971

Introduction
Te development of liquid oral sustained release for-
mulations has gained much interest recently. Tese
formulations eliminate the problems associated with the
solid dosage forms while maintaining the advantages
and convenience of sustained release drug delivery.
Alternative strategies have been adopted to develop
such systems. One of the techniques examined the use of
suspended microspheres which have been incorporated
as a dispersed phase in a suspension
1,2
. Other strategies
investigated the use of ion exchange resins or employing
sparingly soluble salts to prepare oral sustained release
suspensions
3
.
Te use of in situ gelling systems provides another
promising alternative with most of the reported inves-
tigations employing the sol to gel phase transition of
alginate solution after addition of polyvalent cations
as calcium. An early study developed a suspension
of theophylline in presence of sodium alginate. Tis
suspension was reported to form a gel when comes
in contact with simulated gastric fuid
4
. In a more
recent study, a liquid sustained release preparation
RESEARCH ARTICLE
Development of modifed in situ gelling oral liquid sustained
release formulation of dextromethorphan
Gamal M. El Maghraby
1,2
, Ehab M. Elzayat
2
, and Fars K. Alanazi
2,3
1
Department of Pharmaceutical Technology, College of Pharmacy, University of Tanta, Tanta, Egypt,
2
Department
of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, and
3
Kayyali Chair for
Pharmaceutical Industry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
Abstract
Context: Alternative strategies are being employed to develop liquid oral sustained release formulation. These
included ion exchange resin, sustained release suspensions and in situ gelling systems. The later mainly utilizes
alginate solutions that form gels upon contact with calcium which may be administered separately or included in the
alginate solution as citrate complex. This complex liberates calcium in the stomach with subsequent gellation. The
formed gel can break after gastric emptying leading to dose dumping.
Objective: Development of modifed in situ gelling system which sustain dextromethorphan release in the stomach
and intestine.
Methods: Solutions containing alginate with calcium chloride and sodium citrate were initially prepared to select the
formulation sustaining the release in the stomach. The best formulation was combined with chitosan. All formulations
were characterized with respect to fow, gelling capacity, gelling strength and drug release.
Results: Increasing the concentration of alginate increased the gelling capacity and strength and reduced the rate
of drug release in gastric conditions with 2% w/v alginate being the best formulation. However, these formulations
failed to sustain the release in the intestinal conditions. Incorporation of chitosan with alginate increased the gelling
capacity and strength and reduced the rate of drug release compared to alginate only system. The efect was optimum
in formulation containing 1.5% w/v chitosan. The sustained release pattern was maintained both in the gastric and
intestinal conditions and was comparable to that obtained from the marketed product.
Conclusion: Alginate-chitosan based in situ gelling system is promising for developing liquid oral sustained release.
Keywords: Dextromethorphane, liquid controlled release, in situ gelling, polyelectrolyte complex,
alginate-chitosan complex
Address for Correspondence: Gamal M. El Maghraby, Department of Pharmaceutical Technology, College of Pharmacy, University of Tanta,
Tanta, Egypt; Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, P.O. Box: 2457, Saudi Arabia.
E-mail: gmmelmag@yahoo.com
(Received 24 May 2011; revised 18 October 2011; accepted 19 October 2011)
Drug Development and Industrial Pharmacy, 2012; 38(8): 971978
2012 Informa Healthcare USA, Inc.
ISSN 0363-9045 print/ISSN 1520-5762 online
DOI: 10.3109/03639045.2011.634811
Drug Development and Industrial Pharmacy
2012
38
8
971
978
24 May 2011
18 October 2011
19 October 2011
0363-9045
1520-5762
2012 Informa Healthcare USA, Inc.
10.3109/03639045.2011.634811
LDDI
634811
972 G. M. El Maghraby et al.
Drug Development and Industrial Pharmacy
for eradication of Helicobacter pylori was developed
in presence of alginate solution. In this study the in
situ gellation was achieved by separate oral adminis-
tration of calcium solution which was taken immedi-
ately after administration of sodium alginate solution
5
.
Shortly after this authors attempted to prepare systems
containing sodium alginate combined with calcium.
Tese systems retained the fuidity in the bottle but
undergo immediate gellation on coming into contact
with gastric or simulated gastric acidity. To inhibit the
interaction of calcium with alginate in the bottle, cal-
cium ions were sequestered with sodium citrate. Tis
complex breaks immediately in strong acidity librating
free calcium which can interact with alginate resulting
in spontaneous gellation
69
. Te optimum quantities
of calcium chloride and sodium citrate that main-
tain fuidity of the formulation before administration
but gel spontaneously after contact with simulated
gastric fuid (pH 1.2) were determined
10
. It should be
noted that this type of gel is pH sensitive and breaks
in presence of intestinal pH. Accordingly, the release
pattern will depend on the gastric emptying rate which
is highly variable. Tis problem draws the attention to
new in situ gelling system with a stronger gel structure
that can maintain the sustained release pattern after
gastric emptying.
Te gel structure of alginate-based systems was
enhanced by combination with chitosan. Tis combina-
tion was employed in development of controlled release
particulate and other solid drug delivery systems. Te
synergism between alginate and chitosan is due to the
electrostatic interactions between carboxyl groups of
alginate and amino groups of chitosan and existence of
interactive coulomb forces. Tese efects increased the
gel strength
11,12
.
Accordingly, the objective of this work was to develop
and optimize in situ gelling sustained release liquid oral
formulation for the delivery of dextromethorphan. Tis
drug was selected as it has high water solubility and short
half-life. To achieve this objective the alginate-based
system was employed but the in situ gelling efect was
induced with calcium ion and chitosan. Te later was
introduced to the formulation with the goal of increasing
the gel strength and maintaining the sustained release
pattern after gastric emptying.
Materials and methods
Materials
High molecular weight chitosan, Brookfeild viscosity
800,000 cPs, was obtained from Sigma-Aldrich, Inc.,
Chemi GmbH, Germany. Sodium alginate (low viscos-
ity grade with M/G ratio of 1.56) was obtained from
ICN Biomedicals, Inc., Germany. Dextromethorphan
hydrobromide was a gift from TABUK pharmaceutical
company, Tabuk, KSA. Calcium chloride anhydrous and
Tri-Sodium citrate were obtained from WINLAB, GEMINI
house, U.K. Methanol HPLC grade and disodium hydro-
gen phosphate were obtained from BDH, Prolabo, Poole,
England. Potassium dihydrogen phosphate was obtained
from Merk, Darmstadt, Germany. All other reagents were
of analytical grade.
Preparation of in situ gelling systems
In situ gelling liquid formulations containing increas-
ing concentrations of sodium alginate were prepared in
absence and presence of chitosan. Te detailed composi-
tion of these is presented in Table 1. Sodium alginate was
added to ultrapure water containing 0.45% w/v sodium
citrate and 0.15% w/v calcium chloride and 0.6% w/v
dextromethorphan hydrobromide. Tese mixtures were
heated to 60C while stirring. Stirring was continued at
ambient temperature until cooling to less than 40C
7
. For
chitosan containing systems, the chitosan amount of chi-
tosan was levigated gradually with the resulting alginate
solution under continuous stirring using a mortar and a
pestle to produce homogenous dispersion.
Viscosity of in situ gelling solutions
Te fow properties and viscosity of all formulations were
determined using a Brookfeld viscometer RVDV-II+
(Brookfeld, Engineering Laboratories Inc., Stoughton,
MA, USA) with small sample adapter at ambient tem-
perature. A typical run comprised changing the angular
velocity from 0.5 to 100 rpm and recording the fow prop-
erties. Te average of the three readings was recorded.
Evaluation of the gel forming property
Tis study was conducted to measure the gel form-
ing property of the tested formulation. Te formula-
tion (10 ml) was packed into cellulose bag. Tis was
Table 1. Te composition of the prepared in situ gelling systems and the release efciency of dextromethorphan hydrobromide in
simulated gastric and intestinal media.
Formulation Alginate (% w/v) Chitosan (% w/v) RE (%) in the acid phase RE (%) in the intestinal phase
A1 1 0 79.6 (11.4) 99.9 (7.9)
A1.5 1.5 0 35.5 (6.9) 98.9 (7.8)
A2 2 0 33.1 (2.6) 83.1 (0.4)
F1 2 0.5 16.5 (5.0) 91.3 (4.8)
F2 2 1 16.7 (1.0) 77.4 (12.5)
F3 2 1.5 16.9 (2.4) 32.8 (1.7)
CH2 0 2 71.0 (2.9) 91.1 (4.1)
Delsym 5.2 (0.7) 20.3 (3.4)
Values between brackets are SD (n = 3).
Liquid oral sustained release formulation 973
2012 Informa Healthcare USA, Inc.
immersed in 0.1 N HCl (100 ml) and maintained at 37C
for 24 hours. Te fuid content of the cellulose bag was
separated from the gel by sieving through a 355 m sieve
for 30 seconds. Te weight of the gel remaining on the
sieve was determined
13
.
Determination of in vitro drug release
Te method of evaluation of drug release from enteric
coated systems was adopted (USP 24). In addition, the
study was further extended to monitor drug release at
pH 7.4. Te release experiments employed a USP disso-
lution apparatus (Model: UDT-804, LOGAN Inst. Corp.,
USA) with a paddle stirrer being maintained at 50 rpm.
Te release medium was 500 ml of simulated gastric fuid
without enzymes (0.1 N HCl, pH 1.2) and the tempera-
ture was maintained at 37 0.2C. Te test formulations
(10 ml) were loaded into a Petri dish (2.7 cm, internal
diameter) before immersion into in the dissolution vessel
containing release medium without much disturbance.
Samples (5 ml) were collected at predetermined time
intervals (5, 15, 30, 60, 90 and 120 minutes, respectively).
Fresh release medium was added to replenish for each
sample. Te samples were fltered through 0.45 m flter,
immediately after collection and the fltrate was analyzed
for drug content using the HPLC method (see below).
After the last sample (2 hours), the pH of the release
medium was adjusted to 6.8 to simulate the intestinal
pH (USP 24). Tis was achieved by addition of 200 ml of
0.3 M dibasic sodium phosphate and 25 ml of 1 N sodium
hydroxide. Sampling was then continued for another 4
hours at the end of which the medium was adjusted to
7.4 using 1 N sodium hydroxide and sampling was con-
tinued for another 2 hours. Tese samples were treated
as before.
Te cumulative amounts of the drug released
(expressed as % of the total drug added) were plotted as a
function of time to produce the drug release profles. Te
release efciency (RE) was calculated from the area under
the release curve at time t (determined using the non-
linear trapezoidal rule) and expressed as a percentage
of the area of the rectangle described by 100% release in
the same time
14
. Te results were compared to the release
data of the marketed formulation (Delsym

suspension).
In addition, the release data for each phase were ftted to
diferent kinetic models to determine the release kinet-
ics. Tis included ftting the data to zero order, frst order
and Higuchi difusion system. Each study was conducted
in triplicate.
Assay of dextromethorphan
Te drug concentration in each sample was determined
using the previously developed HPLC method of analy-
sis
15
. Te study employed a high pressure liquid chro-
matograph (Waters

600 controller, USA) equipped with

a variable wavelength detector (SPD-10 AV, Shimadzu,
Kyoto, Japan) and an automatic sampling system
(Waters

717 Plus Autosampler, USA). Te whole system

was under computer contro1. Separation was performed
on a reversed phase column 15 cm 3.9 mm (i.d.) C18,
Bondapak

, Waters

, with an average particle size of 10

m. Te mobile phase comprised methanol and 0.1 M
potassium dihydrogen phosphate bufer (45:55, v/v),
fowing at 1.2 ml/min after being adjusted to pH 3 with
phosphoric acid. Te column efuent was monitored at
220 nm and the chromatographic data analysis was per-
formed with the Millennium

Program (Waters, USA).

Filtered samples were loaded into the HPLC vials before
injecting 30 l into the HPLC.
Statistical analysis
One-way analysis of variance (ANOVA) with was per-
formed using the SPSS 18 software to compare the
mean values of drug released from diferent formulation.
Multiple Range Test (Fishers least signifcant diference
procedure, LSD) was used to test for signifcance
16
. Te
level of confdence was set at 95%.
Results and discussion
Viscosity and ow behavior of the in situ gelling
systems
Te study developed and evaluated a modifed alginate-
based in situ gel forming system as liquid oral sustained
release formulation. Te modifcation was performed
with the goal of increasing the gelling strength and con-
trolling the release over extended period of time. Tis was
achieved by incorporation of chitosan. Alginate-based
systems were frst developed and evaluated. Te best
alginate formulation was the combined with increasing
concentrations of chitosan. Tese were compared with
the marketed product (Delsym

suspension). As fuidity
is an essential parameter for development of liquid oral
formulations, it was taken as the frst measure in prepa-
ration of traditional alginate-based systems before incor-
poration of chitosan. Formulations containing sodium
alginate at a concentration of 3% w/v or more were too
viscous. Tus a series of alginate solutions comprising
1, 1.5 and 2% w/v of sodium alginate was prepared and
evaluated. Figure 1 shows the fow behaviour of these
formulations. Te data revealed a dependency of the vis-
cosity on the shear rate with the viscosity reducing upon
application of the shear (Figure 1). Tis shear thinning
behaviour provides an advantage for the administra-
tion process. Shaking of the formulation will enhance its
fuidity pourability. With respect to the recorded viscos-
ity values, they were increased with increasing alginate
concentration. For comparison the values recorded at
a shear rate of 0.47 sec
1
were considered. Te recorded
viscosity values were 100, 250 and 525 mPaS for sols con-
taining alginate at a concentration of 1, 1.5 and 2% w/v,
respectively. Te marketed product showed similar fow
profle but the recorded viscosity values were higher than
the tested alginate-based systems (Figure 1). Similar fow
behaviour was recorded for alginate-based in situ gelling
system
9
. To increase the gelling strength and modify the
release pattern of the drug chitosan was incorporated in
974 G. M. El Maghraby et al.
Drug Development and Industrial Pharmacy
the alginate sol formulation (A2). Chitosan was included
at increasing concentrations of 0.5, 1 and 1.5% w/v to
produce the formulations F1, F2 and F3, respectively
(Table 1). Addition of chitosan did not result in signifcant
increase in the viscosity of the systems with the behaviour
being shear thinning as well (Figure 1). Te viscosity of
the alginate sols was increased from 525 mPaS in absence
of chitosan to 533.3, 566.7 and 650 mPaS in presence of
chitosan at concentrations of 0.5, 1 and 1.5% w/v, respec-
tively. Te lack of signifcant increase in the viscosity after
incorporation of chitosan can be explained on the bases
that the pH of the formulations (pH = 7.2) is not suitable
for dissolution of chitosan which requires acidic envi-
ronment to dissolve
11,12
. Te fnal formulation was a fne
dispersion of chitosan in alginate sol. Tis will exclude
any interaction between chitosan and alginate during
storage in the bottle. Te pH of the formulation (7.2) was
selected to maintain the calcium ions in a complex form
with citrate. Tis ensured the fuidity of the formulation
and will prevent gel formation in the bottle
68
. Te vis-
cosity of the prepared sols in presence and absence of
chitosan was lower than that recorded for the marketed
product, Delsym (Figure 1). Tis ensures the fuidity of
the formulations which allows easy administration of the
tested formulation.
Gel forming property
Te gel forming property of the formulations is another
important factor that can afect the drug release pat-
tern from the liquid formulation. It provides a measure
for the in situ gelling capacity of the formulations. Tis
was monitored by packing the sol into cellulose bags
before incubation in 0.1 N HCl at 37C. Te gelling was
monitored visually and the relative weight of the gel
phase was taken as a measure for the gel strength
13
.
Figure 2 shows photomicrographs of the gel which was
formed in situ after incubation of diferent formulation
in simulated gastric pH. Te photomicrographs revealed
a dependence of the gelling capacity and the gelling
strength on the composition of the sol. Chitosan-free
alginate sols containing alginate at a concentration of 1
or 1.5% w/v (A1 and A1.5) produced very soft gel. Te
gel became relatively frmer on increasing the alginate
concentration to 2% w/v as in formulation A2 (Figure 2).
Tese observations were confrmed further by monitor-
ing the weight of the gel (Figure 3). Te recorded weight
values confrmed the dependence of gelling capacity on
alginate concentration with A2 producing the greatest
gelling capacity compared to A1 and A1.5. Te increase
in the gel forming ability of the in situ gelling system with
increasing alginate concentration indicates the adequacy
of calcium and citrate ions. Te in situ gelling behaviour
of simple alginate-based solutions (A1, A1.5 and A2) can
be explained on the bases that the acidic environment
librated the calcium ions from the citrate complex. Te
free calcium ions interacted with the alginate sols result-
ing in immediate gellation
610
.
Combination of chitosan with the alginate-based sys-
tems enhanced the gel forming property and increased
the in situ gelling capacity. Tis is clearly indicated from
Figure 2 which shows the frm gel with the frmness being
increased upon increasing the concentration of chitosan.
Te efect of chitosan was investigated further by monitor-
ing the weight of the gel. Te data indicated that incorpora-
tion of chitosan into alginate sols resulted in better in situ gel
forming capacity compared with chitosan-free system (A2).
Tis is revealed from the relative increase in the weight of the
gel in presence of chitosan. Tis efect of chitosan depended
on its concentration as well (Figure 3). Tese results sug-
gest a synergistic efect for chitosan. Tis synergism is
due to the formation of polyelectrolyte complex resulting
from electrostatic interactions between alginate and chi-
tosan and existence of interactive coulomb forces. Tese
efects can increase the in situ gelling capacity and gel
strength
11,12
. Te complexing efect of chitosan provided
a synergistic efect for the calcium induced gelation. Te
presence of calcium ion with chitosan in the in situ gell-
ing system can guarantee rapid gelation in acidic envi-
ronment of the stomach due to rapid liberation of the free
divalent calcium ions which interact with the guluronic
acid moieties of alginate. Chitosan will further enhance
the cross-linking by forming polyelectrolyte complex
with alginate but this efect involves initial dissolution
Figure 1. Comparison of the dependency of viscosity profles of
diferent in situ gelling systems on the shear rate. Formulation
details are in Table 1 (Delsym is the commercial suspension).
Liquid oral sustained release formulation 975
2012 Informa Healthcare USA, Inc.
of the chitosan in the acidic pH before forming the com-
plex. Tis explains the synergistic efect of calcium and
chitosan in induction of in situ gelation of alginate.
Drug release pattern from dierent in situ gelling
systems
Te release pattern of the drug is the true measure for
the in situ gelling capacity. Te release experiments were
designed to mimic the in vivo conditions. Tus the drug
release was initially monitored in simulated gastric pH
for 2 hours at the end of which the system was adjusted to
simulated intestinal pH (pH 6.8 for 4 hours and pH 7.4 for
another 2 hours). Tis design will monitor drug release
after in situ gellation in the gastric environment with an
investigation of the change in the release pattern after
gastric emptying. Te release profles of the drug from
diferent in situ gelling systems are shown in Figures 4
and 5. Te calculated RE values are presented in Table 1.
Te drug release profle from alginate-based in situ
gelling systems revealed a dependence of drug release on
the concentration of sodium alginate with the release rate
decreasing on increasing alginate concentration (Figure 4),
and Table 1). Te formulation containing 1% w/w alginate
(Formulation A1) showed very rapid release with more
than 63% of the labeled drug being released in the frst 5
minutes. Tis initial rapid release was followed by gradual
release in the rest of the acid phase to liberate more than
94%. Tis rapid release can be attributed to the weak gell-
ing capacity at low alginate concentration. Increasing the
concentration of alginate to 1.5 and 2% w/v (formulations
A1.5 and A2, respectively) resulted in signifcant (P < 0.05)
reduction in the drug release rate with the formulation
librating 55.3 and 40%, respectively of the labeled drug
in the gastric phase. However, both formulations librated
the rest of the labeled drug in the early stage after chang-
ing the pH to 6.8 (Figure 4). Tese results indicate that
the in situ gelling alginate can control drug release in the
stomach only but liberate all the entrapped drug very
shortly after gastric emptying. Tis is further evidenced by
calculating the RE in the gastric and intestinal phase. Te
recorded RE values in the gastric phase were 79.6, 33.5 and
33.1% for A1, A1.5 and A2, respectively. Te later two val-
ues were signifcantly lower (P < 0.05) than that obtained
with A1. In the intestinal phase the RE values were 99.9,
98.9 and 83.1% for A1, A1.5 and A2, respectively (Table 1).
Te release pattern in the gastric phase showed a better
ft to Higuchi release kinetics (Table 2). Similar release
pattern was recorded for alginate-based systems
9
. Higichi
Figure 2. Photomicrographs of the gel formed after incubation of diferent in situ gelling systems in 100 ml of simulated gastric fuid (pH
1.2) at 37C for 24 hours. Formulation details are in Table1.
976 G. M. El Maghraby et al.
Drug Development and Industrial Pharmacy
equation was not applied to alginate based system in the
intestinal phase as the gel dissolved completely shortly
after changing the pH to 6.8. Te reduction in the release
rate after increasing the concentration of alginate can be
attributed to the relative increase in the gelling capacity
and gelling strength. Further increase in alginate was not
possible due to reduced fuidity.
Te failure of pure alginate-based in situ gelling
system to control the release of the drug after gastric
emptying refects the possibility of dose dumping after
administration of such system. Tis highlights the need
for improvement of such systems. To achieve this, the
current study was extended to investigate the efect of
combining chitosan with alginate-based system. Te
formulation containing the highest concentration of
alginate (A2) was selected for this purpose and chitosan
was incorporated at 0.5, 1 and 1.5% w/v (F1, F2 and F3,
respectively). Combination of chitosan with alginate-
based system resulted in a signifcant reduction in the
drug release rate compared to the alginate-based system
(A2). Tis reduction was apparent in the acid phase even
at the smallest tested chitosan concentration (F1) with
the drug release in the intestinal phase depending on
the concentration of chitosan (Figure 5). In the intestinal
phase the drug release reduced gradually with increas-
ing the concentration of chitosan. Te RE was signif-
cantly reduced (P < 0.05) in the intestinal phase in case
of F3 which comprised 1.5% w/v chitosan in combina-
tion with 2% w/v alginate. Te kinetics of drug release
were shown to follow Higuchi matrix difusion system
(Table 2). Tis is expected taking into consideration the
in situ gellation which results in a matrix like network
structure through which the drug has to difuse. Tese
data highlighted the potential of F3 as sustained release
liquid oral system. Accordingly, this formulation was
compared to the marketed product (Delsym) which is an
ion exchange resin based liquid oral sustained release
system of the same drug. Te release profle of the mar-
keted product was conducted at the same experimental
conditions. Te recorded data revealed slow drug release
both in the gastric and intestinal phases (Figure 5 and
Figure 3. Efect of the composition of the in situ gelling systems
on the weight of the gel formed after incubation of the solutions in
0.1 N HCl for 24 hours at 37C. Formulation details are in Table 1.
Figure 4. In vitro release profles of dextromethorphan
hydrobromide from in situ gelling alginate solutions; A1, A1.5
and A2. Release was conducted in simulated gastric fuid, pH 1.2,
for of 2 hours and subsequently in simulated intestinal fuid (pH
6.8, for 4 hours and pH 7.4 for 2 hours). Formulation details are
in Table 1.
Figure 5. In vitro release profles of dextromethorphan
hydrobromide from in situ gelling alginate and alginate-chitosan
based systems and the marketed product (Delsym). Release was
conducted in simulated gastric fuid, pH 1.2, for of 2 hours and
subsequently in simulated intestinal fuid (pH 6.8, for 4 hours and
pH 7.4 for 2 hours). Formulation details are in Table 1.
Liquid oral sustained release formulation 977
2012 Informa Healthcare USA, Inc.
Table 1). Te RE values were 5.2 and 20.3% as compared
from 16.9 and 32.8% which were recorded from F3 in
the gastric and intestinal phases respectively. Te kinet-
ics of drug release from the marketed product followed
zero order kinetics which is expected due to absence of
difusion with the ion exchange resin acting as a depot
providing slow but continuous drug release. Overall the
developed liquid formulation (F3) is simple and can be
a promising substitute for liquid oral sustained release.
Te recorded slow release pattern after combination of
chitosan with the alginate-based system may be further
explained on the bases of increased retention of the gel
in the intestinal environment. Considering the tested in
situ gelling system in absence and presence of chitosan
it is important to emphasize that alginate-based systems
(A1, A1.5 and A2) failed to retain the gel structure in
the intestinal environment. A1 dissolved in the frst few
minutes of the intestinal phase but A1.5 disintegrated
initially and dissolved shortly after that. For A2 which
contained the highest alginate concentration, the gel
eroded gradually before complete disappearance 1.5
hours after adjusting the pH to the intestinal condi-
tion. Incorporation of chitosan increased the intestinal
retention of the gel. At low chitosan concentration (F1)
the gel showed gradual erosion in the frst 2 hours of the
intestinal phase before being disintegrated into small
pieces. Te erosion was slower in formulations contain-
ing higher chitosan concentration with F3 preserving
the intact gel structure throughout the intestinal phase.
F3 retained more than 50% of its size at the end of the
dissolution experiment. Tese results indicate that the
combination of chitosan at optimum concentration with
alginate system can improve the intestinal retention of
the gel. Tis will exclude any possibility of dose dump-
ing and will guarantee sustained drug release before and
after gastric emptying.
Pure chitosan dispersion, 2% w/v (CH2) failed to pro-
vide signifcant control for the drug release with more
than 53% of the drug being liberated in the frst 5 minutes
in the acid phase. Te amount of drug released exceeded
75% at the end of the gastric phase. Te rest of the drug
was rapidly released during the early stage of the intestinal
phase. Tis is clear from the RE values which were 71 and
91.1% in the gastric and intestinal phases respectively
(Table 1). Tese results clearly support the synergistic
efect between chitosan and alginate. Tis synergism can
be attributed to the formation of polyelectrolyte complex
between the carboxylic group of alginate and the amino
group of chitosan. Tis synergism was widely employed
to develop solid controlled release particles. Tese sys-
tems depended mainly on cross-linking of alginate fol-
lowed by coating the beads with chitosan
12,1719
.
Conclusion
Tis study introduced alginate-chitosan based in situ
gelling system as a promising liquid oral sustained
release system for easy administration of dextrometho-
rphan for elderly and child patients. Tis system
employed the complexation process between alginate
and chitosan to sustain the drug release in the stomach
and intestine after gastric emptying. Such system will
thus reduce the possibility of dose dumping after gastric
emptying.
Acknowledgments
Te authors would like to thank Kng Abdulaziz City
for Science and Technology, Riyadh, Saudi Arabia and
SABIC Co., Saudi Arabia for funding the work with an
acknowledgement to Kayyali chair of pharmaceutical
industry for hosting the work.
Declaration of interest
Te authors report no declaration of interest. Tis work
was funded by SABIC Co, Saudi Arabia.
References
1. Dalal PS, Narurkar MM, (1991). In vitro and in vivo evaluation
of sustained release suspensions of ibuprofen. Int J Pharm,
73:157162.
Table 2. Te coefcient of variation (R
2
) obtained after ftting the drug release data to diferent kinetic models.
Formulation Phase
R
2
Zero order First order Higuchi
A1 Acid 0.783 0.744 0.902
Intestinal NA NA NA
A1.5 Acid 0.922 0.775 0.986
Intestinal 0.957 0.934 NA
A2 Acid 0.883 0.804 0.968
Intestinal 0.785 0.735 NA
F1 Acid 0.965 0.879 0.997
Intestinal 0.935 0.854 0.953
F2 Acid 0.969 0.888 0.998
Intestinal 0.933 0.838 0.963
F3 Both phases 0.963 0.826 0.986
Delsym Both phases 0.996 0.809 NA
978 G. M. El Maghraby et al.
Drug Development and Industrial Pharmacy
2. Emami J, Varshosaz J, Ahmadi F, (2007). Preparation and
evaluation of a liquid sustained-release drug delivery system for
theophylline using spray-drying technique. Research in Pharm
Sci, 2:111.
3. Shah KP, Chafetz L, (1994). Use of sparingly soluble salts to prepare
oral sustained release suspensions. Int J Pharm, 109:271281.
4. Zatz JL, Woodford DW, (1987). Prolonged release of
theophylline from aqueous suspensions. Drug Dev Ind Pharm,
13:21592178.
5. Katayama H, Nishimura T, Ochi S, Tsuruta Y, Yamazaki Y, Shibata
K et al. (1999). Sustained release liquid preparation using sodium
alginate for eradication of Helicobacter pyroli. Biol Pharm Bull,
22:5560.
6. Miyazaki S, Aoyama H, Kawasaki N, Kubo W, Attwood D. (1999). In
situ-gelling gellan formulations as vehicles for oral drug delivery. J
Control Release, 60:287295.
7. Miyazaki S, Kubo W, Attwood D. (2000). Oral sustained delivery of
theophylline using in-situ gelation of sodium alginate. J Control
Release, 67:275280.
8. Miyazaki S, Kawasaki N, Kubo W, Endo K, Attwood D. (2001).
Comparison of in situ gelling formulations for the oral delivery of
cimetidine. Int J Pharm, 220:161168.
9. Kubo W, Miyazaki S, Attwood D. (2003). Oral sustained delivery
of paracetamol from in situ-gelling gellan and sodium alginate
formulations. Int J Pharm, 258:5564.
10. Rohith G, Sridhar BK, Srinatha A. (2009). Floating drug delivery of
a locally acting H2-antagonist: An approach using an in situ gelling
liquid formulation. Acta Pharm, 59:345354.
11. Wang L, Khor E, Lim LY. (2001). Chitosan-alginate-CaCl(2) system
for membrane coat application. J Pharm Sci, 90:11341142.
12. Ribeiro AJ, Silva C, Ferreira D, Veiga F. (2005). Chitosan-reinforced
alginate microspheres obtained through the emulsifcation/
internal gelation technique. Eur J Pharm Sci, 25:3140.
13. Itoh K, Kubo W, Fujiwara M, Watanabe H, Miyazaki S, Attwood D.
(2006). Te infuence of gastric acidity and taste masking agent on
in situ gelling pectin formulations for oral sustained delivery of
acetaminophen. Biol Pharm Bull, 29:343347.
14. Khan KA. (1975). Te concept of dissolution efciency. J Pharm
Pharmacol, 27:4849.
15. Louhaichi MR, Jebali S, Loueslati MH, Adhoum N, Monser
L. (2009). Simultaneous determination of pseudoephdrine,
pheniramine, guaifenisin, pyrilamine, chlorpheniramine and
dextromethorphan in cough and cold medicines by high per-
formance liquid chromatography. Talanta, 78:991997.
16. Alanazi F, Li H, Halpern DS, ie S, Lu DR. (2003). Synthesis,
preformulation and liposomal formulation of cholesteryl carborane
esters with various fatty chains. Int J Pharm, 255:189197.
17. Murata Y, Miyamoto E, Kawashima S. (1996). Additive efect of
chondroitin sulfate and chitosan on drug release from calcium-
induced alginate gel beads. Int J Pharm, 138:101108.
18. Mi FL, Sung HW, Shyu SS, (2002). Drug release from chitosan-
alginate complex beads reinforced by a naturally occurring cross-
linking agent. Carbohydr Polym, 48:6172.
19. Wong TW, Chan LW, Kho SB, Sia Heng PW. (2002). Design of
controlled-release solid dosage forms of alginate and chitosan
using microwave. J Control Release, 84:99114.
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