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ABSTRACT
The aim of the present study is to develop colon targeted drug delivery systems
for aceclofenac using guar gum (GG) and xanthan gum (XG) as carrier. Matrix and
compression coated tablets of aceclofenac containing proportions of guar gum: xanthan
gum such as (1.25:1.25), (1.5:1) and (1.75:0.75) were prepared. All the formulations were
evaluated for the hardness, friability, thickness, weight variation, drug content
uniformity, and in vitro drug release studies. Matrix tablets of aceclofenac released 14.52
-17.04% of the aceclofenac, within the 5 h dissolution study, in the physiological environment of
the stomach and small intestine, depending on the proportion of guar gum: xanthan gum
used in the formulation. Thus the matrix tablet of aceclofenac failed to control the drug
release within 5 h of the dissolution study. The compression coated formulations have
been formulated to release less than 4% of aceclofenac within 5 h dissolution study in the
physiological environment of the stomach and small intestine and the dissolution study was
continued in rat cecal contents, the compression coated tablet of aceclofenac released 63.7579.90% of aceclofenac after degradation by colonic bacteria at the end of 24 h of the dissolution
study. The results of the dissolution study showed that compression coated tablet CT3 with guar
gum: xanthan gum (1.75:0.75) is most likely to provide targeting of aceclofenac for local action
in the colon owing to its minimal release of the drug in first 5 h.The aceclofenac compression
coated tablets showed no change either in physical appearance, drug content or in drug release
pattern after storage at 40º C/ 75% RH for 3 months.
Key words: Aceclofenac; Guar gum; Xanthan gum; Colon targeting; Compression coating.
INTRODUCTION
The oral route is considered to be most convenient for administration of drugs to
patients. After oral administration of conventional dosage forms normally dissolves in the
stomach fluid or intestinal fluid and is absorbed from these regions of the GIT depends
upon the physicochemical properties of the drug. It is a serious drawback in conditions
where localized delivery of the drugs in the colon is required or in conditions where a
1
drug needs to be protected from the hostile environment of upper GIT. Oral delivery of
drugs to the colon is valuable in the treatment of diseases of colon (ulcerative colitis,
Crohn’s disease, carcinomas and infections) whereby high local concentration can be
achieved while minimizing side effects that occur because of release of drugs in the upper
GIT or unnecessary systemic absorption. The colon is attracting interest as a site where
poorly absorbed drug molecule may have an improved bioavailability. The region of
colon is recognized as having a somewhat less hostile environment with less diversity
and intensity of activity than the stomach and small intestine. Additionally, the colon has
a longer retention time and appears highly responsive to agents that enhance the
absorption of poorly absorbed drugs. Apart from retarding or targeting dosage forms, a
reliable colonic drug delivery could also be an important starting position for the colonic
absorption of per-orally applied, undigested, unchanged and fully active peptide drugs.
As the large intestine is relatively free of peptidases such special delivery systems will
have a fair chance to get their drug sufficiently absorbed after per oral application [1]
Aceclofenac is a non-steroidal anti-inflammatory drug that is effective in the
treatment of painful inflammatory diseases. It has short half life of 4 h
[2]
. Aceclofenac is
a prostaglandin synthetase (cyclooxygenase) inhibitor, which inhibits lipoxygenase and
decreases prostaglandin production, thereby inhibiting the inflammatory process.[3]
Various approaches have been used for targeting the drugs to the colon including,
formation of a prodrug,multicoating time-dependent delivery systems, coating with pHsensitive polymers, pressure-dependent systems, and systems formulated making use of
biodegradable polymers. Every system has advantage as well as shortcoming. However,
biodegradable systems formulated making uses of naturally occurring polysaccharides
are increasingly being developed. Natural polysaccharides remain undigested in the
stomach and the small intestine and are degraded by the vast anaerobic microflora of the
colon.[4] Xanthan gum is known to have greater drug-release retarding property and
synergistically enhanced the gel properties in the presence of galactomannan gums like
guar. Guar gum is used in colon- specific drug delivery as matrix forming material and as
compression coat.
2
The present investigation deals with development of novel colon targeted drug
delivery system by using compression coating technique. Compression coating is a
pharmaceutically accepted and industrially applied technique used in formulating tablets.
The core tablet of aceclofenac was compression coated with guar gum and xanthan gum
combinations to target into the colon, because after reaching the colon the polysaccharide
gets degraded by the microflora of the colon and drug will be release to the target site.
The prepared core and compression coated tablets subjected for their different evaluation
parameters and the stability studies were carried out according to the ICH guidelines.
MATERIALS AND METHODS
Materials
Aceclofenac was obtained as gift sample from Amoli Pharmaceutical Pvt.Ltd,
Mumbai, India. Guar gum was procured from Loba.Chemicals.Mumbai.Xanthan gum
was obtained as gift sample from Rajesh Chemicals, Mumbai. Sodium starch glycolate,
Magnesium stearate, Microcrystalline cellulose, Talc were purchased from S.D.Fine
Chemicals. All chemicals used in the experiment were of analytical grade.
Methods
Preparation of aceclofenac matrix tablet [5]
The formulation for matrix tablets of aceclofenac is given in Table 1. Matrix
tablets of aceclofenac were prepared by wet granulation technique using starch paste as
binder. Microcrystalline cellulose was used as diluents and mixture of talc and
magnesium stearate was used as lubricant. Firstly all the ingredients were accurately
weighed. Aceclofenac was separately passed through mesh (60) then Guar gum; xanthan
gum and microcrystalline cellulose were sieved through mesh (44) and mixed with drug.
Then powders were blended and granulated with starch paste. Then the granules were
passed through mesh (22) and then granules were dried at 50o C for 2h. Then dried
granules were passed through a mesh (22) and were lubricated with a mixture of talc and
magnesium stearate. The lubricated granules were compressed using 10 mm flat plain
punches on compression machine.
3
Table 1.Formulation of Matrix tablets
Sl.No
1
2
3
4
5
6
7
Ingredients
Aceclofenac
Guar Gum
Xanthan Gum
starch
MicrocrystallineCellulose
Magnesium stearate
Talc
MT1
100
125
125
20
25
3
2
MT2
100
150
100
20
25
3
2
MT3
100
175
75
20
25
3
2
Preparation of aceclofenac core and compression coated tablets [5]
The core tablets were prepared by direct compression technique. Sodium starch
glycolate was included in the formulation to obtain aceclofenac tablets with fast
disintegration characteristics .The formula for the core tablet is given in Table 2.
Aceclofenac, microcrystalline cellulose and sodium starch glycolate were firstly sieved
and weighed then mixed in the geometric fashion. Then mixture was lubricated with
magnesium stearate and talc and then the mixture equivalent to 100 mg of aceclofenac
(130mg) was weighed and then compressed by single station tablet punching machine
using 8 mm flat punches, optimizing the hardness and die cavity of the machine, so that
the tablets will be of uniform hardness and with minimal weight variation.
Table 2. Core Tablet Formulation
Sl.No
1
2
3
4
5
Ingredients
Aceclofenac
Microcrystalline cellulose
Sodium starch glycolate
Magnesium stearate
Talc
Core
tablet
100
25
3
0.5
1.5
The three formulations of compression coating (XG1, XG2, and XG3) for coating
the core tablet are shown in Table 3 were prepared by wet granulation technique using
starch paste as binder. Guar gum, xanthan gum and microcrystalline cellulose were
sieved through mesh (44) and mixed with drug. Then powders were blended and
granulated with starch paste. Then the granules were passed through mesh (22) and then
granules were dried at 50o C for 2 h.The dried granules were passed through a mesh (22)
4
and were lubricated with a mixture of talc and magnesium stearate. Then 47% weight of
Coating mixture then kept in die cavity and then core tablet was placed on it in centered
position and then remaining 53% of coating mixture was added to cavity and compressed
in to tablets, by using the punches of 10mm diameter optimizing the hardness and die
cavity of the machine, so that the tablets will be of uniform hardness and with minimal
weight variation.
Table 3. Composition of Compression coat Formulations
Sl.No
1
2
3
4
5
6
Ingredients
Guar Gum
Xanthan Gum
Starch
Microcrystalline Cellulose
Magnesium stearate
Talc
XG1 XG2
125 150
125 100
20
20
25
25
3
3
2
2
XG3
175
75
20
25
3
2
Table 4. Compression Coating Tablets with Percent Gum content
Sl. No
1
2
3
Formulation
code
CT1
CT2
CT3
Drug: GG: XG
1:1.25:1.25
1:1.5:1
1:1.75:0.75
Evaluation of granules [6 – 8]
The granules of matrix tablet and compression coating was evaluated for their
angle of repose, bulk density and compressibility index.
Evaluation of tablets [9 – 11]
Hardness
For each formulation, the hardness of 10 tablets were determined using the Monsanto
hardness tester (Cadmach).
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Friability
For each formulation, the friability of 20 tablets were determined using the Roche
friabilator. Percent friability (F) was calculated as follows,
Initial weight - final weight
F=
X 100
Initial weight
Thickness
For each formulation, the thicknesses of 10 tablets were determined using Vernier
caliper.
Weight variation Test
To study weight variation, 20 tablets from each batch were weighed using an
electronic balance (AW-220, Shimadzu), and the test was performed according to the
official method.
Drug content uniformity
Five tablets were weighed individually and triturated. Powder equivalent to the
average weight of the tablet was weighed and drug was extracted in water for 6 hours.
The solution was filtered through 0.45µ membrane. The absorbance was measured at
275 nm [12] after suitable dilution.
In Vitro Release Studies of matrix and compression coated tablet
The dissolution study of Matrix tablets of aceclofenac were carried out using a
USP XXIII dissolution rate test apparatus (37°C at 100 rpm). In vitro drug release studies
were carried out in three different media i.e. 0.1N HCl (pH 1.2) in 900ml as dissolution
medium, as the average gastric emptying time is 2 h, for 3 h in phosphate buffer (pH 7.4)
in 900ml dissolution medium, as the average small intestinal transit time is 3 h and then
the dissolution was continued with the pH 6.8 phosphate buffer (control) for 19 h. At the
end of the time periods, two samples each of 5 ml were taken, suitably diluted and
analyzed for aceclofenac at 275 nm using a double beam UV/VIS Spectrophotometer.
The same dissolution procedure for compression coated tablets (CT1, CT2 and
CT3) in the absence of rat cecal content were carried out as that of the matrix tablet. The
dissolution procedures for CT1, CT2, and CT3 in the presence of rat caecal content were
carried out in 0.1N HCl for 2 h and then continued with the pH 7.4 phosphate buffer for
6
3 h. Then the dissolution study was continued in the presence of rat cecal content to
check the susceptibility of guar gum coats to the enzymatic action of colonic bacteria.
The rat cecal content medium was prepared as described previously.[13] The drug release
studies were carried out in USP dissolution rate test apparatus (37°C at 100 rpm,) with
slight modification. The basket containing tablet immersed in a beaker (capacity 150 ml,
internal diameter 55 mm) containing 100 ml of dissolution medium [100 ml of pH 6.8
phosphate buffer containing 4% w/v of rat cecal content] was immersed in the water
maintained in the 1000 ml vessel, which in turn, was in the water bath of the apparatus.
The 5ml samples were withdrawn then the volume was made upto 10 ml with Phosphate
buffer then filtered and the filtrate was analyzed for aceclofenac content at 275 nm and
the same volume was replaced to the dissolution medium. [14]
Stability Studies [15]
The stability studies were performed as per ICH guidelines at temperature of
40º C / 75% RH for 3 months. The samples were analyzed for drug content.
Statistical analysis
The cumulative percent of aceclofenac released from compression-coated
tablets(n=3) in the dissolution medium at 24 h with and without rat cecal contents
(control study) was compared, and the statistical significance was tested by using
Student’s t-test. A value of P<0.05 was considered statistically significant
RESULTS AND DISCUSSION
Evaluation of granules
The angle of repose for all formulation was in the range of 22.68º-24.52º i.e. less than
30(n=3), which indicate good flow properties of the granules. This was further supported by lower
compressibility index values below15%, as shown in Table 5.These result indicated good to
excellent flow properties
7
Table 5. Evaluation of granules properties
Formulation
code
LBD*
(g/ml)
TBD*
(g/ml)
Carr’s index* Angle of
(%)
Repose*(º)
MT1
0.568±0.01 0.648±0.03
14.26±0.02
24.3±0.01
MT2
0.591±0.05 0.66±0.04
12.67±0.04
23.9±0.02
MT3
0.584 ±0.04 0.65±0.03
12.40±0.04
22.68±0.03
XG1
0.568±0.03 0.649±0.04
14.26±0.02
24.52±0.04
XG2
0.584±0.02 0.65±0.02
12.30±0.04
23.95±0.01
0.591±0.04 0.64±0.02
8.29±0.03
23.52±0.04
*Mean ± SD,n =3
*Mean ± SD,n =3
Evaluation of tablets
All the formulations showed uniformity in thickness and weight variation. The
XG3
drug content for all the formulations was found to be in between 98.99 to 100.16%. In the
present study the percentage friability for all the formulations was below 0.5% shown in
Table 6. All the tablet formulations showed acceptable properties and complied with the
in-house specifications for weight variation, thickness, drug content, hardness and
friability were within acceptable official limits.
Table 6. Evaluation of tablet properties
Hardness*
(Kg/cm2 )
Friability*
(%)
Thickness Weight
variation*(
* (mm)
mg)
Drug
Content*(%)
MT1
4.0±0.2
0.37±0.2
3.85±0.02
400±9
99.36±0.05
MT2
4.2±0.3
0.35±0.3
3.91±0.03
402±11
100.16±0.06
MT3
4.4±0.3
0.41±0.4
3.87±0.02
404±8
98.99±0.04
CT1
4.2±0.2
0.43±0.3
3.93±0.04
428±9
99.51±0.03
CT2
4.4±0.2
0.41±0.4
3.86±0.02
420±11
99.86±0.04
CT3
4.8±0.3
0.43±0.2
3.95±0.04
430±9
99.76±0.02
Core tablet
2.8±0.2
0.45±0.4
2.30±0.04
128±2
99.21±0.03
Formulation
Code
*Mean ±
SD,n =3
8
Dissolution study
A) In vitro drug release studies of matrix tablets
When the matrix tablets were subjected to in vitro drug release studies, aceclofenac
tablets MT1, MT2 and MT3 remained intact and slightly swollen at the end of 5 h and
aceclofenac released from MT1, MT2 and MT3 were found to be 14.52%, 15.72%, and 17.04%
respectively. Where as in next 19 h of dissolution study it was 62.40%, 64.40%, and 66.85%
respectively is shown in Fig 1. The release of less percent of aceclofenac from the formulations
MT1, MT2 than MT3 in 0.1N HCl, pH 7.4 phosphate buffer and pH 6.8 phosphate buffer without
rat cecal content (control) was seen because of increased concentration of xanthan gum, which
results in increased path length due to formation of viscous gel layer of more thickness. Hence,
further studies on the in vitro dissolution of the formulations in rat cecal contents medium were
not carried out on formulations MT1, MT2 and MT3 as they also released almost 15 to 17 % of
its drug in physiological environment of stomach and small intestine. The results thus showed
that the matrix formulations of aceclofenac MT1 MT2, MT3 of GG: XG failed to control the drug
release in the physiological environment of stomach and small intestine.
Hence, it was planned to control the release of aceclofenac by preparing compression
coated tablets of same GG: XG [1.25:1.25, 1.5:1and 1.75:0.75] ratios.
B) In vitro drug release study of compression coated aceclofenac tablets
In view of the unsuccessful delivery of the matrix tablets of aceclofenac in the
physiological environment of colon, it was essential either to prevent or minimize the release of
aceclofenac in the physiological environment of stomach and small intestine. Hence it was
planned to apply guar gum and xanthan gum as a compression coat over the fast disintegrating
aceclofenac core tablets. The core tablets of aceclofenac were found to have the required
characteristics for colon targeting in the form of a guar gum and xanthan gum compression coat
over the core tablet. The cumulative amount of aceclofenac released from tablets coated with coat
formulations CT1, CT2 and CT3 (1.25:1.25, 1.5:1, 1.75:0.75 of GG: XG) was found to be less
than 4% after 5 h of the dissolution study in 0.1 N HCl and Phosphate buffer pH 7.4.
Thus, guar gum and xanthan gum in the form of a compression coat is capable of
protecting the drug released in the physiological environment of stomach and small intestine. To
assess the integrity of the coats, drug release studies were carried out without the addition of rat
caecal contents to pH 6.8 phosphate buffers. At the end of the 24 h of the dissolution study, all the
tablets coated with coat formulations CT1, CT2 and CT3 were found intact and the percentage
9
drug release was found to be 27.82%, 30.26% and 32.52%, respectively, as shown in Fig.2.This
indicates that until the coat is degraded the gum will not permit the release of the bulk of the drug
present in the core tablet. When the dissolution study was carried out in the presence of rat cecal
content medium, the percent of aceclofenac released at the end of 24 h from CT1, CT2 and CT3
was 63.75%, 73.36% and 79.90% respectively is shown Fig 3.This is because of the presence of
rat cecal content, the guar gum and xanthan gum coat gets degraded by colonic microbial
enzymes present in the colon and thus complete drug release occur in the colon.
Comparison of dissolution profiles of compression coated formulation with and
without rat cecal content.
In vitro dissolution studies were carried out in the absence of rat cecal content
medium, the percent drug released from aceclofenac tablets coated with coat formulation
CT1,CT2 and CT3 at the end of 24 h was found to be only 27.82%,30.26% and 32.52%
respectively and the coat was remained intact. In the presence of rat cecal content the
percent of drug release at the end of 24 h from the CT1,CT2 and CT3 was found to be
63.75%,73.36% and79.90% respectively. A significant difference (P<0.001) was
observed in the amount of aceclofenac released at the end of 24 h of the dissolution study
is shown in Fig 4.
The coat in CT3 was almost degraded in the presence of rat cecal contents thereby
releasing the drug into the dissolution medium. Since the xanthan gum content of coat in CT3 (75
mg) was lesser as compared to coat in CT2 (100 mg) and CT1 (125 mg) and the coat might have
been completely hydrated and subsequently form smallest path length among all three
formulations for movement of aceclofenac from core tablet towards the dissolution medium and
resulting in the release of about 79.90 % of aceclofenac from CT3 was observed. The results
showed drug release from compression coated formulation in the order of CT3> CT2> CT1.The
compression coated formulation CT3 was completely degraded in stimulated colonic fluids
whereas CT2 and CT1 formulations were less degraded in stimulated colonic fluids compared to
CT3.
The higher proportion of xanthan gum in (CT1) 125 mg, only 63.75% of the drug was
released at the end of 24 h of dissolution study. The gel strength of the swollen coat of xanthan
gum might be too high and prevented the drug release from the formulation. The colonic bacterial
10
action of the rat cecal medium might not be sufficient to enter in to a high strength gel barrier of
the swollen CT1 compression coated formulation. Hence by decreasing the proportion of xanthan
gum by 25 mg in CT2 gives only 73.36% of drug release. Therefore decreased the proportion of
xanthan gum by 25 mg in CT3 than CT2 gives 79.90 % of drug release at the end of 24 h.
Stability study
In view of the potential utility of CT3 formulation for targeting of aceclofenac to colon,
stability studies were carried out at 40°C / 75% RH for 3 months to assess their long term
stability. There is no appreciable change in dissolution profile of CT3 formulation after storage at
40°C / 75% RH for 3 months as shown in Fig 5.
CONCLUSION
The present investigation was carried out to develop colon targeted drug delivery
systems for aceclofenac for an effective and safe therapy of colonic diseases. Matrix tablets of
aceclofenac MT1, MT2, MT3 (1.25:1.25, 1.5:1, 1.75:0.75 of GG: XG)
formulation failed to
release the drug in the physiological environment of colon. In view of this result, alternative
colon targeted drug delivery systems were developed which could release minimal quantity of
aceclofenac until colonic bacteria act upon the formulation. Fast disintegrating aceclofenac core
tablets were compression coated with coat formulation containing various quantities of guar gum
and xanthan gum in ratio (1.25:1.25, 1.5:1, 1.75:0.75) i.e.CT1, CT2 and CT3.The compression
coated CT3 (1.75:0.75 of GG:XG) degraded in dissolution medium containing rat cecal contents
there by releasing 79.90 % of the drug is most likely to provide targeted delivery of aceclofenac
to the colon. From the investigation it was clear that compression coated tablet proves to
be a novel colonic delivery system as compared to colon targeted matrix tablets.
11
Fig 1: Dissolution profile of matrix tablet without rat cecal content
Fig 2: Dissolution profile of CT1, CT2 & CT3 in the absence of rat cecal content
Fig 3:Dissolution profile of CT1,CT2 and CT3 in rat cecal content
12
CT1without caecal
content
Cumulative % drug release
90
80
CT1 with caeal
content
70
60
50
40
CT2 without caecal
content
30
CT2 with caecal
content
20
10
CT3without caecal
content
0
0
2
4
6
8
10 12 14 16 18 20 22 24
Tim e (hrs)
CT3 with caecal
content
Fig 4: Percent of aceclofenac released from CT1,CT2 and CT3 formulation with
and without rat cecal content
90
80
% drug released
70
60
50
CT3 Before storage
40
CT3 after storage
30
20
10
0
0
2
4
6
8 10 12 14 16 18 20 22 24 26
Time (hrs)
Fig 5.Release profile of CT3 before and after stability stud
ACKNOWLEDGEMENT
The authors are grateful to R. R. K. Samithi’s College of pharmacy Bidar for
providing necessary facilities to carry out the work and also thankful to Amoli
Pharmaceutical Pvt.Ltd, Mumbai, for providing the gift sample of aceclofenac.
13
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