Design and Development of Mucoadhesive
Microcapsule of Aceclofenac for Oral Controlled Release by Ionic-Gelation Technique
M.
Surendra*, T. Venkateswara Rao, K. Lokeswara Reddy and A. Ramesh Babu
Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla,
Guntur (D.t), Andhra Pradesh-522101, India.
ABSTRACT:
Microencapsulation by Ionic gelation technique is an approach to achieve controlled
release of drug and mucoadhesive microcapsules were
designed to improve the absorption and bioavailability of drug. Microcapsules
of Aceclofenac were formulated by employing sodium alginate, two natural
polymers-gum kondagogu and gum karaya. The prepared microcapsules were free flowing,
discrete spherical shape was characterised by
scanning electron microscopy (SEM). Microencapsulation efficiency was in the
range of 60-80% and they exhibited good mucoadhesive
property. Invitro dissolution data revealed that
formulations exhibit the zero order kinetics and followed non-fickian diffusion transport mechanism. The GI residence time
of microcapsules were studied by X-Ray photographs. In-vitro release profile of
formulation (F3) was found similar to that of marketed formulation.
Pre-clinical pharmacological activity i.e. analgesic activity was conducted.
This formulation exhibited the significant analgesic activity Mucoadhesive microcapsules prepared with sodium alginate,
gum karaya and gum kondagogu
found to be suitable for oral controlled release.
KEYWORDS: Aceclofenac, Ionic-gelation method,
Entrapment efficiency, In vitro release.
INTRODUCTION:
Microencapsulation and the resulting microcapsules have
gained good acceptance as a process to achieve controlled release. It is an
application of thin coating to individual core material to obtain a size range
of 5-5000 μm. Aceclofenac is an effective
analgesic and anti-inflammatory drug, has short biological half-life 4hrs, oral
dose for adults 100mg twice a day. Due to its short biological half-life and
frequent administration, there was a need to develop microcapsules in the form
of control release manner. Hence controlled release formulations of Aceclofenac
designed to increase the absorption from GI tract.
Ionic- gelation technique for microencapsulation is the method 
which prolongs the duration of drug effect
significantly, provides
symptomatic relief to the patient and improves
patient compliance. Eventually the total dose and few adverse reactions may be
reduced since a steady plasma concentration is maintained. Hence in the current
study formulation and in vitro evaluation of sustained released
Aceclofenac microcapsules with
polymers like gum kondagogu and gum karaya employing emulsification gelation technique. The prepared
formulations were studied
for their flow properties, encapsulation efficiency, in vitro
release studies and
drug release kinetics. The optimized
formulation was subjected
for Scanning electron microscopic study.
NSAIDs have become widely used in the treatment
of these illnesses for their pain-relieving and anti-inflammatory properties. Since long-term NSAID treatment is indicated
for osteoarthritis, the ideal agent should have good efficiency and a low propensity to cause adverse
events. Aceclofenac appears
to be particularly well tolerated
among the NSAIDs, with a lower incidence of gastrointestinal adverse
effects. This good tolerability profile results in a reduced
withdrawal rate and greater compliance with treatment. (Legrand, 2004). Aceclofenac is an NSAID of a phenyl acetic acid class. It is indicated in arthritis and
osteoarthritis, rheumatoid arthritis, ankylosing spondylitis. Aceclofenac phenyl
acetic acid derivative 2-[(2,6-Dichlorophenyl)amino] phenyl acetoxy acetic
acid indicated in the symptomatic treatment of pain and inflammation with a reduced
side effect profile especially regarding gastrointestinal complications (Parfitt 1999, Brogden et al. 1996). To reduce the dosing
frequency and adverse
effects during prolong treatment it is needed to formulate
in long acting dosage form. Aceclofenac directly blocks prostaglandin E2 secretion at the site of inflammation by inhibiting IL-Beta and Tumour necrosis
factor in the inflammatory cells. To
reduce the frequency
of administrations and to improve patient compliances, Aceclofenac is suitable for making sustain
release dosage form. (Trivedi P, 2008).
Microcapsules
are homogeneous, monolithic particles which improve the treatment by providing localization of the drug at the site of action and by prolonging the drug release. These techniques are widely used in pharmaceutical research (Breghausen SW., 2002). Multiparticulate delivery
systems like microcapsules are prepared to obtain
prolonged or controlled drug delivery, to
improve bioavailability or stability and to target drug to specific sites
(S Haznedar., 2004). They can distribute in the GI tract
homogeneously, thus maximizing drug absorption and reducing
peak plasma fluctuations, minimizing the risk of local GI tract irritation and dose dumping, decreasing dosing frequency
and increasing patient
compliance, improving the safety and
efficacy of the active
ingredient
(ShaviGV., 2009).
MATERIALS:
Aceclofenac was
received as gift sample from Orchid Pharma, Chennai.
Sodium alginate was purchased from S. D. Fine Chem. Ltd., Mumbai. Gum Karaya and Gum Kondagogu were
obtained from Obtained from Girijan Co-operative Ltd.
Visakhapatnam. All other chemicals and solvents used
in the study were of LR grade.
EXPERIMENTAL WORK:
Preparation:
Microcapsules of Aceclofenac were prepared
by Ionic-gelation method (Kim C. K., 1992, Hari P.C., 1996) with sodium alginate, natural polymers-gum
kondagogu (F1, F2, F3) and gum karaya
(F4,F5,F6) in the core: coat of 1:1, 1:2 and 1:3. Sodium alginate (1.0 g) and
polymers of gum karaya (or) gum kondagogu
(1.0 g) were dissolved in purified water. Core material, Aceclofenac (2.0 g)
was added to polymer solution and mixed thoroughly to
form a smooth viscous dispersion. The resulting dispersion was then
manually dropped into 10% w/v of 100ml Calcium Chloride solution through a
syringe with a needle of size no.18. The added droplets were retained in the
Calcium Chloride solution for 15 minutes to complete the curing reaction and to
produce spherical rigid microcapsules. The microcapsules were collected by
decantation and the product thus separated was washed repeatedly with water and
dried at 450c for 12 hours.
Evaluation
of microcapsules:
The following evaluation parameters were
studied:
Size Distribution and Size
Analysis:
For size distribution analysis, different sizes in a batch were
separated by sieving, using a range of standard sieves. The amounts retained on
different sieves were weighed. The mean particle size of the samples was
calculated by the formula.(Goudanavar,
2010).
Where n is the
frequency weight and d is the mean size.
Determination
of Flow Properties:
Angle of
Repose:
The flow properties of different mucoadhesive
microcapsules were studied by measuring the angle of repose employing fixed
funnel method. The angle of repose was calculated by using the following
formula.(de Souza et al 2007)
Where h = height of the pile, cm r
= radius of the base of the pile, cm.
Bulk density:
Accurately weighed amount of
the beads and transferred into 50 ml measuring cylinder. It was subjected to
tapping for 3 times and the volume occupied by the beads was noted. Bulk
density was estimated by using the following formula.(Ozyazici
et al., 1996).
Bulk density = Weight of the
beads / Bulk volume of the beads.
Tapped density:
Accurately weighed amount of
the beads and transferred into 50 ml measuring cylinder. It was subjected to
tapping for 3 times and the volume occupied by the beads was noted. (Ozyazici et al., 1996).
Tapped density =
Weight of the beads
/ Tapped volume of the beads.
Hausner
ratio:
It can be calculated by using
the formula(Vijay Kumar et al., 2001).
Hausner’s ratio = Tapped density / Bulk density.
Carr’s index:
It can be calculated by using
the formula(Ozyazici et al., 1996).
Tapped density
– Bulk density
Carr’s index (%) =
--------------------------------- X 100
Tapped
density
True density:
It was done by using Liquid displacement
method by using Specific gravity bottle. This method is possible if the beads
were non porous. For this solvent is selected in such way a loaded beads were
insoluble in it.
True density =
weight of sample/ weight of liquid displaced
by solids.
Determination
of Moisture content:
The formulations were subjected to moisture content study(I.P., 1996); by placing the microcapsules at 600C
for 10 min in an IR moisture balance.
Surface Accumulation study:
This study was
conducted to estimate the amount of drug present on the surface of the
formulations which may shows immediate release in the dissolution media.50mg of
formulation were suspended in 50ml of phosphate buffer(PH6.8). The samples were
shaken vigorously for 30 min by hand shaking. The amount of drug leached out
from the surface was analyzed spectrophotometrically at 275 nm. Percentage of
drug released with respect to entrapped drug in the sample recorded(Abu et al.,
1996).
Wall Thickness:
Wall thickness of
micro capsules was determined by the method of (Luu
et al., 1973) using the equation
Where
h is the wall
thickness
r is the arithmetic mean radius of
the microcapsules
d1 is
the density of the core material
d2 is
the density of the coat material,
p is the
proportion of the medicament in the microcapsules.
Drug content evaluation:
Aceclofenac
content in the microcapsules was estimated by an UV spectrophotometric
method based on the measurement of absorbance at 275 nm in phosphate buffer of
pH 6.8. Estimated percent drug content was determined from the analysis of 50mg
microcapsules and the theoretical percent drug content was calculated from the
employed coat: core ratio in the formulation of microcapsules (Ozyazici et al., 1996).
Microencapsulation
Efficiency:
Microencapsulation
efficiency was calculated using the following formula (Sarfaraj
et al., 2010).
Scanning Electron Microscopy (SEM):
The samples for the
SEM analysis were prepared by sprinkling the microcapsules on one side of the
double adhesive stub. The stub was then coated with fine gold dust. The
microcapsules were then observed with the scanning electron microscope (Leica Electron Optics, Cambridge, USA) at 15 kv (Sarfaraj et al., 2010).
In Vitro Release Studies:
Microcapsules
(16/22 mesh size (1141.5 µ) containing equivalent to 200 mg of Aceclofenac were
packed in ‘5’ size hard gelatin capsule and subjected to in vitro drug release studies. Release of Aceclofenac from the
capsule was studied in phosphate buffer of pH 6.8 (900 mL)
using a United States Pharmacopoeia (USP)XXIV
8-station dissolution rate test apparatus (Model TDT - 08L, M/s Electro
lab, Mumbai, India) with a rotating paddle stirrer at 100 rpm and 37 OC
± 1 OC. Samples of dissolution fluid were withdrawn through a filter
(0.45 µ) at different time intervals and were assayed at 275 nm for Aceclofenac
content using a Shimadzu UV-1700 double beam spectrophotometer (Shimadzu
Corporation, Japan). The drug release experiments were conducted in
triplicate(A. Hoffman et al., 1986). The dissolution studies of the following marketed SR
formulation of Aceclofenac were
also conducted to compare with formulated microcapsules.
Drug release kinetics14:
Data obtained from dissolution
studies was fitted to various kinetic equations. Were kinetic model used were a
zero order equation (Q=Q0-k0t), first order equation (Ln Q=LnQ0-k1t) and Higuchi
equation(Q=Kht1/2)1/2), Korsemeyer-peppas
equation logQt vs. logt, were Qt, is the cumulative amount of
drug released at time t and Q0is the initial amount the drug
present in the microcapsules. k0 is the zero order release rate constant,k1 is
the first order release rate constant and kh
is the diffusion rate constant(Choudary, et
al., 2003).
Permeability Studies:
The permeability constant Pm of the
microcapsules was calculated as described by Koida et al15 using the equation.
Where V is the volume of the dissolution medium (cm3),
H is the wall thickness of the microcapsules (mm), A is the surface area of the
microcapsules (cm2), Cs is the solubility of the core
material (mg) in the dissolution medium and K is the release rate constant
(mg/hr or hr-1).
For a given microcapsule and under standard testing
conditions the values of V, A and Cs remain constant and hence the
equation can be written as Pm = K x H where K is the release rate
constant and H is the wall thickness of the microcapsule (Koida
Y.et al 1986).
Evaluation tests for mucoadhesion. by in-vitro wash-off test:
The mucoadhesive property of
the microcapsules was evaluated by an in
vitro adhesion testing method known as the in vitro wash-off method. Freshly excised pieces of intestinal
mucosa (2 × 2 cm) from sheep were mounted onto glass slides (3 × 1 inch) with cyanoacrylate glue. Two glass slides were connected with a
suitable support. About 50 microcapsules were spread onto each wet rinsed
tissue specimen, and immediately thereafter the support was hung onto the arm
of a USP tablet disintegrating test machine. When the disintegrating test
machine was operated, the tissue specimen was given a slow, regular up-and-down
movement in the test fluid at 37°C contained in a 1 L vessel of the machine. At
the end of 30 minutes, at the end of 1 hour, and at hourly intervals up to 8
hours, the machine was stopped and the number of microcapsules still adhering
to the tissue was counted. The test was performed at both gastric pH (0.1N HCl, pH 1.2) and intestinal pH (phosphate buffer, pH 6.8).
(Madhusudhan Rao Y.et al.,
1998).
In-vivo method:
Studies on pharmacodynamic
response:
The analgesic activity for selected formulation was
determined by acetic acid induced writhing test in mice. The study protocol was
approved by IAEC-I-8/BCOP/2007-2008 before the commencement of study.
Evaluation of Analgesic Activity:
The analgesic activity was determined by acetic acid
induced writhings test in mice. For the analgesic activity mice
weighing about 15- 25 grams were divided into three
groups each group consisting of 6 mice. The group-l animals received 1 ml of
gum kondagogu
(0.5% w/v) suspension containing Aceclofenac (14 mg/kg body weight orally) and served as standard. The group-ll animals received selected mucoadhesive
microcapsules containing Aceclofenac
at a dose (14 mg/kg body weight orally)
and group- III animals were treated as disease control. Writhings
were produced by intraperitoneal
injection of the 1% v/v acetic acid solution 1, 2, 4 and 6 hrs after the administration of standard Aceclofenac
and its mucoadhesive microcapsules to respective groups. The numbers of writhings
were observed for about 6 hrs. The
graphs of mean writhings were plotted against time
for each group of mice to compare the analgesic activity of prepared formulations
with that of standard Aceclofenac
(pure drug).
Where C = Control
S = Standard
Experimental
results:
The results of physical characteristics of
microcapsules were shown in the below Table
1and 2. The particle size of the microcapsules were found in the range of
1015μm -1467 μm and exhibited
the good flow properties.
Table 1:
Characterization of Aceclofenac microcapsules formulated with gum konda gogu and gum karaya
|
Technique
|
Core: Coat Ratio
|
Angle of
Repose
|
Bulk Density
(g/cm3)
|
Carr’s Index
|
Hausner’s Ratio
|
True Density
(g/cm3)
|
Average Particle Size (μ)
|
|
F1
|
1:1
|
26.22
|
0.35
|
28.57
|
1.39
|
3.76
|
1015.45
|
|
F2
|
1:2
|
21.53
|
0.44
|
22.8
|
1.28
|
6.67
|
1293.9
|
|
F3
|
1:3
|
18.76
|
0.52
|
16.1
|
1.19
|
8.31
|
1337.66
|
|
F4
|
1:1
|
27.11
|
0.35
|
30.0
|
1.41
|
3.89
|
1338.7
|
|
F5
|
1:2
|
23.59
|
0.43
|
25.86
|
1.34
|
6.80
|
1385.33
|
|
F6
|
1:3
|
19.47
|
0.49
|
18.33
|
1.22
|
8.55
|
1467.4
|
Table
2: Characterization of Aceclofenac microcapsules formulated with gum kondagogu and
gum karaya
|
Technique
|
Core: Coat Ratio
|
Moisture content
(%)
|
Surface
Accumulation
study (%)
|
Drug content
|
Entrapment efficiency (%)
|
Wall
thickness (mm)
|
Permeability coefficient
(mmg\hr)
|
|
F1
|
1:1
|
4.0
|
4.01
|
44.56
|
89.12
|
70.11
|
1974.29
|
|
F2
|
1:2
|
3.6
|
3.03
|
42.58
|
85.17
|
80.43
|
1880.45
|
|
F3
|
1:3
|
2.8
|
2.47
|
39.91
|
79.82
|
90.07
|
1781.59
|
|
F4
|
1:1
|
4.6
|
4.20
|
44.88
|
89.76
|
68.03
|
2264.71
|
|
F5
|
1:2
|
3.8
|
3.35
|
43.21
|
86.43
|
79.56
|
2100.38
|
|
F6
|
1:3
|
2.6
|
2.96
|
41.12
|
82.24
|
89.56
|
1972.11
|
All the formulations have uniform drug
content and good entrapment efficiency. The wall thickness of microcapsules was
found to be increased with increase in concentration of coating material, that
exists good correlation ship in between wall thickness and release rate
constant. By increase in the polymer concentration, % Surface
Accumulation study decreased significantly, due to high entrapment of
drug. Results of low moisture content in all the microcapsules indicate the
effectiveness of the optimized drying condition. Low moisture level ensures
better stability of the drug in the microcapsules.
Shape of microcapsules were characterised by SEM analysis as Fig 1 and microcapsules
having good mucoadhesive property found by Invitro wash-off test. Invitro-wash-off
was relatively rapid in phosphate buffer than in acid fluid. The results of
wash-off test indicated fairly good Mucoadhesive
property of the microcapsules (Table3).
The microcapsules were subjected to in-vitro release studies in 6.8 pH
phosphate buffer. GI Residence Time for F3
formulations were carried out by X-ray photographs, as shown Fig2 . The X-Ray studies showed
that the mucoadhesive microcapsules formulated with
Aceclofenac and gum kondagogu remained in the gastric
region even after 10 hours of administration indicating good retention period
in the stomach region. The % drug release for F1, F2, F3, F4, F5 and F6 were
98.56±0.78, 99.38±0.64, 98.93±0.54, 99.47±0.51, 99.03±0.60 and 99.009±0.97 at
the end of 7 hrs, .8.5 hrs,10 hrs, 6hrs, 7.5hrs and 9hrs respectively. The %
drug release profiles were shown in Fig
3and4.
Fig1 : Sem
photographs of Aceclofenac mucoadhesive microcapsules
formulated with mc by employing Ionic-gelation techniques
Fig 2: X-ray photographs of mucoadhesive
microcapsules containing gum kondagogu and barium sulphate
The formulation F3 control the release over
the period of 12 hrs among the all the formulations.
The rate of drug release from the formulations followed zero order kinetics
exhibited peppas
transport mechanism. The exponential coefficient value were found >0.5
indicating the non-fickian transport
mechanism. Hence microcapsules prepared with
gum kondagogu suitable for oral control release, this
may be due to coating of the polymer surrounding the core material.
Fig 3: Release
profile of Aceclofenac microcapsules formulated with gum kondagogu
by employing Ionic-gelation
technique
Fig 4: Release
profile of Aceclofenac microcapsules formulated with gum karaya
by employing Ionic- gelation
technique
To compare the efficacy
of these polymers,
the formulations has to be formulated with the same technique
under similar set of conditions and having same thickness as it is not possible practically to obtain microcapsules having same thickness,
Liner regression analysis was applied to obtain the corresponding release rate constants
from the microcapsules produced with different polymers. The release rate constants of these microcapsules
made with these polymers were found to be
permeable to drug and order of drug release
form microcapsules were gum karaya < gum
kondagogu (Table
4).
Table
3: Results of in vitro wash-off test to assess mucoadhesive
property of Aceclofenac microcapsules formulated by employing ionic gelation
technique
|
Microcapsules
|
Percent of microcapsules
adhering to tissue at 5 times (h)
|
|
0.1 N HCL, PH 1.2
|
Phosphate buffer, PH 6.8
|
|
1
|
2
|
4
|
6
|
8
|
1
|
2
|
4
|
6
|
8
|
|
Gum kondagogu
|
92
|
88
|
84
|
82
|
80
|
80
|
73
|
65
|
59
|
48
|
|
Gum karaya
|
88
|
86
|
80
|
80
|
78
|
76
|
68
|
61
|
53
|
40
|
Table 4: Comparison of drug
release form gum kondagogu
and gum karaya by Ionic gelation
techniques
|
Polymer
|
Regression Equation
(Ionic- gelation)
|
Release Rate Constant K0 (mg/hr)
for a wall thickness of 10µ (Ionic- gelation)
|
|
Gum kondagogu
|
Y=-0.4203X+57.487
|
53.2
|
|
Gum karaya
|
Y=-0.4753X+64.264
|
59.51
|
Table5: Analgesic
activity data of Aceclofenac and its mucoadhesive
microcapsules
|
Time (hr)
|
No. of Mean Writhings
|
% Inhibition
|
|
Standard
|
Formulation
|
Standard
|
Formulation
|
|
1
|
8±0.577
|
27±0.966
|
88.70±0.856
|
58.41±1.487***
|
|
2
|
12±0.577
|
20±1.064
|
81.51±1.643
|
69.84±1.634(ns)
|
|
3
|
15±1.155
|
15±0.966
|
76.88±1.634
|
76.88±1.122*
|
|
4
|
22±1.238
|
10±0.966
|
66.11±1.643
|
84.56±1.480*
|
|
5
|
25±0.931
|
10±0.966
|
61.5±1.631
|
84.56±3.489*
|
|
6
|
30±1.155
|
11±1.064
|
53.8±2.177
|
83.03±1.480*
|
All values expressed on mean±SEM, ns=non significant,
*=p<0.05, **=p<0.01, ***=p<0.001when compared with standard
formulation
Analgesic activity:
The analgesic activity of
Aceclofenac and mucoadhesive microcapsules containing
Aceclofenac was evaluated based upon the number of writhing from each group
including control for about 20 min. Mean writhings
were calculated for each group of mice. The analgesic activity of formulation
was compared with the pure drug based on the % inhibition of writhings. The number of mean writhings
were plotted against time and shown
in Fig5. The results were shown in Table: 5 and
the data were treated statistically to obtain the level of significance. The
results indicated the maximum % inhibition of writhings
at 1 hour (88.70%) and 6 hours (83.03%) from the pure drug and mucoadhesive microcapsules respectively. The statistical data
indicated that the formulation exhibited significant analgesic activity than
standard.
Fig: 5: Analgesic activity of Aceclofenac from pure
drug and mucoadhesive
microcapsules
CONCLUSION:
Microcapsules of Aceclofenac formulated by
Ionic- gelation method employing sodium alginate with gum karaya
and gum kondagogu were successfully developed for
oral controlled release. The observations made during study and results obtained showed the suitability of the investigated polymers for
microencapsulation of Aceclofenac for its sustained release. The
Ionic-gelation method
was easy to adopt and also to achieve
high drug entrapment efficacy. All the formulations indicated accurate drug content
and content uniformity. The in vitro drug
release studies revealed that the drug release by zero order and non-fickian controlled release mechanism for all the formulations studied. The
wash
off test showed
the mucoadhesive nature
of microcapsules that in turn helps for steady and slow drug release which
is essential for sustain release dosage form.
Analgesic activity of standard Aceclofenac showed a very rapid onset of action
and the effect was observed for a period of 1 hr. Where as in the case of
Aceclofenac mucoadhesive microcapsule treated group,
the onset of action was delayed and prolonged action was observed for a period
of 6 hrs. The studies have further scope for investigation of formulation and process variables
with polymer to formulation method to study their influence
on drug release at
desired rate.
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CONCLUSION
The observations made during
study and results obtained
showed the suitability of the investigated
polymers for
microencapsulation of aceclofenac for
its sustained release. The
ionic gelation method was
easy to adopt and
also to achieve high
drug entrapment efficacy. All the
formulations indicated
accurate
drug content and
content uniformity. The in vitro drug release
studies revealed that the drug release by zero order and non-fickian
controlled release mechanism for all the formulations studied. The
wash off test
showed the mucoadhesive nature of microcapsules
that in turn
helps for steady and
slow drug release
which is
essential for sustain release dosage form. The
studies have further
scope for investigation of formulation and
process variables with
polymer to
formulation method to study
their influence on
drug
release at desired rate.
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