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Abstract
Non-steroidal antiinflammatory drugs, such as ibuprofen, are amphiphilic substances capable of self-association in aqueous solutions and
able to be sorbed onto polymers through hydrophobic and electrostatic bonds. The aim of this work was to analyze the association processes
of sodium ibuprofen with cationic celluloses (Celquat® H-100 (PQ-4) and SC-230M (PQ-10)) and cationic guar gums (Ecopol® 261-S and
14-S) and their repercussions on the properties of the aqueous dispersions and cross-linked hydrogels. The interaction process was studied
in aqueous dispersions through transmittance, surface tension, fluorescence, conductivity, viscosity and oscillatory rheometry measurements.
Below cmc, the drug molecules weakly interact with the polymers through hydrophobic and ionic interactions. Around the cmc (4%), a
notable decrease in the viscosity, and storage and loss moduli of the dispersions (even precipitation in PQ-10 systems) was observed. An
additional increase in drug concentration induced the dispersions to recover their initial properties. Since ibuprofen/polymer cationic groups
ratio were in all cases above 1, these observations indicate that drug self-association induces the polymer to coil around the micelles and, as
the number of micelles increases (more drug concentration) the polymer chains interact with more of them, un- coiling again to some extent.
Polymer (1%) dispersions containing 6% ibuprofen showed drug diffusion coefficients much lower than in water. When a surfactant, sodium
dodecylsulfate, was added to these systems the diffusion coefficients decreased even more, suggesting the formation of new associative
structures. Chemically cross-linked hydrogels made of these cationic polysaccharides absorb consid- erable amounts of ibuprofen (up to 15
g/g) and showed a pH-dependent release process. At acidic pH, drug–polymer affinity is main- tained, preventing drug release. In contrast,
at pH 8 the interactions are broken and the release process is sustained for more than 4 h. In summary, ibuprofen interactions with
cationic polysaccharides strongly determine the performance of their aqueous dispersions and hydrogels.
© 2003 Elsevier B.V. All rights reserved.
Keywords: Amphiphilic drugs; Cationic cellulose; Cationic guar gum; Sodium dodecyl sulfate; Polymer–surfactant interactions
0928-0987/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2003.09.004
430 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438
and Hannan, 1977; Hoffman et al., 1996; Chronakis and Coulombic forces. These interactions may induce changes in
Alexandridis, 2001). Additionally, the high bioadhesive ca- the system which can be foreseen as useful to achieve an effi-
pacity (Gruber and Kreeger, 1996) and low toxicity (Annon, cient control of the release process from aqueous dispersions
1988) of hydrophilic cationic polysaccharides make them (Paulsson and Edsman, 2001; Jimenez-Kairuz et al., 2002)
particularly useful for preparing cosmetic preparations and or chemically cross-linked hydrogels (González-Rodr´ıguez
drug delivery systems able to combine long residence times et al., 2002; Rodr´ıguez et al., 2003a).
at the application site with adequate mechanical properties. The aim of this work was to analyze the association pro-
As classical surfactants, many kinds of drugs—i.e., tri- cesses of sodium ibuprofen with cationic celluloses and
cyclic antidepressants, þ-blockers, phenotiazine tranquiliz- cationic guar gums and their repercussions on the properties
ers, antihistamines, non-steroidal antiinflammatory drugs of the aqueous dispersions and cross-linked hydrogels. Two
(NSAIDs) and local anesthetics—are surface-active sub- varieties of cationic hydroxyethyl celluloses and two vari-
stances capable of self-association in aqueous solutions eties of cationic guar gums, differing in molecular weight
(Florence and Attwood, 1998; Taboada et al., 2001) and able and content and distribution of the cationic groups, were
to be sorbed onto polymers through hydrophobic and elec- used to evaluate the influence of polymer molecular struc-
trostatic bonds (Hugerth, 2001; Mura et al., 2003; Yomota ture. Additionally, the effect of the concomitant presence of
and Okada, 2003). The repercussions of these phenomena an anionic surfactant, sodium dodecylsulfate, which may
on the properties of polymer gels depend on the tendency compete with the drug for the binding to the polymer, was
of the drug to aggregate and on the strength of its interac- considered. Since NSAIDs are suitable candidates for incor-
tions with the polymer (Alvarez-Lorenzo and Concheiro, poration into polymer dispersions (physical gels) for topical
2003). In Carbopol® 1342 gels, alprenolol forms, at low application or into hydrogels that release them at the small
drug concentrations, micelle-like aggregates with the poly- intestine, minimizing the adverse gastric drug effects after
mer lipophilic residues, increasing the elastic and viscous oral administration (Dominkus et al., 1996), a preliminary
moduli of the gels. However, as the drug concentration is evaluation of the potential interest of the dispersions and
raised, the consistency decreases, the gel collapses and, hydrogels as drug delivery systems was also carried out.
when alprenolol amino groups neutralize the carboxylic acid
groups of the acrylic polymer, precipitation occurs
(Paulsson and Edsman, 2002). The changes observed in 2. Materials and methods
alprenolol diffusion rate are a consequence of both the
interactions with the polymer and the changes induced in 2.1. Materials
the viscosity of the systems. Interaction of phenothiazines
Polyquaternium-4 (PQ-4) (Celquat® H-100, batch FGS
(chlorpromazine, trifluoromazine, promazine, and promet-
1014) and Polyquaternium-10 (PQ-10) (Celquat® SC-230
hazine) with hyaluronate causes the gels made of this an-
M, batch GFS 1139) were provided by Na- tional Starch
ionic polymer to shrink; the minimum drug concentration
and Chemical Ltd., UK. Ecopol® 261-S (E-261, batch
required for that being proportional to the critical micellar
L10159215) and Ecopol® 14-S (E-14, batch L10159214)
concentration, cmc (Yomota and Okada, 2003). The po-
were from Economy Polymers & Chemi- cals, USA.
tential as periodontal drug delivery systems of non-ionic
Sodium ibuprofen, sodium dodecylsulfate and
cellulose ether–surface-active anesthetic drug gels was high-
ethyleneglycol diglycidylether (EGDE, 50 vol.% in water)
lighted by Scherlund et al. (2000). Lidocaine and prilocaine
were from Sigma–Aldrich Chemical Co., USA. Purified
do not interact with ethylhydroxyethyl cellulose (EHEC) or
water by reverse osmosis (MilliQ®, Millipore Spain) with
hydrophobically modified EHEC (HM-EHEC) but strongly
resistivity >1.82 MK cm was used. All other reactives were
affect their interactions with sodium dodecylsulfate and
of analytical grade.
myristoylcholine bromide. In consequence, the drug loaded
systems notably differed from polymer–surfactant disper- 2.2. Methods
sions in the storage and loss moduli.
Non-steroidal antiinflammatory drugs (NSAIDs), such as 2.2.1. Preparation of the dispersions
sodium ibuprofen, adsorb onto the non-ionic cellulose ethers Aqueous dispersions containing 1.0% (w/w) cationic cel-
non-cooperatively up to the cmc and cooperatively above lulose and a wide range of ibuprofen concentrations (0–8%,
this concentration (Ridell et al., 1999). Near cmc, ibupro- fen w/w) were prepared by dispersing the required amounts of
causes phase separation of EHEC dispersions, because of a each component in 100 ml of water under stirring. The sys-
strong hydrophobic interaction that shrinks the polymer tems were left to stand for 24 h before characterization. All
chains but, above cmc, micelles of ibuprofen solubilize the
studies were carried out at 25 ◦C.
hydrophobic parts of the polymer. The presence of apolar re-
gions and ammonium groups in the cationic polysaccharides 2.2.2. Cloudiness
could enhance the intensity of interactions with the aromatic The cloudiness of dispersions was determined by mea-
ring and the hydrophilic carboxylic group of NSAIDs, mak- suring transmittance at 800 nm (Shimadzu UV-240, Japan)
ing it possible to combine both hydrophobic association and against a blank of cationic polysaccharide dispersion.
R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438 431
2.2.3. pH magnetic rod. Samples (0.10 ml) were taken from the recip-
The measurements were made with a pH-meter Crison, ient compartment at intervals over a 10-h period, for deter-
model GLP22 (Spain), equipped with a sensor (Ag/AgCl) mination of ibuprofen on the basis of absorption at 273 nm
for viscous media no. 52-21. (Shimadzu UV-240, Kyoto, Japan); in each case, recipient
medium volume was immediately made up with iso-osmotic
2.2.4. Conductivity solution. Diffusion coefficients were estimated by non-linear
Conductance measurements were made in a rhadiometer regression applying the Higuchi (1962) equation
conductivity meter model CDM2e (Denmark) equipped with 1/2
2.2.5. Surface tension where Q/A is the amount of ibuprofen released per unit area
The measurements were made using the platinum ring at the time t, and C0 is the initial concentration of ibuprofen
method with a Lauda tensiometer TD1 (Germany) applying in the dispersion.
the necessary density corrections.
2.2.10. Hydrogel synthesis
2.2.6. Steady-state fluorescence measurements Hydrogels were synthesized as described previously
Pyrene (Py) emission spectra (λ=350–450 nm) were (Rodr´ıguez et al., 2003a). Briefly, EGDE (2 ml) was added
recorded in a Perkin-Elmer LS50B fluorescence spectropho- to a 3% cationic cellulose dispersion in 0.10 M NaOH
tometer (UK), with the excitation wavelength set to 310 nm medium (10 ml) or to a 2% cationic guar gum solution in
and slits set to 5 and 5, for excitation and emission, respec- 0.05 M KOH medium (10 ml). After stirring for 5 min, the
tively. The samples were prepared by the addition of polymer
mixture was transferred to a test tube of 10.5 mm i.d., and
(0.5% cationic celluloses or 0.1% cationic guar gums) and
hermetically closed. The tubes were kept at 60 ◦C for 6 h, in
ibuprofen (0.5–7%) to a pyrene aqueous solution (10−6 M)
the case of guar gums, and 24 h, in the case of cationic
and stored at 25 ◦C for 24 h. The ratio of the intensity at the celluloses. After cooling, the hydrogels were carefully re-
first (I1 at 373 nm) and the third (I3 at 392 nm) vibronic peaks moved and immersed in ultrapure water for 24 h to swell.
was used as an index of the local hydrophobicity of the The hydrogels were then transferred to HCl 0.1N solution
polymer–surfactant aggregates (Rodr´ıguez et al., 2003b). for 12 h to neutralize the basic medium, and finally kept in
ultrapure water for 1 week, changing the medium every 12 h
2.2.7. Viscosity to allow a complete wash out of non-reacted substances.
Determinations of apparent and specific viscosity were
carried out in Cannon-Fenske capillary viscometers (Afora, 2.2.11. Equilibrium swelling of hydrogels
Spain). After being immersed in ibuprofen solutions (as explained
below), equilibrium diameters d of pieces of cylindrical gels
2.2.8. Viscoelastic behavior were measured using a digital micrometer. The degree of
The rheological behavior of the polymer dispersions with swelling was expressed as
and without ibuprofen was evaluated, in triplicate, in a Rheo- 3
= V
lyst AR-1000N rheometer (TA Instruments, UK) equipped . Σ
Swelling ratio (2)
with an AR2500 data analyzer, fitted with a Peltier temper- V0 = d
ature control, and a 6 cm cone-plate measuring geometry, d0
covered with a solvent trap. Oscillatory shear responses (G± where d0 was the diameter of gel discs upon synthesis
(10.5 mm).
or storage modulus, and G±± or loss modulus) were deter-
The water content of the hydrogel was estimated by the
mined at 0.1 Pa over the frequency range of 0.01–50 rad s−1.
difference between the weight of fully swollen hydrogel
The test conditions were inside the linearity range of the
samples (W), after careful wiping of their surfaces with a soft
viscoelastic properties.
tissue, and the weight of the samples after being dried (W0)
2.2.9. Ibuprofen diffusion assays for 1 week at 40 ◦C
Teknokroma, Spain) after previous storage at the same tem- 0.785 cm2. A sample of 2.5 ml was placed in the donor com- partment;
perature for at least 1 h. The area available for diffusion was while 6.0 ml of iso-osmotic NaCl aqueous solu- tion filled the recipient
432
compartment R. Rodr´ıguez
and was stirred with a et al. / European Journal of Pharmaceutical
Pieces ofSciences 20 (2003) 429–438
the cylindrical gels (2–3 mm thickness) were
placed in 10 ml aqueous solutions of 1–8% drug for 3 days
at room temperature. The amount loaded was determined as
the difference between the initial amount of drug and the
amount remaining in the outer solution after the 3 days,
R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438 433
evaluated when the hydrogels where immersed first in pH H H H O (CH CH O) CH CHOHCH N+(CH )
2 2 n 2 2 3 3
3 medium (for 2 h) then, transfer to pH 6 medium (for 2 h), P Q-4
Mt n
Ibuprofen ONa
= Kt (4)
M∞
H H H H
groups (Higgins et al., 2001).
Table 1
Molecular weight (MW), intrinsic viscosity in water at 25 ◦C
([η]), and characteristics of substitution of the cationic
celluloses and cationic guar gums (Rodr´ıguez et al., 2001)
Polymer MWa [η] (dl/g) MSHECb %N Ammonium
group/sugar
repeating unit
PQ-4 1400000 14.59 2.71 1.27 1:5.3
PQ-10 1700000 70.09 1.28 1.95 1:2.9
E-14 500000 46.78 – 1.16 1:6.5
E-261 200000 45.85 – 0.91 1:8.5
a Dataprovided by the supplier.
b MSHEC average number of hydroxyethyl substituents =
bonded to each glucopiranose unit.
R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438 435
120 1000 70
Viscosity (mPa·s)
80 600 50
60 400
40
40 200
30
20 0 P
210 6000 70
E-261
180
Viscosity (mPa·s)
150 4000
50
120 3000
2000 40
90
1000
30
60
0
012345678 012345678 012345678
Ibuprofen (%)
Fig. 2. Transmittance, viscosity and surface tension of aqueous dispersions of cationic polysaccharides (1%) containing different proportions of ibuprofen (P:
precipitation of PQ-10 dispersions).
measurements as a function of drug concentration were that of the polymer dispersions in the absence of the drug
recorded. With both techniques, the cmc obtained for (Fig. 2). The effect was less pronounced for PQ-4 systems
ibuprofen in water, 4%, was similar to the value found by that showed, as the E-14 dispersions, a significant increase
Ridell et al. (1999). The minimum observed can be at- in viscosity for lower drug concentrations. In general, the
tributed to some surface-active impurities in the drug. The values of G± and G±± followed a tendency similar to that of
micropolarity of the medium was measured by the changes viscosity and continuously decreased until the drug con-
in the I1/I3 ratio in the emission spectra of pyrene. The I1/I3 centration reached the cmc (4%). An additional increase in
ratio is higher in a polar medium (1.87 in water) than in an drug concentration induced the dispersions to recover their
apolar medium (0.66 in cyclohexane) (Anthony et al., 1998). initial properties, showing G± and G±± values similar to or
Without ibuprofen, cationic polysaccharides showed a I1/I3 even greater than those of polymer alone dispersions (Figs.
ratio around 1.2. In the presence of 5% ibuprofen, this value 3 and 4).
decreased to 0.9, in PQ-4 dispersions, and to 0.70–0.75, in These observations may be explained taking into account
the other cationic polysaccharide systems. The greater I1/I3 the electrostatic and hydrophobic interactions that may be
ratio of PQ-4/ibuprofen dispersions is ex- plained by the established between the drug and the polymers. Even for the
more hydrophilic character of this polymer, which have lowest drug concentration studied (0.5%), the molar ra- tio
more hydroxyethyl groups. The surface tension of the of carboxylic drug groups/ ammonium polymer groups was
ibuprofen–cationic polysaccharide dispersions de- creased, greater than 1; this means that in all systems there are
from 50–60 mN/m, in the presence of the drug to reach a enough ibuprofen molecules to ionically neutralize all
minimum, 30 mN/m, around 4% ibuprofen (Fig. 2). No cationic groups of the polymer. Therefore, although be- low
significant differences were observed in the surface ten- sion cmc the interaction seems to be scarcely significant, some
patterns with respect to that obtained in the absence of drug molecules may act as bridges between different
polymer, which indicates that none of these cationic polymer chains, favoring the formation of a three dimen-
polysaccharides significantly interferes in the micellization sional network of slightly greater consistency. Considering
process of the drug and that the main interactions may hap- the viscosity and transmittance data, the critical aggrega-
pen for drug concentrations around or above cmc. These tion concentration, cac, may be established to be around 2%
observations were confirmed by the changes that occurred in ibuprofen. When the cmc is reached, the drug molecules self-
the transmittance and rheological properties of the dis- associate causing the polymer chains to coil to wrap the
persions. The viscosity of the systems containing ibuprofen micelles. This folding favors intramacromolecular bonds
at a concentration around cmc was considerably lower than and, in consequence, produces a decrease in the consistency
436 R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438
101
100
10-1
G´´ (Pa)
10-2
10-3
10-4
10-5
101
100
G´ (Pa)
10-1
10-2
10-3
10-4
10-5
0.01 0.1 1 10 100
Angular frequency (rad/s)
16 60
PQ-10
14 PQ-4
4 10
2
0
0 0 60 120 180 240
(A) Time (min)
16
E-14
14 E-261
12
10
8
6
4
2
0
3600 3000 2400 1800 1200 600
0 1 2 3 4 5 6 7 8
(B) Wavenumbers (cm-1)
Ibuprofen (%)
Fig. 7. (A) Ibuprofen release profiles in water from PQ-10 hydrogels loaded
Fig. 6. Ibuprofen sorption isotherms on chemically cross-linked cationic
celluloses and cationic guar gums. in 6% (O), 7% (☐ ), and 8% ( ) ibuprofenO solutions; and (B) from top to
the bottom, FT-IR spectra of freshly prepared PQ-10 hydrogel, of PQ-
10 hydrogel after ibuprofen loading in 6% solution and release in water,
for E-14 hydrogels in which drug sorption was limited to and of pure ibuprofen sodium.
8 mg/mg.
ions. This explains that when the hydrogels were transferred
3.2.2. Drug release
to pH 8 phosphate buffer, all ibuprofen was released. This
Ibuprofen release profiles in water from the hydrogels
allowed to confirm the total amount of ibuprofen initially
loaded in 6, 7, or 8% ibuprofen solutions are shown in Fig.
loaded by the hydrogels.
7A. The release process reached equilibrium after 2 h, when
Fig. 8 shows the release profiles of hydrogels subse-
a 40–50% of the amount of ibuprofen loaded (60, 72, or 80
mg per disc, respectively) still remained in the hydro- gels, quently immersed in media of increasing pH, simulating the
which did not experiment significant changes in volume in vivo situation after oral administration. At pH 3 (diluted
during the process. The release occurred by Fickian diffu- HCl aqueous solution), the hydrogels just released a low
sion (Eq. (4), n = ± r > 0.98). The permanence of the
0.46 0.5, 2
80
cm−1 ionized carboxylic groups) were still clearly vis- ible.
Also, the bands corresponding to the carboxylic groups of 60
ibuprofen were slightly moved to lower wave numbers,
suggesting ionic interactions with the polymer. Therefore,
40
only the unbound or weakly bound drug molecules are re-
leased from the hydrogel. The remaining drug molecules are
ionically trapped by the ammonium groups of the polymer 20
network, similarly to that observed by Jimenez-Kairuz et al.
(2002) for lidocaine in carbopol gels. Note that ibuprofen 0
0 60 120 180 240 300 360 420 480 540 600
concentration is, in all cases, clearly below its solubility co-
efficient in water (Cs=20%; Bustamante et al., 2000). An Time (min)
increase in pH and the presence of more ions in the medium Fig. 8. Effect of pH on ibuprofen release rate from PQ-10 (O), PQ-4 (●),
facilitate the diffusion of all ibuprofen, by acting as counter- E-14 (☐ ), and E-261 (■ ).
R. Rodr´ıguez et al. / European Journal of Pharmaceutical Sciences 20 (2003) 429–438 439