
0.0017
0.28
0.0033
0.0036
0.036
0.14
0.15
0.67
1.36
5.15
12.00
12.14
12500c
7353c
45
3788c
3472c
347c
89
83
19
9
2
1
1
25000c
14706c
89
7576c
6944c
694c
179
167
37
18
5
2
2
50000c
29412c
179
15152c
13889c
1389c
357c
333
75
37
10
4
4
a
Critical limit: <250 mL.2–4
Highest tablet strength of IR solid oral dosage forms on USA and EU market.
c
Exceeds critical limit.
b
DOSAGE FORM PERFORMANCE
over, diclofenac is not on the list of except APIs
from in vivo BE studies by the Dutch Regulatory
Authorities.56
Excipients and/or Manufacturing Variations
Excipients present in diclofenac sodium and
diclofenac potassium IR solid oral drug products
with an MA in the US and some European
countries are shown in Table 1. These products
are ‘‘plain’’ tablets and are intended to be
swallowed intact. In Table 2, the same information is shown for IR soluble tablets, dispersible
tablets and powders for oral solution. In view of
the MAs, it is presumed that these drug products
successfully met the in vivo BE criteria. Unlike
other APIs, diclofenac products were not
exempted from in vivo BE studies for some time
by the German Regulatory Authorities.55 More-
In Vivo Bioequivalence
Several studies demonstrated BE among
diclofenac potassium IR products.39,52,57,58 In a
randomized, single dose, two-way crossover study
in 66 subjects, a 12.5 mg diclofenac potassium
tablet formulation was shown to be bioequivalent
in terms of log transformed Cmax, AUC0t and
AUC0–1 to its reference, Voltarol Dolo 12.5 mg
tablets (Norvatis, Basel, Switzerland).57 Dissolution profiles of test product were reported to be
similar to the reference products marketed in
various European countries.57
Table 4. Solubility of Diclofenac Potassium at Room Temperature and the Corresponding Dose/Solubility (D/S)
Ratio’s for Three Tablet Strengths
D/Sb (mL)
pH
Medium
Solubility (mg/mL)a
12.5 mg
25 mg
50 mgc
4.5
6.8
7.4
Acetate buffer
Phosphate buffer
Phosphate buffer
0.0014 (0.0001)
0.7167 (0.0165)
2.341 (0.016)
8929d
17
5
17857d
35
11
35714d
70
21
a
Between brackets: standard deviation of mean.
Critical limit: <250 mL2–4.
c
Highest tablet strength of IR solid oral dosage forms on USA and EU market.
d
Exceeds critical limit.
b
DOI 10.1002/jps
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CHUASUWAN ET AL.
In another single dose study in 24 healthy
volunteers, a diclofenac potassium 50 mg sachet
formulation containing excipients such as potassium hydrogen carbonate, mannitol, aspartame,
saccharin sodium, glyceryl dibehenate, and flavors proved to be bioequivalent to the reference
tablet formulation Voltfast in terms of AUC0–1,
although Cmax was twofold larger from the
sachet formulation.58 No dissolution studies were
performed because the test formulation is a
powder for oral solution.
Neuvonen59 reported no significant change in
the pharmacokinetics of diclofenac when coadministered with magnesium hydroxide, but this
study was carried out with enteric coated tablets
and hence of very limited value for IR dosages
forms.
Dissolution and In Vitro/In Vivo Correlation
For diclofenac potassium tablets, the USP30
dissolution specification is not less than 80% (Q)
of the labeled amount to be dissolved within
60 min in 900 mL simulated intestinal fluid
(without enzyme) at 50 rpm in the paddle
apparatus.27 The Ph.Eur and the BP do not
contain monographs for IR diclofenac tablets. No
in vitro/in vivo correlations were identified in the
literature for diclofenac IR solid oral dosage forms.
DISCUSSION
Solubility
Tables 3 and 4 show the dose/solubility ratio (D/S)
of each salt at pH 6.0 and above to be less than the
critical limit of 250 mL for highly soluble
according to the present BCS Guidances.2,3,60
The solubility reported by Kincl et al.29 at pH 3.0
in 0.001 N HCl appears unexplainably high. All
other data show diclofenac to be below pH 4.5 (or
pH 5.8, depending on the tablet strength) to be not
highly soluble. Although most solubility data have
been collected at room temperature, it is unlikely
that solubility values would be much different at
378C to change the interpretation in terms of the
BCS classification.
supported by in vitro data. Some reports indicate
that a permeability coefficient of more than
1 106 cm/s in Caco-2 model is considered to
imply high permeability and/or complete absorption.49,61,62 Others report that a permeability
coefficient over 10 106 cm/s implies high
permeability11 or >70% absorption in humans.63
Diclofenac exceeds both criteria. The artificial
membrane permeability data and the partitioning
data further support the classification of diclofenac as being highly permeable.
BCS Classification
According to all Guidances, the data presented
above classify diclofenac in BCS Class II.2–4 Using
the disposition characteristics of the API as an
estimate for its permeability, Wu and Benet64
assigned diclofenac to Class II in a Biopharmaceutics Drug Disposition Classification System
(BDDCS).
Risk for Drug Products to be Bioinequivalent
Tables 1 and 2 show excipients and their quantity
limits used in diclofenac IR products with MAs in
a number of countries. By virtue of their MAs, it
may be assumed that these drug products passed
in vivo BE studies. Hence, it is inferred that none
of the excipients tabulated in these tables has had
a significant effect on the extent nor the rate of
diclofenac absorption. It is worthy of note that
some drug products contain sodium lauryl sulfate,
which has been reported to improve drug dissolution of poorly soluble drugs.65 However, it appears
that even if there was improved dissolution,
sodium lauryl sulfate did not lead to the drug
product to be bioinequivalent. It is deduced that
these excipients in these reported limits do not
cause interactions that result in bioinequivalence
for diclofenac.
We conclude that the low solubility of diclofenc
at pH values of 4.5 and below does not pose a
substantial risk for bioinequivalence. This may be
the result of diclofenac high permeability, as
well as the dynamic character of the uptake
processes.66
Surrogate Techniques for In vivo BE Testing
Absorption and Permeability
The complete 100% absorption classifies diclofenac as highly permeable.2,3,60 This classification is
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
The rate-limiting step in the absorption of
diclofenac from a drug product is gastric emptying, disintegration in vivo or dissolution in vivo.
Comparative in vitro dissolution testing in
DOI 10.1002/jps
BIOWAIVER MONOGRAPH FOR DICLOFENAC
discriminatory media is a sensible technique to
detect significant differences in disintegration
in vivo or dissolution in vivo between a test drug
product and comparator. In vitro dissolution
testing in SIF (pH 6.8) without enzyme is
suggested by USP and FDA for IR diclofenac
potassium drug products as the quality control
test.27,67 SIF without pancreatin and SIF without
pancreatin with 1% (w/v) Tween 20 has been
suggested as discriminatory dissolution media for
diclofenac sodium prolonged release tablets.68
Dissolution in these media can be considered as
discriminatory dissolution test for IR dosage
forms. The BCS Guidance prescribes comparative
in vitro dissolution testing between test and comparator in pH 1.2, 4.5, and 6.8 buffers and also
provides criteria for the assessment of dissolution
profile similarity.2–4 In media pH 1.2 and pH 4.5, no
dissolution is expected, providing evidence that no
dissolution enhancers are present.
Since diclofenac permeability is high, intestinal
absorption is not limiting. An excipient interaction with the permeation process is unlikely. This
risk of interaction is even lower if the test product
contains excipients that are known to exert no
such influence, that is, the excipients tabulated in
Tables 1 and 2.
Patient’s Risks Associated With Bioinequivalence
Bioinequivalence with respect to AUC can cause
subtherapeutic drug level, resulting in low
analgesic efficacy, or supra-bioavailability, which
may lead to cardiovascular and gastrointestinal
side-effect risks. However, diclofenac products are
used for non-life-threatening conditions, which
require achieving minimal effective plasma concentration. The issue of supra-bioavailability is
not critical, as diclofenac is a relatively safe drug
with wide therapeutic range69,70 Most diclofenac
drug products carry a leaflet in which patients are
advised to observe and report back any signs or
symptoms related to cardiovascular and gastrointestinal events to the physician.
CONCLUSION
According to the current FDA and EMEA BCS
Guidances, only BCS class I APIs are eligible for
the biowaiver,3,60 and diclofenac would not qualify
for such a biowaiver. However, the recent WHO
Guidance2 opens a possibility for biowaiving of
drug products containing BCS Class II APIs with
DOI 10.1002/jps
1215
weak acidic properties. This viewpoint for highly
permeable acidic APIs has been supported for
NSAIDS generally.49 Certain conditions must be
fulfilled, such as requirements with respect to
in vitro dissolution; the excipients should be
critically evaluated; and the risk of an incorrect
biowaiver decision need to be assessed in terms of
public health and risks to individual patients.2
Diclofenac fulfills these criteria.
The question regarding the acceptability of
biowaiving between pharmaceutical alternatives
requires further discussion. Pharmaceutical
alternatives are drug products containing the
same molar amount of the same API, but differing
in dosage form (e.g., tablet vs. capsule; ‘‘plain’’
tablet vs. dispersable tablet), or chemical form
(e.g., different salts, different esters), delivering
the same active moiety by the same route of
administration.2
In in vivo BE testing, different salt forms of the
API present in test and comparator are potentially
allowed if there is no safety concerns.60,71 However, in in vitro BE testing, a more conservative
approach is prudent in granting biowaivers
between different salt forms of an API. Moreover,
these two salts sometimes have different therapeutic indications, as diclofenac potassium is
sometimes claimed to be absorbed faster than the
sodium salt and hence recommended for the
treatments that need short onset of action. Hence,
we recommend against a biowaiver when the test
and comparator do not contain the same salt form
of diclofenac.
The FDA, EMEA, and WHO Guidance provide
some possibility for in vivo BE testing between
pharmaceutical alternatives that differ in dosage
form, such as IR tablets versus IR capsules.60,71
Available diclofenac IR solid oral dosage forms
include plain tablets, dispersible tablets, and
powders for solution which are different dosage
forms. As above, a more conservative approach
is prudent in granting biowaivers between different solid oral dosage forms of an API. We
recommend against a biowaiver when the test and
comparator do not contain the same dosage form
of diclofenac.
In summary, a biowaiver for IR solid oral dosage
forms of diclofenac potassium and diclofenac
sodium are scientifically justified, provided that:
(a) test and comparator contain the same diclofenac salt; (b) the dosage form of the test and
comparator is identical; (c) the test product
contains only excipients present in diclofenac
drug products approved in ICH or associated
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
1216
CHUASUWAN ET AL.
countries in the same dosage form, such as
those shown in Tables 1 and 2, in amounts that
are usual for that dosage form; (d) test drug
product and comparator dissolve 85% in 30 min
or less in 900 mL buffer pH 6.8, using the paddle
apparatus at 75 rpm or the basket apparatus at
100 rpm; and (e) test product and comparator
show dissolution profile similarity in pH 1.2, 4.5,
and 6.8.
ACKNOWLEDGMENTS
7.
8.
9.
Supported in part by a grant from AstraZeneca
Pharmaceuticals. Kik Groot, RIVM, is acknowledged for producing Tables 1 and 2.
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