Applied Clay Science 53 (2011) 374378

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Applied Clay Science

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l a y

Research Paper

Intercalation and release of antiinammatory drug diclofenac into nanosized ZnAl

hydrotalcite-like compound
L. Perioli a, T. Posati b, M. Nocchetti b,, F. Bellezza b, U. Costantino b, A. Cipiciani b,
a
Dipartimento di Chimica e Tecnologia del Farmaco, Universit degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy
b
CEMIN - Centro di Eccellenza Materiali Innovativi Nanostrutturati, Dipartimento di Chimica, Universit degli Studi di Perugia, via Elce di Sotto 10, 06123 Perugia, Italy

a r t i c l e i n f o a b s t r a c t

Article history: A nanostructured hydrotalcite-like compound of formula [Zn0.72Al0.28(OH)2] Br0.280.69 H2O has been used as
Received 12 November 2009 inorganic layered host of the anionic form of diclofenac (DIK), a Non Steroidal Antiinammatory Drug. The
Received in revised form 24 June 2010 obtained intercalation compound has been characterized by chemical analysis, X-ray powder diffraction pattern,
Accepted 30 June 2010
thermogravimetrical analysis and SEM and TEM microscopy. The nanohybrid ZnAl-DIK, with empirical formula
Available online 10 July 2010
[Zn0.72Al0.28(OH)2]DIK0.281.35 H2O and interlayer spacing 22.5 , was made up of submicrometric hexagonal
Keywords:
platelets. The drug loading was 41.8% w/w. The material was submitted to in vitro drug release studies using three
Nanoparticles different simulated intestinal media. The release proles were tted by mathematical models describing various
Hydrotalcite kinetics in order to investigate the drug release mechanism. The results were compared to literature data
Diclofenac obtained with micro-sized MgAl-DIK.
Drug release 2010 Elsevier B.V. All rights reserved.
Kinetics

1. Introduction mol of solvent S (generally water) intercalated per formula weight of

In recent years, considerable attention has been focused on synthesis
of new materials, namely nanocomposites, to be employed as carriers of
proteins, DNA, drugs and more in general active products. Nanocompo-
sites can be dened (Ajayan et al., 2003) as multiphase solid materials
where one of the phases has one, two or three dimensions of less than
100 nanometers, or structures having nano-scale repeated distances
between the different phases that make up the material.
In the broadest sense this denition can include colloids, gels,
copolymers, porous media, and inorganic layered materials as clays.
These latter inorganic materials can exist in great variety and possess
well dened, ordered inter lamellae space potentially accessible by
foreign species. This ability allows them to act as matrices or hosts for
organic molecules, yielding interesting hybrid nano-composite materi-
als (Choy et al., 2009a). The general class of organic/inorganic
nanocomposite materials to be used as drug and biological active
species carries is a fast growing area of research and synthetic
hydrotalcite (HTlc) hybrids are mainly investigated.
Synthetic HTlc have general formula [M(II)1-x M(III)x (OH)2] x+
[An- x/n]x-.mS, where M(II) is a divalent cation (typically Mg, Zn, Ni, Co),
M(III) is a trivalent metal cation (Al, Fe, Cr), x is M(III)/M(III)+ M(II)
molar ratio and generally ranges between 0.2 and 0.4 and determines the
positive charge density and hence the anion exchange capacity, An- is an
inorganic or organic or organo-metallic anion of charge n-, and m are the
Corresponding authors. Tel.: + 39 0755855540; fax: + 39 0755855560.
E-mail addresses: nocchett@unipg.it (M. Nocchetti), cipan@unipg.it (A. Cipiciani).
compound (Trir and Vaccari, 1996; Jones and Newman, 1998; Rives,
2001; Khan and O'Hare, 2002; Leroux and Taviot-Guho, 2005).
HTlc based on Mg/Al and Zn/Al, together with the possibility to
produce a large number of hybrid materials by changing the nature of
An- via anion exchange procedure, possess other important properties
such as low toxicity, good biocompatibility and possibility to control the
guest release, accounting for the incessant interest to their development
for application in pharmaceutical, cosmetic and medical elds.
For example, Carretero et al. (2007) and Frunza et al. (2007) have
recently reported the intercalation of salycilate in ZnAl-hydrotalcites,
and this matrix has been also used in cosmetic eld to prepare new
sunscreen products (Perioli et al., 2006a, 2006b, 2008; Costantino et al.,
2008). Furthermore, MgAl hydrotalcite-like compounds have found
application in medicinal chemistry as antacids (Lin et al., 1998; Linares
et al., 2004; Konturek et al., 2007), and as hosts for intercalation of
molecular drug anions with the aim to study these intercalation
compounds for storage, transport and ultimately controlled release of
drugs (Ambrogi et al., 2001, 2002, 2003; Choy et al., 2001; Costantino
and Nocchetti, 2001; Del Arco et al., 2004; Dupin et al., 2004; Li et al.,
2004; Mohanambe and Vasudevan, 2005; Williams and O'Hare, 2006,
Del Hoyo, 2007; Perioli et al., 2007; 2008; Costantino et al., 2008, 2009a,
2009b; Rives et al., 2009).
Most of above cited papers deals with the intercalation and release of
non steroidal anti-inammatory drugs (NSAID) which are aromatic
organic compounds with easily ionizable carboxylate groups. Upon
intercalation the apparent drug solubility increases (Ambrogi et al.,
2003); moreover the hydrotalcite matrix has shown barrier properties
similar to those of gastric mucus and may provide mucosal protection to

0169-1317/$ see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.clay.2010.06.028
 L. Perioli et al. / Applied Clay Science 53 (2011) 374378
the side effect of the drug (Grubel et al., 1997). Thanks to the particular
interaction of drug with the mucus network, its co-administration with
hydrotalcite can ensure not only a protective effect, but also improve the
drug permeability through gastric mucus as observed for paracethamol
(Shaw et al., 2005), urbiprofen (Perioli et al., 2006c) and indomethacin
(Del Arco et al., 2004).
The MgAl and ZnAl-HTlc used as precursors in these studies are
generally obtained by co-precipitation or urea methods (de Roy et al.,
2001) that produce microcrystalline powders having a particle size in
the 1-5 m range. At our knowledge, there are no studies on the effect
of the particle dimension on the uptake and release of a NSAID, apart
from a recent paper of Choy et al. (2009b) that deals with the effect of
nanoparticle size on the cellular uptake rate of MgAl hydrotalcites.
Recently, zinc aluminium hydrotalcite nanoparticles, presenting
uniform size (150 50 nm), have been prepared and characterized in
our laboratories (Bellezza et al., 2009). It seemed of interest to use
these nanosized HTlc for the intercalation and release of diclofenac,
chosen as a representative example of NSAID.
This paper reports studies on preparation and characterization of an
intercalation compound of nanosized ZnAl hydrotalcite-type material
containing the anionic form of diclofenac (DIK) in the interlayer region
and on the surface of the nanoparticles. The samples have been prepared
by anion exchange procedure and characterized by different physico-
chemical techniques to choose the optimum experimental conditions to
obtain pure samples with a high drug loading. The drug release from the
obtained nanocomposite was followed in three different simulated
intestinal media. The release prole data were tted by mathematical
models describing various kinetic mechanisms and compared with
those obtained with micro-sized MgAl-HTlc.
2. Experimental part
2.1. Materials
[Zn0.72Al0.28(OH)2] Br0.280.69 H2O was obtained as previously
described (Bellezza et al., 2009). Briey, for the reader convenience, two
microemulsions designated A and B were prepared by dispersing 12.5 g
(0.034 mol) of CTABr and 15.5 mL (0.169 mol) of n-butanol in 36.2 mL
(0.219 mol) of isooctane. The aqueous phase of A was a solution of Zn
(NO3)2 6H2O (0.4 M) and Al(NO3)3 9H2O (0.125 M), while the aqueous
phase of B was a NH3 solution (1.25 M). Equal volumes of the two
microemulsions, A and B, were mixed to obtain the precipitation of ZnAl
hydrotalcites in the reverse micelles. The resulting system was stirred at
room temperature for 15 min, after which it became cloudy and was
aged at 75 C for 15 h. After aging, the particles were recovered by
centrifuging (12000 rpm for 10 min), and a semitransparent gel was
obtained. The gel, was washed with isooctane (1 30 mL), with water
(2 30 mL), and a methanol chloroform mixture (1:1 v/v) (3 30 mL)
and then dried at 60 C under oil pump vacuum to give a ne powder.
Diclofenac sodium salt (DIK Na) was purchased from Sigma
Chemical Company. Other chemicals and solvents were of reagent
grade and were used without further purication.
2.2. Intercalation of DIK into HTlc
Intercalation reactions were performed by equilibrating 1 g of ZnAl-Br
with 46 mL of a hydroalcoholic (50% vol/vol) solution 0.1 M of DIK Na (Br-/
DIK- molar ratio 1:2) under a nitrogen atmosphere at 60 C for 2 days.
After cooling, the mixture was centrifuged with an AllegraTM 64R Centri-
fuge (Beckman Coulter) at 12000 rpm for 10 minutes. The residue was
washed 3 times with carbon dioxide-free water and nally dried at 50 C.
2.3. Characterization
Metal analyses were performed by Varian 700-ES series Induc-
tively Coupled Plasma-Optical Emission Spectrometers (ICP-OES)
375
using solutions prepared by dissolving the samples in some drops of
concentrated HNO3 solution and properly diluted.
The intercalation compound morphology was investigated with a
Philips XL30 Scanning Electron Microscope (SEM). A drop of the
aqueous hybrid dispersion was deposited on a holder and the solvent
was evaporated at room temperature. The samples were metallized
with gold.
Moreover, the same dispersion was analyzed with a Philips 208
Transmission Electron Microscope (TEM). A small drop of the
dispersion was deposited on a copper grid pre-coated with a Formvar
lm and then evaporated in air at room temperature.
The X-ray powder diffraction (XRPD) patterns were taken with a
Philips X'PERT PRO MPD diffractometer operating at 40 kV and 40 mA,
step size 0.0170 2Theta degree and step scan 20 s, using the CuK
radiation and an X'Celerator detector.
Coupled thermogravimetric (TGA) and differential thermal (DTA)
analyses were performed with a Netzsch STA 449C apparatus, in air
ow and heating rate of 10 C/min.
2.4. Release of DIK from HTlc-DIK
Drug release studies were performed in the dissolution apparatus
F.U. XII paddle type (Steroglass, Perugia, Italy). The paddle rotation
speed was 60 rpm and the vessels were kept in a thermostatically
controlled circulation water bath at 37.0 0.5 C. The dissolution
media were a) simulated intestinal uid at pH 7.5 0.1 without
pancreatine according to U.S.P. XX, b) phosphate buffer at pH 7.0 0.1
according to F.U. XII, and c) a solution designed to mimic the ionic
condition present in the small intestine (Randall Holmes-Farley et al.,
1997) (20 mM sodium hydrogen phosphate, 80 mM sodium chloride,
30 mM sodium carbonate and some drops of concentrated hydro-
chloric acid solutions to get pH 7.0 0.1). Successively these media
will be indicated as a, b and c, respectively.
The release studies were done by placing 667 mg of HTlc-DIK
(containing 280 mg of diclofenac) in 1000 ml of medium under sink
conditions. Samples of 4 ml were withdrawn at predetermined
intervals, followed by replenishment after each withdrawal with the
same volume of fresh medium equilibrated at 37.0 0.5 C. Samples
were appropriately ltered (lter type: 0.22 m, white GSWP, 25 mm,
MILLIPORE 13 mm), diluted when necessary and analysed by UV
spectrophotometry (Agilent 8453) at max = 276 nm according to
previously determined calibration curves (y = 0.00173 + 10.1575x,
r = 0.9998 for a and b; y = 0.00743 + 10.2154x, r = 0.9999 for c). The
percentage released at each time point was expressed as a fraction of
the total amount of diclofenac. Drug release was monitored for
24 hours; diclofenac concentration was reported as an average of 3
determinations and the error expressed as standard deviation (S.D.).
3. Results and discussion
The nanostructured ZnAl-HTlc has been synthesized with the
double microemulsion technique (Bellezza et al., 2009) that allows
HTlc nanoparticles to be obtained in form of stable gel and containing
bromide as balancing anions. The presence of easily exchangeable
bromide ions makes the functionalization of the inorganic matrix with
other guest species relatively simple.
To obtain the intercalation of DIK anions, the nanosized HTlc with
formula [Zn0.72Al0.28(OH)2]Br0.28 0.69 H2O has been equilibrated with
hydroalcoholic solution 0.1 M of DIK Na (see experimental part). Fig. 1
shows X-ray powder diffraction pattern of the obtained nanohybrid
ZnAl-DIK and that of the pristine ZnAl-HTlc for comparison. The
interlayer distance of the bromide form (8.06 ) increases to 22.5 in
the intercalation compound; this value is in good agreement with that
of conventional MgAl-DIK hydrotalcite (Ambrogi et al., 2002, 2003).
The TG curve (Fig. 2) of ZnAl-DIK shows in the temperature range 25-
250 C a weight loss of 21.4% of the initial sample mass due to three
376 L. Perioli et al. / Applied Clay Science 53 (2011) 374378

Fig. 1. X-ray powder diffraction patterns of the ZnAl-HTlc precursor in bromide form (a)
and of the ZnAl-DIK intercalation compound (b).

endothermic processes, namely removal of surface adsorbed water,

removal of co-intercalated water and water loss due to the de-
hydroxylation of the brucitic layers. The DTA curve shows, between 250
and 600 C, an intense exothermic peak due to DIK combustion (loss of
41.7% of the initial sample mass). Known the Zn/Al molar ratio and taking
into account that ZnO and ZnAl2O4 are formed at 1000 C, it was possible
to assign the following composition to the intercalation compound:
[Zn0.72Al0.28(OH)2]DIK0.281.35 H2O (DIK content 41.8% w/w).
The morphology and size of ZnAl-DIK nanohybrid have been
estimated from SEM and TEM analyses (Fig. 3). It should be noted the
presence of small hexagonal platelets having a diameter of about
200 nm together with some larger platelets (about 350 nm), likely
Fig. 3. SEM (a) and TEM (b) micrographs of the ZnAl-DIK intercalation compound.
due to the formation of aggregates.

3.1. In vitro drug release studies
In vitro drug releases were performed in a phosphate buffer at pH 7.5
(medium a), in a phosphate buffer at pH 7.0 (medium b) and in a
phosphate buffer at pH 7.0 containing sodium chloride and sodium
carbonate (medium c), in order to mimic the small intestine environment.
The proles are reported in Fig. 4. It is possible to note that the
drug release prole at pH 7.5 (a) was higher than those obtained in
the other two media (b and c), which are similar.
In the rst case (a), the drug release from ZnAl-DIK was 55% after
15 min, 65% after 30 min, 80% after 1 hour, 86% after 3 hours, 90% after
8 hours and almost complete after 24 hours. This prole was charac-
terized by a clear burst effect during the rst hour and a slow release
from rst to 24th hour. The rst part of release can be explained with the
liberation of DIK anions taken up on the surface of the nanocrystals and
those intercalated at the edges of the interlayer regions.
The residue was recovered from the vessel by centrifugation at the
end of the release experiment. It was dried and submitted to X-ray
powder diffraction analysis. The absence of the DIK phase reections
and the lost of the crystallographic order (data not shown) indicate
the complete drug release.
The proles b and c were similar (Fig. 4) and the drug release was 18-
22% after 15 min, 27% after 30 min, 34-40% after 1 hour, 50-58% after
3 hours, 62-67% after 8 hours and 72% after 24 hours. It is remarkable
that after 24 hours the DIK anions were not completely exchanged even
when Cl- and CO2-3 species, characterized by a very high afnity for HTlc,
are also present in the medium.

Fig. 2. TG and DTA curves of ZnAl-DIK. (Operative conditions: 10 C/min heating rate,
air ow). Fig. 4. Release curves of DIK from ZnAl-DIK in different conditions (a, b and c, see text).
 L. Perioli et al. / Applied Clay Science 53 (2011) 374378 377

XRDP of the recovered material, as above described, showed a residue
DIK phase (data not shown). Since Cl- and CO2- 3 anions are not able to
displace completely the organic guests from the interlayer spaces, another
important reason should be responsible for the release interruption.
The incomplete and slower release of antiinammatory drug at pH
7.0 value, in comparison to that at pH 7.5, can be explained on the basis
of higher concentration of di-hydrogen phosphate specie in the
medium. At this pH value, H2PO-4 specie is the prevalent form and its
presence is more important than the Cl- and CO2- 3 incidence. The acidic
H2PO-4 anions, in fact, can react with hydroxyl groups of HTlc producing a
layered zinc and aluminum hydroxyphosphate, by a solid state grafting
reaction (Costantino et al., 1997). As described for the system HTlc-
urbiprofen (Perioli et al., 2007), the strong bonds between the grafted
phosphates and layers are able to stop the ion exchange mechanism and
to cause the obstruction of HTlc galleries, entrapping the diclofenac
anions into the internal part of interlayer region.
Dissimilar behaviours at these different pH values were observed
also in the case of HTlc-DIK microparticles (Ambrogi et al., 2002).
The DIK release can be controlled rst by the diffusion through the
hydrotalcite interlayer region (particles diffusion) and then by diffusion
through the stagnant layer and bulk solution surrounding the particle
(lm diffusion). Generally, the drug release rate may be affected by both
steps. When the ion-exchange mechanism controls the diffusive process
from the crystals to the medium uid, the particles diffusion appears to
be the rate limiting step.
3.2. In vitro drug release kinetics: mathematical models
In order to investigate the exact mechanism of drug release from the
matrix, the release prole data were tted by mathematical models
describing various kinetics. Firstly, the Ritger and Peppas's kinetics
mathematical model equation Mt/M = Ktn (where Mt/M is the
fraction of drug released at time t, and K a constant) (Ritger and Peppas,
1987) was applied to evaluate the diffusional exponent (n) (Table 1).
When its value is 1, the drug release occurs as an apparent zero-order
mechanism (transport case II), not dependent on time; for 0.5 value the
release is controlled by a pure Fickian diffusion mechanism, while a
value between 0.5-1 indicates an anomalous mechanism (not Fickian).
Since a mechanism of ion-exchange is involved in the presence of HTlc,
Bhaskar equation (Bhaskar et al., 1986) was applied in order to establish
if the diffusion from the particle to the medium uid is the rate limiting
step (Table 1); nally, rst order kinetic was investigated.
From the observation of the correlation coefcient (r) values,
showed in Table 1, it is evident that the drug release mechanisms are
the same in all cases (a, b and c).
The release proles, in fact, showed lower r values for n = 1 meaning
that the drug release rate is a function of time. This is conrmed by the
increase of r value from n = 1 to n = 0.5 demonstrating that the diffusion
(Fickian type) from the particle to the medium uid is controlling
the drug release. Particularly, in the case of Higuchi model (n= 0.5,
release window until 60%) the best linearity was obtained (prole
(a) r = 0.9860; prole (b) r = 0.9895; prole (c) r = 0.9839).
It is noteworthy to underline that the Bhaskar equation tting
produces r values higher than those of Higuchi suggesting that drug
diffusion through HTlc is not passive but strictly controlled by matrix.
HTlc is a particular matrix; it could be able to control guest release by
two processes: i) chemical, due to the selectivity towards different
anions and ion-exchange mechanism, ii) physical, due to the length of
the obliged ways of galleries. In this case the rst process plays the key
role for all release time.
The physical control is negligible in the initial part of the process
because the release of the rst DIK species begins from external part of
the particle and they reach the stagnant layer in a short time. The release
of internal species needs long paths; in the nanosized ZnAl-HTlc
particles the galleries are short so the release of internal DIK guests takes
shorter time to achieve the boundary phase (solid-liquid) and to
dissolve in the medium. The reduction of the distance to achieve the
external part of the crystals in the nanosized particles in comparison to
bigger size particles (Ambrogi et al., 2002) is the only aspect which
inuences the drug release rate.
By comparing r values obtained by Bhaskar kinetics model with those
obtained by rst order kinetics, it is evident that DIK release depends on
diffusive mechanism from the particle to the medium uid and not on the
drug concentration in the matrix. Therefore, the drug concentration is not
the driving force conrming further a no passive diffusion.
3.3. Drug release from nano- and micro-HTlc-DIK
In order to study the effect of the particle size on the DIK release,
the (a), (b), and (c) proles obtained with nanosized ZnAl-DIK were
compared with literature data reported by Ambrogi et al. (2002) with
micro-MgAl-DIK and carried out in the same experimental conditions.
The (b) and (c) proles obtained with nano-ZnAl-DIK and the prole
obtained with micro-MgAl-DIK performed at pH 7.0, are very similar
conrming the key role of the high selectivity of HTlc towards H2PO-4
species and of the ion-exchange mechanism, ruining the particles size
effect.
On the other hand, the release proles at higher pH value (7.5) show
different guest release times within the rst hours (DIK released from

Table 1
Mathematical model tting of release data.

Equations Phosphate Buffer Phosphate Buffer Buffer Na2HPO4/NaCl/Na2CO3

pH 7.5 (a) pH 7.0 (b) pH 7.0 (c)

Mt/M = Ktn n = 1 (zero order) y = 0.8941x + 31.856 y = 0.1087x + 24.406 y = 0.1968x + 20.25
r = 0.9088 r = 0.9307 r = 0.9145
n = 0.9 y = 1.4001x + 29.473 y = 0.2022x + 22.965 y = 0.3529x + 18.438
r = 0.9188 r = 0.9439 r = 0.9279
n = 0.8 y = 2.2106x + 26.48 y = 0.3779x + 21.221 y = 0.6364x + 16.21
r = 0.9286 r = 0.9565 r = 0.9410
n = 0.7 y = 3.5302x + 22.614 y = 0.7106x + 19.042 y = 1.1566x + 13.389
r = 0.9382 r = 0.9680 r = 0.9535
n = 0.6 y = 5.728x + 17.435 y = 1.3501x + 16.21 y = 2.1268x + 9.6761
r = 0.9475 r = 0.9784 r = 0.9651
n = 0.5 y = 9.5117x + 10.15 y = 2.6076x + 12.33 y = 3.9824x + 4.5319
r = 0.9562 r = 0.9871 r = 0.9756
n = 0.5 (Higuchi 0-60% release) y = 3.3x + 7.1111 y = 2.7127x + 11.518 y = 4.6698x + 0.4992
r = 0.9860 r = 0.9895 r = 0.9839
-kt 0.65
Mt/M = 1-e ionic exchange (Bhaskar) y = -0.0472x - 0.0232 y = -0.0073x - 0.0695 y = -0.0117x - 0.0322
r = 0.9878 r = 0.9918 r = 0.9852
-kt
Mt/M = 1-e rst order y = -0.0096x - 0.1405 y = -0.0008x - 0.1172 y = -0.0015x - 0.0938
r = 0.9710 r = 0.9637 r = 0.9546
378 L. Perioli et al. / Applied Clay Science 53 (2011) 374378
nano- and micro-HTlc: 55% and 38% after 15 min.; 80% and 53% after
60 min., respectively).
The decrease of the particle sizes determines the increase of the
crystal edges and of the amount of intercalated species in the
nanocrystal external part. Moreover, the diffusion of the anions through
the ZnAl nanoparticles is faster than that through the micro-particles
due to the decrease of the length of the HTlc galleries. The above
considerations allow afrming that the guest release time from HTlc,
within the rst hour, depends on the particle sizes. After the burst effect,
the nano- and micro-HTlc-DIK proles are similar.
4. Conclusions
The present paper deals with nanosized hydrotalcite-type materials
(zinc and aluminium) containing the NSAID diclofenac in the interlayer
spaces. After characterization and drug loading determination, these
nanoparticles were submitted to in vitro drug release studies in order to
compare their proles with those obtained from HTlc-DIK microparti-
cles (having a bigger size) and to understand the mechanism governing
the drug liberation.
Release tests demonstrated a complete drug release when carried
out in medium at pH 7.5 and a not complete release when performed in
two different media at pH 7.0. The behaviour of studied materials seems
to be more sensible to H2PO-4 acidic species than CO2- -
3 and Cl anions.
The release proles were rather similar to those obtained in presence
of the microparticles suggesting that the HTlc particles size is not the
main control factor; the ion-exchange mechanism is the most
responsible for drug liberation and this hypothesis is conrmed by
highest r values (best tting) obtained in the case of Bhaskar model
(resinate model).
In vitro release studies can furnish much information on materials
but cannot predict the real behaviour in vivo conditions, if it will be
administered. Moreover it is possible to suppose that the ZnAl-HTlc
nanostructured materials could offer some advantages as i) improve-
ment of solubilization and adsorption rates, ii) protection of gastroin-
testinal mucus from ulcerogenic activity, typical of NSAID as DIK.
Acknowledgments
The authors wish to thank Mr. Marco Marani for the precious
collaboration and technical assistance.
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