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International Journal of Pharmaceutics 465 (2014) 284–290
Contents lists available at ScienceDirect
International Journal of Pharmaceutics
journal homepage: www.elsevier.com/locate/ijpharm
The difficulties for a photolabile drug in topical formulations:
The case of diclofenac
Giuseppina Ioele ∗ , Michele De Luca, Lorena Tavano, Gaetano Ragno
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy
a r t i c l e
i n f o
Article history:
Received 31 December 2013
Received in revised form 23 January 2014
Accepted 25 January 2014
Available online 1 February 2014
Keywords:
Diclofenac
Photodegradation
Photostabilization
Gel formulation
Light-absorbers agents
Cyclodextrin
a b s t r a c t
Topical commercial formulations containing diclofenac (DC) were submitted to photostability tests,
according to the international rules, showing a clear degradation of the drug. The degradation process was
monitored by applying the multivariate curve resolution technique to the UV spectral data from samples
exposed to stressing irradiation. This method was able to estimate the number of components evolved
as well as to draw their spectra and concentration profiles. Three photoproducts (PhPs) were resolved
by the analysis of photodegradation kinetics, according to two consecutive reactions with a mechanism
postulated as DC > PhP1 > PhP2 and PhP3 . Photodegradation rate of DC in gel was found to be very fast,
with a residual content of 90% only after 3.90 min under a radiant exposure of 450 W m−2 .
Because of a very slow skin uptake of DC, a prolonged time of exposure to light could lead to a significant decrease of drug available or the uptake of undesired photoproducts. New gel formulations were
designed to increase the photostability of DC by incorporating chemical light-absorbers or entrapping the
drug into cyclodextrin. Drug photostability resulted increased significantly in comparison with that of the
commercial formulations. The gel containing the light-absorbers such as octisilate, octyl methoxycinnamate and a combination thereof showed a residual DC of 90% up to 12.22 min, 13.75 min and 15.71 min,
respectively, under the same irradiation power. The best results were obtained by incorporating the drug
in -cyclodextrin with a degradation of 10% after 25.01 min of light exposure.
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
Diclofenac, (2-[(2,6-dichlorophenyl)amino] phenylacetate)
(DC), is a non-steroidal anti-inflammatory drug (NSAID), commonly used for the treatment of arthritis, soft tissue injuries
(Fei et al., 2006; Todd and Sorkin, 1988), dysmenorrhoea, and
menorrhagia (Dawood, 1993). On the other hand, DC treatment
may have some adverse effects, such as gastrointestinal damage,
platelet dysfunction, and convulsion. These effects are likely to
be associated with the ability of this compound to compete with
arachidonic acid for binding to cyclo-oxygenase, resulting in
decreased prostaglandin formation (Small, 1989; Vane, 1996).
Clinical evidence suggests that the topical use of NSAIDs is safer
and at least as efficacious as oral administration in the treatment
of rheumatic diseases (Boinpally et al., 2003; Heyneman et al.,
2000). Unfortunately, DC is not easily absorbed on transdermal
application (Nishihata et al., 1987), and many strategies have been
suggested in order to overcome the low permeability of drugs
through the skin (Barry, 1983; Nokhodchi et al., 2002).
∗ Corresponding author. Tel.: +39 0984 493268; fax: +39 0984 493201.
E-mail address: giuseppina.ioele@unical.it (G. Ioele).
0378-5173/$ – see front matter © 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2014.01.030
DC has been reported to be not stable and undergo degradation processes. Stability studies of this compound showed
several potential impurities (Gaudiano et al., 2003; Hartmann
et al., 2008; Hofmann et al., 2007). The main impurity, 1(2,6-dichlorophenyl)indolin-2-one, may occur in pharmaceutical
formulations after long-term storage (Hájková et al., 2002).
One of the most studied degradation processes relating to DC
is its photodegradation in the aquatic environment. Zhang et al.
(2011) have studied the kinetic model for DC photodegradation in
water and the variation of the degradation profile in the presence
of different forms of nitrogen in the aquatic environment under
simulated sunlight. Newly, Salgado et al. (2013) have investigated
the degradation kinetics of DC by UV radiation used for wastewater disinfection. The identified photoproducts presented a quinone
imine structure, probably obtained by decarboxylation and oxidation followed by dehalogenation and cyclization.
Monitoring of drug degradation in dosage forms can be more
difficult by the fact that its mechanism may vary depending on the
formulation. Moreover, degradation may be influenced by temperature, humidity, light, container and often from the combination of
these factors (Galmier et al., 2005). No studies have been reported
up today about the photodegradation of DC in the semi-solid commercial specialties. Being the global consumption of DC estimated
to be 940 tons per year (Vieno et al., 2007; Wiegel et al., 2004) and
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G. Ioele et al. / International Journal of Pharmaceutics 465 (2014) 284–290
in consideration of the slow absorption of the drug through the
skin, a detailed photostability study of DC and the design of novel
light-stable semi-solid formulations seemed interesting.
In this work, an in depth study about the photodegradation of DC
in solution and semi-solid formulations is reported and attempts
for the photostabilization of gel formulations containing DC are
proposed through addition of chemical UV-absorbers or incorporating the drug into cyclodextrin supramolecular matrices. The
protecting action of the UV-absorber compounds is based on the
property of absorbing, partially or wholly, visible and/or UV sun
radiations, showing absorption spectra overlapping that of the photosensitive drugs (Aloui et al., 2007; Atarashi et al., 2012; Gaspar
and Maia Campos, 2006, 2007; Kockler et al., 2012; Mahltig et al.,
2005; Venditti et al., 2008). However, the choice of these additives is limited as a result of the pharmaceutical, toxicological and
economic requirements. Derivatives of 2-hydroxybenzophenone
are extensively employed as UV absorbers (Negreira et al., 2009).
In the European Union (EU), 2-hydroxy-4-methoxybenzophenone5-sulphonic acid (BP-4) and 2-hydroxy-4-methoxybenzophenone
(BP-3) have been approved to be used as UV filters in sunscreens at
maximum concentrations of 5% and 10%, respectively. In this work,
UV absorbers were added in gel formulations of DC, at concentrations recommended by law (Parlamento Europeo, 2009), in order to
increase the photoprotection of the drug but without altering the
transparency of the gel. Mixtures of UV-absorbers were also tested
to study possible synergic effects.
Photostabilization of DC was besides approached by incorporation of the drug in cyclodextrins. Cyclodextrins are hydrophilic
water-soluble oligosaccharides that form hydrophobic cavities in
which water-insoluble drugs can be entrapped thus leading to a
significant increase in the concentration of the drug in solution
and, at the same time, to a physical shield from light. Actually,
supramolecular systems have been proposed in the last years for
enhancing the stability of drugs to light and many studies reporting
significant successes in this field have been published. In particular, cyclodextrins have shown the most promising results (Garnero
and Longhi, 2010; Wang et al., 2013) for the improvement of the
chemical stability.
The photodegradation kinetics of the new proposed formulations was defined and compared with that of the DC commercial
gel specialties. The quantitative determination of the drug was
performed by applying a chemometric approach to the analysis
of the spectral data avoiding so any previous separation of the
analytes. The algorithm Multivariate Curve Resolution-Alternating
Least Squares (MCR-ALS) was selected for its ability in well describing the kinetics of drug photodegradation, offering a fast and
powerful tool for the mathematical resolution of unknown mixtures (de Juan et al., 2009; Gemperline, 1999; Rajko and Istvan,
2005; Wentzell et al., 1998) with the estimation of the pure spectra and the concentration (time) profiles of the photoproducts (de
Juan et al., 2000, 2009; De Luca et al., 2010, 2013; Mas et al.,
2008). The results about the DC photodegradation process were
compared with the data reported in the literature (Zhang et al.,
2011).
2. Materials and methods
2.1. Chemicals
Diclofenac (DC), propylene glycol, microcrystalline cellulose,
2-hydroxy-4-methoxybenzophenone (BP-3), octocrylene (OC),
octisilate (OS), octyl methoxycinnamate (OMC), ␣-cyclodextrin
(␣C), -cyclodextrin (C), methyl-- cyclodextrin (mC), ␥cyclodextrin (␥C) were purchased from Sigma–Aldrich (Germany);
ethanol, methanol and acetonitrile were from J.T. Baker (Holland).
285
All other reagents were of the highest purity commercially available.
Pharmaceutical specialties Voltaren Emulgel® 1% and Voltaren
Emulgel® 2% (Novartis Farma SpA, Italy) were obtained commercially.
2.2. Instruments
UV spectra of the samples in a 10 mm quartz cell were registered on a Perkin-Elmer Lambda 40P Spectrophotometer at the
following conditions: range 200–450 nm, scan rate 1 nm s−1 ;
time response 1 s; spectral band 1 nm. The software UV Winlab
2.79.01 (Perkin-Elmer) was used for spectral acquisition and elaboration.
All chemometric procedures were performed under Matlab®
computer environment (Mathwork Inc., version 7). MCR routine
computer methods were implemented as MATLAB functions.
Photodegradation experiments were performed according
to the ICH Guideline for photostability testing (International
Conference on Harmonization, 2003) by using a light cabinet
Suntest CPS+ (Heraeus, Milan, Italy), equipped with a Xenon lamp
and an electronic device for measuring and controlling both irradiation and temperature inside the box. The system is able to closely
simulate sunlight and to select spectral regions by interposition of
filters. In the present study, the samples were irradiated in a range
between 300 and 800 nm, by means of a glass filter, according to
the ID65 standard of ICH rules. The spin-dryer was a Multispeed
centrifuge PK 121 (ALC International s.r.l., Italy).
2.3. Standard solutions
Two sets of DC standard solutions were prepared in the range
of 5.0–50.0 mg ml−1 . The spectrophotometric analyses were performed after appropriate dilution with methanol for the first
solutions set and Britton–Robinson buffer for the second ones.
These solutions were used also to prepare validation samples.
2.4. Preparation of DC gel
Gel formulation (20 g) was prepared as reported in the Pharmacopoeia (Council of Europe, 2010). 0.20 g of DC (1%, w/w) was
dispersed in propylene glycol 2 g under continuous stirring for
15 min and so obtaining a complete emulsification. 0.60 g of microcrystalline cellulose (gelling agent) and 17.2 g of water were then
added and the final emulsion was stirred for 50 min getting a homogeneous white gel.
2.5. Preparation of DC–UV absorbers gel
DC gel with the addition of UV-absorbers was prepared in a manner similar to that of DC gel, where the UV-absorbers were added in
propylene glycol together the DC powder. The optimal concentration of any compound was tested by varying the added percentage
in the range 0.25–5.0%, according to the amount permitted in pharmaceutical and cosmetic formulations (Parlamento Europeo, 2009).
Anyhow, the concentration of absorber was controlled that did not
adversely affect the rheological properties of the gel. The eventual
additive or synergistic effect from a combination of UV absorbers
was also tested by preparing further formulations containing OS
and OMC at concentrations between 0.25% and 0.50% were also
tested.
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2.6. Preparation of DC–cyclodextrin gel
245 mg of DC were dissolved in 10 ml of cyclodextrin solution (1.32 g of cyclodextrin in 100 ml ethanol, 10 mM). 10.0 ml of
Britton–Robinson buffer at pH 6.57 (0.04 M phosphoric acid; 0.04 M
acetic acid; 0.04 M boric acid; 0.2 M NaOH) was added under stirring for 20 h at 37 ◦ C. A control drug-free solution was prepared
under the same conditions. Four series of samples (4 × 5) were prepared by using ␣C, C, mC, and ␥C. All the samples were stored
for 4 days at 4 ◦ C and then filtered through a 0.45 m membrane.
The gel formulation containing the complex cyclodextrin–DC
was prepared by adding 17.2 g of the complex solution to propylene
glycol 2 g and microcrystalline cellulose 0.60 g under continuous
stirring for 50 min. The concentration of DC in this preparation was
measured to be about 1%.
For the solubility tests, 245 mg of DC was added to each
cyclodextrin with concentrations of 1, 5, 7.5 and 10 mM in 10 ml
buffer. The suspensions were shaken at 25 ◦ C for 48 h. The sample for UV analysis was prepared by filtering an aliquot through
a 0.45 m filter. The quantity of DC was measured by using the
standard buffer solutions as reference.
2.7. Preparation of the analytical samples
Gel 0.5 g was uniformly stratified on 5 glass plates
(10 cm × 5 cm) to form a layer thickness of 0.25 mm and then
exposed to forced irradiation. After each irradiation dose, the
glass was plunged in acetonitrile 25 ml and sonicated for 10 min
at room temperature. 10 ml of the suspension obtained was then
centrifuged at 5000 rpm for 10 min. The supernatant was analyzed
after 1:10 dilution with methanol. The concentration of drug
residue was calculated by MCR applied on the UV spectrum of the
methanol extract.
The extraction procedure was optimized to maximize the drug
recovery by evaluating the volume of acetonitrile, sonication time
and centrifugation time. The final procedure was validated on a
series of twenty reference gel samples with drug content in the
range of 150–300 mg obtaining a percentage recovery between 91%
and 108%.
2.8. Photodegradation test
To minimize DC photodegradation, all laboratory experiments
were carried out in a dark room under the illumination of a red
lamp (60 W), kept at a distance of about 2 m.
The stressed tests, according to the standard ID65 of ICH rules,
were executed on DC in solution, in quartz cells perfectly stoppered, to prevent any evaporation of the solvent, and on gel. The
samples were irradiated under an irradiance power of 450 W m−2 ,
corresponding to 27 kJ m−2 min, at a constant temperature of 25 ◦ C.
The samples were assayed by UV spectrophotometry after appropriate preparation as described above. Analysis was performed just
after preparation (t = 0 min) and at the following exposure times:
5–10–20–30–60 min.
2.9. Multivariate curve resolution-alternating least squares
(MCR-ALS)
The multivariate resolution methods provide to decompose an
experimental data matrix from a chemical process into the pure
contributions of the single components. The experimental data
matrix, D, is decomposed into the product of two smaller factor
matrices, C and ST :
D = C · ST + E
Fig. 1. Absorbance spectra of DC methanol solution before ( ) and after irradiation
intervals (··· ).
where D is the data matrix obtained from the experimental spectral
measurements and contains as many rows as absorption spectra
recorded along the chemical process (time, reaction conditions,
etc.), C is the concentration matrix of n components involved in
the process, ST is the spectral matrix of the pure components and E
contains the unexplained data variance (Skoog and West, 2004).
In a photodegradation study, the pathway of the process is often
unknown and many products can be generated. The number of
species involved is so difficult to determine and chemical rank analysis can give a lower number of components than the real number
of absorbing species giving so a rank-deficiency (Izquierdo-Ridorsa
et al., 1997). The rank deficiency problems could be removed by
the simultaneous analysis of multiple experiments, under different
conditions and/or together with simpler subsystems, via columnwise data matrix augmentation. In this way, the estimation of the
correct number of components and the resolution of the whole
system are achieved (Norgaard and Ridder, 1994).
In this work, UV spectrophotometric data matrices from
photodegradation experiments on different DC gel were simultaneously analyzed with the UV data matrices built from the
calibration curves of DC solutions at five concentration levels. The
spectral data of the absorber agents and cyclodextrin were added
to the calibration matrices in modeling MCR. No interference was
observed from cyclodextrins for the absence of overlap of the UV
spectra. On the contrary, the UV spectra of the absorber agents
overlapped the DC spectrum. Therefore, their spectral data were
introduced in building the MCR method. Validation was made by
removing one sample at a time from the calibration step and performing the calibration with all other samples. The concentration of
the sample removed was then predicted with the obtained model.
This step was in turn repeated for each sample considered.
3. Results and discussion
3.1. Photodegradation of DC solution
A methanol solution of DC 10.0 mg ml−1 was subdued to forced
photodegradation, under the standard conditions above reported.
Degradation was monitored by spectrophotometry along irradiation after appropriate dilution of sample. The spectra, depicted
in Fig. 1, were recorded just after the preparation and at several
exposure times.
The spectral data, as an average of six experiments, collected
during the photodegradation tests, were used to construct the data
matrix to be analyzed by MCR-ALS. Data elaboration showed the
formation of one major photoproduct (PhP1 ) and traces of other
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287
Fig. 3. Concentration profiles of DC and photoproducts in the specialty Voltaren
Emulgel® 1% from MCR elaboration.
3.2. Photodegradation of the commercial specialties
Fig. 2. Concentration profiles of DC (20.43 g ml−1 ) and photoproducts (a) and relative absorbance spectra (b) from MCR elaboration.
two by-products (PhP2 and PhP3 ). The spectra of these compounds
were in accordance with those reported in the HPLC study by Zhang
et al. (2011). Fig. 2 shows the concentration profiles (Fig. 2a) of
DC and photoproducts and their absorbance spectra (Fig. 2b). The
relative standard deviation values of all the points resulted ranging
in the interval of 1.92–6.01%.
The profile of photodegradation kinetics was hypothesized
according to two consecutive reactions, with a mechanism postulated as DC > PhP1 > PhP2 . A third photoproduct PhP3 was
also revealed in the first 10 min of irradiation but its content decreased until to a complete disappearance after about
40 min. Salgado et al. (2013) reported PhP1 corresponds to
the decarboxylated product (E)-6-[2,6-dichlorophenyl)-imino]-3oxocyclohexa-1,4-dienecarbaldehyde.
A full degradation of DC was observed after about 44.01 min. The
degradation process proceeded via first-order kinetics, described
by the following equation:
The fast photodegradation of DC in solution suggested to extend
the study to the semi-solid specialties containing this drug. Two
commercial formulations with DC concentration 1% and 2%, respectively, were exposed to forced degradation and then analyzed at
various times as above described. A clear degradation of the drug
was showed and degradation kinetics of first-order was confirmed.
In particular, the values of t0.1 resulted 4.38 and 6.22 min for DC formulations at 1% and 2%, respectively. These experiments confirmed
the high rate of degradation for both gel and its increase when the
initial concentration of DC decreased, in accordance with Zhang
et al. (2011). The specialty at 2% also contained butylated hydroxytoluene (BHT) as an excipient, usually used in pharmaceuticals
for its antioxidant properties (Hocman, 1988). The better results
obtained in photostability of this formulation was probably due
also to the presence of this component. The complete disappearance of the drug was observed at 182.7 and 264.7 min for 1% and 2%
formulations. MCR application to these data confirmed the formation of PhP1 as the main photoproduct. On the contrary, PhP2 was
formed in minor amount while PhP3 was revealed only in traces, as
shown in Fig. 3.
As the photodegradation of the drug may be affected by the
mode and the amount of the spread formulation, the influence of
the thickness of the gel layer was also tested. For this aim, the 1%
gel was spread uniformly over four glass plates to form layers of
0.25–0.50–0.75 and 1.0 mm thickness.
The thickness of the gel was selected by using a purpose-built
device. Two sheets of aluminum with a known thickness 0.25 mm
were placed on a glass surface at a distance of 2 cm (Fig. 4). The
gel was then layered on the glass by sliding a steel spatula on the
aluminum sheets. Higher thicknesses were made by overlapping
the aluminum sheets to each other up to a maximum thickness of
1 mm.
log[%DC] = −k1 · t + 2
where %DC is the percentage of residual drug, k the photodegradation rate constant, t the time (min), and 2 the logarithm of the
starting concentration (100%).
The parameter t0.1 (time to cause 10% degradation) was chosen
as a criterion to compare the degradation behavior of the tested
samples. This parameter is conventionally adopted because a drug
can no longer be used when its purity falls below 90%. The value of
k1 was 0.0681 and t0.1 resulted to be 2.52 min, corresponding to a
radiant exposure of 68 kJ m−2 .
Fig. 4. Device for gel layering.
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Fig. 5. Influence of the gel layer thickness on DC photodegradation after 60 min of
light irradiation.
These samples were submitted to forced irradiation and analyzed up to 60 min. As shown in Fig. 5, the degradation decreased
with increasing layer thickness, most likely for a simple physical
effect of shielding the light. The layer thickness of 0.25 mm was
so adopted for further photodegradation experiments in order to
maximize the amount of drug exposed to light.
3.3. Photodegradation of DC–UV absorber gel
Photodegradation of DC could involve not only the reduction of
the therapeutic dose but also the formation of secondary products
with unknown activity for health. For this purpose, new semi-solid
preparations containing DC were designed to reduce drug photodegradation.
In the recent years, the employment of UV filters added to topical
formulations is one of the efficacious strategies proposed to prevent contact photosensitivity and drug photodegradation (Atarashi
et al., 2012; Gaspar and Maia Campos, 2007). Among the various
UV absorbers proposed in the literature, BP, OC, OS and OMC were
selected to be added to the DC gel because of the overlap of their
absorption spectra with that of DC. These formulations were prepared as described in the experimental part, with the filter content
in the range 0.25–5%. As a control sample, a standard DC gel was
prepared with DC at 1%. All gel formulations were then exposed to
forced degradation up to 60 min and the residual drug analyses was
then carried out.
The standard gel presented a DC residual of 19.50%, whereas
photostability resulted influenced in different manner for the other
samples. Fig. 6 shows the drug percentage residue in the samples
containing the absorbers at the various concentrations.
Fig. 7. Phase-solubility diagram of the DC–cyclodextrin complexes.
The OS and OMC samples showed a clear increase of the photostability for the absorber concentration 0.5% with a residual DC
concentration of 64% and 68%, respectively. However, these values
remained constant for the samples with higher content of these
absorbers. Unsuccessful results were on the contrary carried out for
the other absorbers BP and OC that showed no significant improvement of the drug stability. This behavior has been reported as a
consequence of photochemical reactions of these molecules, such
as trans-cis isomerization or keto-enol tautomerism (Kockler et al.,
2012) or, moreover, production of by-products after light irradiation (Shaath, 2010).
The degradation process of the DC control sample was confirmed to follow the first-order kinetics. The samples containing
the absorbers instead showed a different behavior. By plotting the
drug percentage concentration against degradation time, a second
order kinetics was observed with straight lines according to the
equation:
1
= k2 · t + 0.01
DC%
where DC% is the percentage of the residual drug concentration, k2
the photodegradation rate constant, t the time (min) and 0.01 is the
reciprocal value of the starting concentration percentage (100%).
MCR-ALS analysis predicted the formation of PhP1 and only
traces of PhP2 and PhP3 . The rate constants and the t0.1 values of the
0.5% absorber formulations were carried out. Successful t0.1 values
of 12.22 min and 13.75 min for OS and OMC, respectively, were calculated showing a notable increase in comparison with a value of
3.90 min measured on the control gel.
As more than one UV-filter is nowadays used in cosmetic preparations (Chatelain and Gabard, 2001; Gaspar and Campos, 2006;
Lhiaubet-Vallet et al., 2010), the combination of OS and OMC was
also verified in affecting photoprotection. Three formulations with
OS/OMC ratio between 0.5 and 2 were tested, but the results did
not show significant additive or synergistic effects.
The best t0.1 value of 15.71 min was measured on the OS/OMC
formulation containing both 0.5%.
3.4. Photodegradation of DC–cyclodextrin gel
Fig. 6. Influence of UV absorber concentration on DC photodegradation after 60 min
of light irradiation.
The entrapment of DC in cyclodextrin was afterwards investigated to minimize light sensitivity of the drug and, at the same time,
to enhance drug solubility in water.
First, the influence of ␣C, C, mC, and ␥C on solubility of DC was
tested as described by Higuchi and Connors (1965). The behavior of
DC in the different cyclodextrins is shown in the phase-solubility
diagram reported in Fig. 7.
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The photodegradation profile of the complex followed secondorder kinetics and was compared in Fig. 8 to that of 1% DC control
sample and 1% commercial specialty.
Table 1 summarizes the degradation rate constants and the values of t0.1 for all the studied matrices.
All results were averages of six experiments. The relative
standard deviation values of all the points resulted ranging in the
interval 2.03–4.99%.
4. Conclusions
Fig. 8. Photodegradation profile of DC in gel control, Voltaren Emulgel® 1% and
C-DC gel.
The most effective cyclodextrin in increasing the solubility of
DC was C. A linear relationship between solubility and C concentration was observed with R2 equal to 0.997. This result was
in agreement with an almost 1:1 inclusion complex (Higuchi and
Connors, 1965). The binding constant (Kb ) of the complexes was
calculated according to the following equation:
Kb =
slope
× (1 − slope)
SDC
where SDC is the solubility in water of DC at 25 ◦ C. The values of Kb ,
expressed as M−1 , followed the order C-DC (1361.32), mC-DC
(484.76), ␣C-DC (33.51), and ␥C-DC (21.83). The higher solubility of
C-DC and mC-DC complexes can be explained by a better fitting
of the drug molecule in the cavity of these cyclodextrins, whereas
␣C seems to have a cavity too small and ␥C, conversely, too large.
C was finally selected to incorporate DC in the preparation of the
gel to be submitted to the photostability test.
The C-DC gel, with DC concentration at 1%, was prepared
as above described and then submitted to the stressing test. DC
residue along the experiments was each time assayed after appropriate dilution of 100 l of C-DC to 10 ml with methanol, in such
a way to assure the drug release. The results from the stress testing
showed a clear decrease of DC degradation, with a very successful
t0.1 value of 25.01 min. The very good performance of this formulation in terms of photostabilization could be attributed to a dual
action of the cyclodextrin complex: a real physical protection of
the entrapped drug by means of a molecular shield (Bayomi et al.,
2002; Mielcarek, 1997) aided by the increase of the drug solubility
in this matrix.
Table 1
Degradation kinetics parameters of DC in different matrices.
Matrix
k1
R2
t0.1
Methanol solution
Voltaren Emulgel® 1%
Voltaren Emulgel® 2%
Standard gel
0.0681
0.0105
0.0074
0.0118
0.978
0.968
0.998
0.979
2.52
4.38
6.22
3.90
BP-DC gel
OS-DC gel
OC-DC gel
OMC-DC gel
OS 0.25/OMC 0.50 gel
OS 0.50/OMC 0.50 gel
OS 0.50/OMC 0.25 gel
C-DC gel
k2
0.0006
0.00009
0.0004
0.00008
0.00006
0.00007
0.00006
0.00004
R2
0.992
0.950
0.961
0.951
0.977
0.967
0.952
0.938
t0.1
1.83
12.22
2.75
13.75
13.92
15.71
13.87
25.01
t is expressed as min.
In this work, the anti-inflammatory drug diclofenac in
commercial gel formulations was demonstrated to undergo
photodegradation. The study was performed by adopting photostability tests defined by international rules. In particular, under
an irradiance power of 450 W m−2 , corresponding to 27 kJ m−2 min
and at a constant temperature of 25 ◦ C, the drug resulted degraded
of 10% in 4.38 min and 6.22 min in 1% and 2% formulations, respectively. The design of photoprotective pharmaceutical matrices for
topical application is particularly important for the greater likelihood of exposure to light with the result of reducing the available
drug and at the same time increasing the risk of formation of toxic
photoproducts. Two different approaches were adopted to reduce
drug photodegradation by incorporation in gel of UV-absorbers
and by entrapping the drug in cyclodextrins. The use of the octisilate or octyl methoxycinnamate as excipients gave good results by
increasing the drug photostability of 1% gel to 12.22 and 13.75 min.
Better results were carried out by incorporating the drug in cyclodextrin, increasing this value up to 25.01 min, corresponding
to a stability increase of almost six times. The systems proposed
here appear to be of certain interest for the development of new
pharmaceutical formulations for topical use of diclofenac, able to
minimize the photodegradation of the drug.
Acknowledgment
This research was supported by grants from M.U.R.S.T. (Italy).
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Gaetano Ragno
Lorena Tavano