Original Article

Colon Specific Drug Delivery: Effect of Eudragit Enteric

Coating on Hydroxypropyl Methylcellulose Matrix
Tablets of Flurbiprofen
Sateesh Kumar Vemula1,2*
1
Department of Pharmaceutics, Chaitanya College of Pharmacy Education and Research, Hanamkonda,
Warangal, Telangana, India.
2
Department of Pharmacy, College of Medical & Health Sciences, Wollega University, Nekemte, P.Box No
395. Ethiopia.
ABSTRACT

Objective: The present research is focused on developing flurbiprofen colon-specific tablets based on timed release and
pH-sensitivity. Methods and Material: This study is designed to study the effect of eudragit coating on the drug release from
hydroxypropyl methylcellulose matrix to achieve the colon-specific release. Hydroxypropyl methylcellulose matrix tablets
were prepared by wet granulation method and coated with eudragit S100 using dip coating method. Then the tablets were
evaluated for different physical parameters, compatibility studies, in vitro dissolution and in vivo x-ray imaging studies.
Statistical Analysis: In the stability studies, paired t-test is employed to determine the significance of difference at 0.05
level. Results: Flurbiprofen colon-specific tablets have been characterized for weight variation, hardness, friability and
drug content. Based on in vitro drug release, the formulation F6 showed the low amount of drug release (18.41 ± 0.68%) in
the initial lag period followed 100.43 ± 3.33% in 24 h. Compatibility studies revealed that there was no interaction between
drug and the polymers. Similarity index value was found as 95.01, which is more than 50 indicates similarity between the
dissolution profile before and after storage. In support of the dissolution studies, x-ray imaging studies revealed that tablets
reached the colon without disintegrating in the upper gastro intestinal tract. Conclusion: From the above results, it is obvious
that the developed flurbiprofen enteric coated matrix tablets are suitable for colonic delivery.
Key words: Dip coating, Lag period, pH-sensitive, Timed release, X-ray imaging study.

INTRODUCTION

Colon-specific drug delivery through the oral route has time-dependent and microbial degradation dependent
gained increased importance to treat local diseases in approaches.3 Combination of any of the above two
colon and to give potential delivery of drugs that are used approaches has superior applicability in colon-specific
to treat colonic disorders.1-2 Traditionally, colon targeting delivery than any single approach. Combining time-
is achieved with approaches like prodrug, pH-sensitivity, dependent and pH-sensitive approaches can result in an
optimum formulation with low polymer content, that can
Access this article online
show negligible drug release in the initial stages but can
Journal Sponsor
release the drug completely and in a sustained fashion when
Website:
www.jyoungpharm.org the tablet reaches colon.4 Examples for such techniques
include flurbiprofen compression coated tablets, 5
DOI: flurbiprofen-sodium alginate compression coated tablets,6
10.5530/jyp.2015.4.12 meloxicam microsponges,7 diclofenac sodium compression
coated tablets,8 ketorolac matrix tablets,9 flurbiprofen-guar
*Address for correspondence:
Dr. Sateesh Kumar Vemula, M. Pharm, PhD, Department of Pharmaceutics, Chaitanya College of Pharmacy Education and Research,
Warangal, AP, India-506001. E-mail: [email protected]

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 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

Graphical Abstract

gum tablets,10 indomethacin matrix tablets,4 time-dependent gift samples from Matrix laboratories, Hyderabad, India.
5-fluorouracil tablets,11 flurbiprofen microsponges12 and All other chemicals used were of analytical grade.
time-dependent ketorolac compression coated tablets.13
Powder characterization
Formulation of matrix tablets is inexpensive method and
easy to manufacture with conventional tabletting facilities Evaluation of powder mixtures flow properties was done
and few process variables.14 To achieve colonic drug by measuring angle of repose, bulk density, tapped density
delivery, preparation of matrix tablets is a simple method and compressibility index. The fixed funnel method was
when compared to other methods. HPMC is a synthetic employed to measure the angle of repose (θ) and it was
release retardant that is widely used as an extended release calculated using the following formula:
agent in the pharmaceutical industry.15 Eudragit S100 with a
threshold pH 7 was selected as the coating material for this Tan θ = h/r ---(1)
study. Eudragit S100’s coating integrity can withstand lower
pH values of stomach and small intestine, but can dissolve In which, θ is the angle of repose, h is the height of the
at the neutral or alkaline pH of the terminal ileum.16-17 cone and r is radius of the cone base. To measure the angle
Flurbiprofen (FLB) is a non-steroidal anti-inflammatory of repose, a funnel was fixed to a stand so that the lower
drug used to treat inflammation and pain related to colon.18 tip of the funnel is 2.5 cm above the surface. A graph paper
The frequent intake of FLB leads to gastric ulceration, was placed on a flat surface. The powder blend was allowed
bleeding and other gastric complications.19 Hence the to fall freely on the graph paper through the funnel, till the
development of FLB colon specific tablets is appropriate tip of the heap formed just touches the funnel. The radius
to reduce its side effects and achieve high local drug of the heap was noted and from this angle of repose was
concentrations in the colon.20 Thus the significant plan determined. Angle of repose less than 30° suggests free
of present study is to develop FLB enteric coated HPMC flowing properties of the material.
matrix tablets for colon delivery by combining time
dependent and pH-sensitive approaches. The bulk density of a powder is calculated by measuring
the volume of a known mass of powder sample that
MATERIALS AND METHODS may have been passed through a screen, into a 50 ml
graduated cylinder. Tapped densities of powder samples
Materials were estimated by a tap density apparatus (Intelli, Kshitij
Innovations, India). The apparatus was set for 500 tappings
Flurbiprofen was a gift sample from FDC Limited, Mumbai, for 5 min at a stroke height of 20 mm.5 The compressibility
India. Various grades of HPMC and Eudragit S100 were index (Carr’s Index) was calculated from the bulk density
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 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

(ρb) and tapped density (ρtap) using the following formula: The tablets were coated at different levels from about 5 to
30% w/w as total solid applied.
Carr’s Index = ((ρtap - ρb)/ρb)/×100 ---2)
Evaluation of physical parameters
Preparation of matrix tablets
The designed formulations were studied for their physical
Wet granulation method was adopted to prepare the properties like weight variation, hardness and friability. For
HPMC matrix tablets. FLB, HPMC and excipients other estimating weight variation, 20 tablets of each formulation
than glidant and lubricant were accurately weighed, passed were weighed using an electronic weighing balance (AW
through 60 mesh sieves and mixed in a poly bag for 5-10 120, Shimadzu Corporation, Japan). The hardness of six
min, and then granules were prepared with the addition of tablets was measured using Monsanto tablet hardness
5% polyvinyl pyrrolidine in alcohol as binding agent, dried tester. Friability was determined on ten tablets in a Roche
at 400C for 15 min and sieved to obtain uniformly sized friabilator (Electrolab, Mumbai, India).
granules (18 mesh and 22 mesh sieves used for granulation
and sieving of dried granules respectively). The obtained Determination of drug content by HPLC method
granules were lubricated with talc and magnesium stearate
by blending for another 5 min. The resultant mixture was For estimation of drug content, ten tablets were crushed,
directly compressed into tablets using 5000 kg compression and 100 mg of the powder was accurately weighed and
pressure with 9 mm round flat punches using 16-station transferred to a 100 ml volumetric flask. Initially about 50
rotary tabletting machine (Cadmach, Ahmedabad, India). ml of mobile phase was added to the volumetric flask and
The final weight of the tablet was adjusted to 300 mg. The allowed to stand for 6-8 h with intermittent shaking to
compositions of the matrix tablets were given in Table 1. ensure complete solubility of the drug. Then the volume
was made up to 100 ml with mobile phase followed by
Enteric coating filtration and analysis for FLB content by the previously
developed HPLC method. Mobile phase used for the
The enteric coating solution was prepared by dissolving analysis consists of phosphate buffer: acetonitrile aqueous
Eudragit S100 in acetone at 10% w/v. Coating of optimized solution in the ratio of 35:65. They were filtered before use
matrix formulation (F3), that showed poor release during through a 0.45 μm membrane filter and pumped through
the initial period of dissolution, was performed by dip the column Symmetry C18 (XTerra, 4.6 x 150 mm) 5 μm,
coating method. Samples were taken, weighed, and the at a flow rate of 1 ml/min. Prior to the injection of the
mean coat weight calculated. The process was repeated drug solution, the column was equilibrated for at least 30
until the desired amount of coating per tablet was achieved. min with the mobile phase flowing through the system.

Table 1: Composition of FLB colon specific matrix tablets

Ingredients
F1 F2 F3 F4 F5 F6
(Quantity in mg/tablet)
Flurbiprofen 100 100 100 100 100 100

HPMC E50 40 - - - - -

HPMC E100 - 40 - - - -

HPMC K4M - - 40 - - 40

HPMC K15M - - - 40 - -

HPMC K100M - - - - 40 -

Eudragit S100 - - - - - 60

Spry dried Lactose 148 148 148 148 148 148

Sodium Lauryl
3 3 3 3 3 3
Sulphate
Talc 6 6 6 6 6 6

Magnesium Stearate 3 3 3 3 3 3

Total Weight 300 300 300 300 300 360

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 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

The analysis was performed at ambient temperature and Stability studies

the run time was set to 8 min. The eluents were monitored
at 254 nm using UV detector.5 Stability studies were carried out according to ICH
guidelines to assess the drug and formulation stability.
In vitro dissolution study Optimized formulation F6 was sealed in aluminum
packaging coated inside with polyethylene, and three
The release of FLB from tablets was carried out using USP replicates were kept in the humidity chamber maintained
XXIV Type I dissolution apparatus (Electro lab, TDT- at 40 ± 2oC and 75 ± 5% RH for six months.23-24 Samples
08L) at a rotation speed of 50 rpm, and a temperature were collected after six months of storage and analyzed
of 37 ± 0.5°C. In order to simulate the gastrointestinal for the drug content and in vitro dissolution rate25 and
transit conditions, the tablets were subjected to different they were subjected to statistical analysis using paired
dissolution media. Initially, the drug release was carried t-test to test the significance of difference at 0.05 level of
out for 2 h in 0.1 N HCl, 2 h in buffer pH 5.5 and finally significance (LS). Then the similarity index was calculated
in phosphate buffer pH 7.4 up to 24 h. At specific time
between dissolution rates of optimized tablets before and
intervals, 5 ml samples were withdrawn and replaced by an
after storage to prove the stability of the dosage form.
equal volume of fresh pre-warmed dissolution medium.
The similarity factor (F2) is a logarithmic reciprocal square
The samples were filtered through 0.45 µm membrane
root transformation of the sum of squared error and is
filter (Millipore, USA) and analyzed at 254 nm using UV
a measurement of the similarity in the percent (%) of
detector by HPLC method.
dissolution between the two curves.
In vitro release kinetics
F2= 50 x log {[1 + (1/n) ∑t=1n (Rt-Tt)2]-0.5 x 100}
The data obtained from the in vitro dissolution studies

was fitted to zero order, first order and Higuchi models
to explain the pattern and the release mechanism from
In vivo x-ray imaging studies
the formulations. Koresmeyer–Peppas model is one of
the mathematical expressions, used to understand the X-ray imaging technique was used to monitor tablets
mechanism of drug release from these formulations.21 throughout the GI system. The inclusion of radio-
The mean dissolution time (MDT) is defined as the sum opaque material into the solid dosage form enables it
of different release fraction periods (release areas) during to be visualized by the use of x-rays. By incorporating
dissolution studies divided by the initial loading dose.22
barium sulphate (20 mg) into the pharmaceutical dosage
T10% and T80% (time in hours to take 10% and 80%
forms, it is possible to follow the movement, location
drug release, respectively) were calculated to clarify the
and integrity of the dosage form after oral administration
colon-specific release from matrix tablets.13
by placing the subject under a fluoroscope and taking a
Drug-polymer interaction studies series of x-ray films at various time points. Three healthy
male human volunteers, between 22-30 years of age and
To study the possible interaction between FLB and HPMC, 50-70 kg body weight, were participated in x-ray imaging
DSC study was carried out on pure drug and optimized studies. They were non-alcoholics, non-smokers and
formulation (F6) and the thermograms were obtained have not taken any drugs. The purpose of the study was
using DSC (Perkin-Elmer, Shelton, U.S). The analyses were fully explained to the volunteers and the volunteers had
performed under nitrogen (nitrogen flow rate 50 ml/min) given their written consent. Each subject ingested barium
in order to eliminate oxidative and pyrrolytic effects at a sulphate containing optimized formulation (F6) orally
standard heating rate of 15ºC/min over a temperature with 200 ml water, after an overnight fast. The tablets
range of (50–350)ºC. The FTIR spectra of FLB and were visualized using films exposed to x-rays. Abdominal
optimized formulation (F6) recorded between 400 to 4000 radiographs were taken after 30 min, 3 h, 6 h, 8 h and 24 h
cm-1 on FTIR to detect the drug-excipient interactions. The in all the subjects. The volunteers were served with food;
FTIR spectra for the test samples were obtained using KBr 2 h (breakfast) and 4 h (lunch) after the administration of
disk method using an FTIR spectrometer (Perkin Elmer the tablet.26 The institutional ethical committee (Approval
FTIR, Perkin Elmer Inst. USA). The resultant spectra No. 338-03/JIPS/JNG/IHEC/2011) approved the
were compared for any possible changes in the peaks of protocol of the x-ray imaging study of colon targeted
the spectra. tablets of FLB.

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 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

Table 2: Characterization of powder mixture

Angle of Bulk Tapped Carr’s

Formulation
Repose* (0) Density (g/cc) Density (g/cc) Index (%)

F1 31.45±0.98 0.336 0.392 16.67

F2 29.83±4.04 0.322 0.383 18.94

F3 31.13±0.93 0.324 0.387 16.28

F4 28.90±1.24 0.332 0.394 18.67

F5 30.14±3.50 0.334 0.397 18.86

F6 30.42±3.76 0.327 0.389 15.94

*All Values Represent Mean ± Standard Deviation, n=3

Table 3: Physical properties of FLB colon specific matrix tablets

Weight Hardness† Friability Drug content‡

Formulation
variation* (mg) (Kg/cm2) (%) (%)

F1 300.45±3.49 6.23±0.46 0.22 99.73±0.58

F2 300.20±3.83 6.07±0.29 0.50 98.69±1.12

F3 299.34±3.79 6.03±0.31 0.39 99.86±0.71

F4 299.75±3.99 6.20±0.36 0.39 98.92±1.45

F5 301.05±4.03 6.40±0.10 0.44 99.24±1.01

F6 361.56±3.12 6.03±0.31 0.39 99.97±2.20

All values represent mean ± standard deviation, *n=20; †n=6: ‡n=3.

RESULTS indicating uniformity of drug content.

Powder characterization Effect of HPMC amount on matrix integrity

The powder mixtures of different formulations were From the cumulative mean percent of FLB released from
evaluated for angle of repose, bulk density (apparent and matrix tablets containing varying amounts of HPMC K4M,
tapped), compressibility index and their values were shown in incorporation of 40 mg of polymer in the total tablet
Table 2. The apparent and tapped bulk density values ranged weight was found to be satisfactory to formulate a tablet
from 0.322 to 0.336 and 0.383 to 0.397 respectively. The with good integrity (data not presented).
results of angle of repose and % Carr’s index ranged from
28.90 ± 1.24 to 31.45 ± 0.98 and 15.94 to 18.94 respectively. Effect of HPMC viscosity grade on matrix integrity

Evaluation of physical parameters Figure 1 showed the release profiles of FLB from the
HPMC matrix tablets of different viscosity grades (F1-
The physical properties of FLB-HPMC matrix tablets were F5). The cumulative mean percent of FLB released from
given in Table 3. In weight variation test, the pharmacopoeial above formulations was found to vary from 21.52 ± 1.05 to
limit for the tablets is not more than 5% of the average 102.22 ± 1.18 after 5 h of testing in simulated gastric and
weight and found to be 299.34 ± 3.79-361.56 ± 3.12. The intestinal fluids and the percent drug release was increased
hardness of the tablets was found to be in the range of 6.03 gradually after 5 h and it was found to be 60.40 ± 2.36 to
± 0.31 to 6.40 ± 0.10 kg/cm2. Another measure of tablets 100.43 ± 3.33 in 24 h.
strength is friability. Conventional compressed tablets that
lose less than 1% of their weight are generally considered Effect of Eudragit S100 coating
acceptable. The percentage friability for all formulations
was below 1% i.e. 0.22-0.50%, indicating that the friability In order to evaluate the effect of the coating level, release
is within the prescribed limits. The tablets were found to profile under pH-gradient, formulation F3 tablets were
contain 98.69 ± 1.12-99.97 ± 2.20% of the labeled amount coated with Eudragit S100 in amounts varying from 5 to
Journal of Young Pharmacists Vol 7 ● Issue 4 ● Oct-Dec  2015 377
 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

Figure 1: Release profile of FLB from uncoated and eudragit S100 coated HPMC
matrix tablets

Table 4: Release kinetics of FLB colon specific matrix tablets

Zero Order First Order Higuchi

Formulation K0­ K1 K
R2 R2 R2
(mg/hr) (hr -1) (mg/hr-1/2)
F1 24.29 0.988 0.93272 0.875 50.74 0.881

F2 21.4 0.978 0.91199 0.891 34.49 0.865

F3 4.499 0.915 0.1543 0.627 23.86 0.922

F4 3.666 0.917 0.152 0.641 19.43 0.923

F5 2.635 0.914 0.14048 0.655 14.04 0.93

F6 4.803 0.939 0.19806 0.694 24.58 0.88

K0-Zero order rate constant, K1-First order rate constant, K-Higuchi model rate constant and R2 -Correlation coefficient.

30% w/w (F6). Figure 1 showed the comparison of release of optimized formulation was found to be 4.5 h and 17.9
profiles of FLB from the enteric coated tablet to uncoated h respectively. All these results were given in Table 5.
tablet. The cumulative mean percent of FLB released from
above coated tablets was found to vary from 18.41 ± 0.68 Drug-polymer interaction studies
after 5 h of testing in simulated gastric and intestinal fluids
and the percent drug release was increased gradually after DSC studies were performed to understand the nature of
5 h and it was found to be complete drug release (100.43 the drug in the formulated tablets. DSC curves obtained
± 3.33%) in 24 h. for pure drug and optimized formulation were showed in
Figure 2. A sharp endothermic peak corresponding to the
In vitro release kinetics melting point of FLB was found at 116°C. An endothermic
peak corresponding to the melting point of FLB in
The values of K, and r2 (correlation coefficient of the optimized formulation was observed at 115.4°C. The FTIR
regression analysis) of zero order, first order and Higuchi spectral analysis of pure FLB and optimized formulation
models of designed formulations were given in Table 4. were showed the principal peaks at similar wave numbers
The n values calculated for different formulations were (Figure 3). The FTIR spectral analysis of FLB alone showed
found in the range of 1.2966 to 2.8776. The MDT values that the principal peaks were observed at wave numbers of
were found to be 2.71-12.21. The T10% and T80% values 1701.22, 1415.75, 1217.06, 923.9, 765.7 and 696.23 cm-1. In
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 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

Table 5: Release kinetics of FLB colon specific matrix tablets

Formulation K n R2 MDT (h) T10% (h) T80% (h)

F1 1.7645 2.8776 0.897 2.71 0.28 3.1

F2 1.6519 2.8171 0.914 2.70 0.42 3.9

F3 1.8217 1.4433 0.915 9.57 2.4 16.5

F4 1.6592 1.3592 0.921 9.16 3.9 23.8

F5 1.5617 1.2966 0.936 8.98 4.0 27.4

F6 1.5289 1.7495 0.905 12.21 4.5 17.9

K-Kinetic rate constant, n-diffusional exponent, r2 -Correlation coefficient, MDT-Mean dissolution time, T10%-Time to release 10% drug release and
T80%-Time to release 80% drug release.

Figure 2: DSC thermograms of 1) FLB 2) F6 tablets

Figure 3: Fourier transform infrared spectra of 1) FLB 2) F6 tablets

the FTIR spectra of the optimized formulation (F6) were Stability studies
1701.22, 1419.61, 1217.06, 925.83, 765.7 and 696.23 cm-1
wave numbers were observed. However, some additional In view of the potential utility of the formulation, stability
peaks were observed with physical mixtures, which could studies were carried out at 40 ± 2°C and 75 ± 5% RH for six
be due to the presence of polymers. months to assess their stability. After storage of six months,
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 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

Table 6: Stability studies of FLB colon specific matrix tablets (F6)

Similarity
Time (h) Before storage After 6 months Paired t-test
Factor
0 0.00±0.00 0.00±0.00

2 0.71±0.15 0.62±0.17

4 6.26±0.33 6.14±0.41

5 18.41±0.68 18.04±0.47
Not Significant at
95.01
0.05 LS
8 49.23±3.30 49.28±3.40

12 73.16±2.13 72.36±0.93

18 82.10±1.33 81.41±1.37

24 100.43±3.33 99.40±1.92
Not Significant at
% Assay 99.97±2.20 99.12±1.57 --
0.05 LS

Figure 4: Positions of the FLB colon specific eudragit coated HPMC matrix tablets
throughout the GI tract at different time points

the formulation was subjected to a drug assay and In vitro The position of tablets at different time points is shown in
dissolution studies (Table 6) and from the statistical analysis the x-ray images of tablet throughout the GI system (Figure
there was no significant difference between before and 4). From the abdominal radiographs, taken at different time
after storage (P<0.05). The similarity index value between points, the tablets entered the colon, varying between 3-6 h
dissolution profiles of optimized formulation before and for all volunteers after tablet administration. These results
after storage was found to be 95.01. are in agreement with the results of Ashford et al. who
observed that the gastric emptying times of 0.6–2.9 h, small
In vivo x-ray imaging studies intestinal transit times of 1.8–8.5 h and colonic arrival time
of 3.2–9.8 h while evaluating pectin as a compression coat
X-ray studies were carried out on the F6 formulation tablets, for colonic delivery, using gamma scintigraphy.27
in order to see the coated tablets throughout the GI system.
Barium sulphate was used as the marker. The position of DISCUSSION
the tablets in the body was monitored at different time
points. The abdominal radiographs showed that, the tablets The angle of repose and % Carr’s index were measured
remained intact in the stomach in all subjects. The transit to determine the flow properties of powder mixtures of
time of the tablets throughout the GI system was variable. all formulations and the results of angle of repose (<35)
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 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

and compressibility index (<23) indicates fair to passable Eudragit S100, a methylacrylic acid-methylmethacrylate
flow properties of the powder mixture. Appreciable flow copolymer, was selected as the enteric coated polymer. It
properties facilitate the flow of powder mixture during has about 30% methacrylic acid units which tend to dissolve
the tabletting process. In a study reported in the literature at pH 7, and therefore, it is considered a suitable coating
i.e., Ketorolac tromethamine-HPMC matrix tablets, similar material for colonic drug delivery, to overcome the lower
type of results were observed.9 gastric and small intestine pH values.3 From the dissolution
studies in different pH media, a progressive lag time
The physical properties like weight variation, thickness, increase and drug release rate decrease was observed with
hardness and friability of all formulations were in increasing the coating amount (data not presented). Study
compliance with pharmacopoeial standards, so all the report on diclofenac sodium compression coated tablets
tablets were with acceptable physical characteristics. In also showed retardation of drug release as the Eudragit
weight variation test, the pharmacopoeial limit for the S100 percentage is increased in the compression coat.8
tablets is not more than 5% of the average weight. The From the in vitro dissolution study the lowest coating level
average percentage deviation of all tablet formulations was to obtain a lag time (5 h) considered suitable for achieving
found to be within the above mentioned limit and hence all colonic targeting was found at 20% w/w of polymeric coat
formulations passed the uniformity of weight as per official (F6). As a consequence of the progressive dissolution of
requirements of Indian Pharmacopoeia, 1996. From the the coating, the matrix tablets take up water rapidly and
physical characterization of all tablet formulations, it was swelling occurs immediately, leading to the formation of
found that they were uniform in hardness, friability and a gel barrier through which the drug can diffuse.
drug content. The hardness and friability are measure of
tablets strength and integrity. The drug release kinetics studies revealed high correlation
coefficient values for zero order than first order indicating
From the preliminary studies to optimize the polymer that the drug release from matrix tablets followed zero
content in the tablet, different formulations were prepared order profile. Zero order release was also observed in a
and evaluated for drug release using the HPMC K4M. study with 5-fluorouracil using HPMC in the compression
From the dissolution studies, the formulation containing coat.11 The high regression value of Higuchi model ensured
40 mg of HPMC showed good drug release pattern in a that the release of drug from matrix tablets followed
controlled manner for 24 h with good physical properties diffusion mechanism. The n values calculated for different
and matrix integrity (data not presented). Dissolution formulations indicate a supercase-II transport. The MDT
study of F1-F5 formulations showed the effect of was higher for formulations with high viscosity HPMC
different viscosity grades of HPMC on release profiles grades compared to low viscosity grades of HPMC,
of FLB from the HPMC matrix tablets. Formulations indicating better controlled release. Literature report on
with HPMC of high viscosity formed swollen gel matrix flurbiprofen compression coated tablets also showed
with substantial integrity and the drug release was in similar type of results.5 Time in hours to take 10% and 80%
a controlled manner which could be due to the better drug release (T10% and T80%) explained the ability of
control of water and drug diffusion. Similar type of colon specific release from matrix tablets that signifies the
results observed in the reported studies of literature.4,11 low amount of drug release in lag period and progressive
On the contrary low viscosity grades of HPMC tablet release in colon.
lacked strength and were eroded quickly after swelling. In
the present investigation, HPMC K4M in comparison to DSC studies were performed to understand the nature
HPMC K15M and HPMC 100M showed negligible drug of the drug in the formulated tablets. Thermogram of
release in the initial lag period and followed by controlled the optimized formulation did not show any significant
release for 24 h, which is the normal residence time of shift in the endothermic peak when compared to pure
solid dosage form in the GIT.28 Thus the formulation F3 drug, indicating that there was no change in FLB in the
with HPMC K4M was considered better among other HPMC matrices. From the FTIR spectral analysis all the
formulations to produce colon specific drug delivery principal peaks observed in pure drug were present in the
of FLB and it is further improved by Eudragit S100 FTIR spectra of the optimized formulation (F6) and some
polymeric coating. The drug delivery systems targeted to additional peaks were observed with physical mixtures,
the colon should not only protect the drug from being which could be due to the presence of polymers. These
released in the physiological environment of stomach results suggest that there is no interaction between the drug
and small intestine, but also release the drug in colon.29 and polymers used in the present study.

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 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

Table 7: FLB colon specific eudragit coated HPMC matrix tablets position throughout the GI tract at
different time points

Time 30 min 3h 6h 8h 24h

Tablet Ascending Ascending
Stomach Cecum Not observed
position colon colon

After storage of six months, the formulation was subjected stomach and small intestine. From the drug release kinetics,
to a drug assay and in vitro dissolution studies and the data above formulation followed zero order profile and the
showed that there was no significant change in formulation mechanism of drug release followed supercase II transport.
in the sense of drug content and dissolution behavior. The Drug-excipients interaction studies and accelerated stability
similarity index value was found as 95.01, which is more studies proved the stability of formulation. The in vivo
than 50 indicates similarity between the dissolution profile x-ray imaging study in human volunteers proved that the
before and after storage.30-31 The in vivo x-ray imaging results tablets (F6) reached the colon without disintegrating in the
showed that the tablets (F6) reached the colon without upper GIT. All in all, development of Eudragit S100 coated
disintegrating in the upper region of the GI system in all HPMC matrix tablets using combination of pH-sensitive
subjects. The x-ray images showed that the tablets slowly and time dependent approaches is a great methodology
disintegrated throughout the colon after reaching it. Colon for colon specific delivery of flurbiprofen.
targeted drug delivery systems have been visualized widely
using gamma scintigraphy in the literature where the tablet
integrity is lost in the colon.32 In the present study x-ray
ACKNOWLEDGEMENTS
imaging studies showed gradual reduction in the size of the
The authors acknowledge FDC Limited, Mumbai, India
tablet with time until it disappeared completely (Table 7).
and Matrix laboratories, Hyderabad, India for gift sample
of Flurbiprofen, HPMC K4M, and Eudragit S100. The
CONCLUSION authors also thank Principal and Management, Jangaon
Institute of Pharmaceutical Sciences for providing facilities.
The present investigation was carried out with significant
plan to develop FLB colon specific tablets. Time- pH-
specific matrix tablets using HPMC and eudragit were ABBREVIATION
decreased the drug release in the upper region of GIT, but
HPMC: Hydroxypropyl methylcellulose
gave good amount of drug release in colon. Based on in vitro
drug release studies, F6 formulation (FLB: HPMC K4M: FLB: Flurbiprofen
Eudragit S100 ratio of 1: 0.4: 0.6) showed the significant DSC: Differential Scanning Calorimetry
level of drug release in the colon with negligible loss in FTIR: Fourier transform infrared spectra

Highlights of Paper
• Combination of time and pH-dependent approaches is able to gain the colon-specific drug release.
• F6 formulation (FLB: HPMC K4M: Eudragit S100 ratio of 1: 0.4: 0.6) showed the significant level of drug release in the colon (100.43
± 3.33%) with negligible loss in stomach and small intestine (18.41 ± 0.68%).
• The T10% and T80% values of F6 formulation was found to be 4.5 h and 17.9 h.
• The similarity factor value between dissolution profiles of F6 formulation before and after storage was found to be 95.01.

Author Profile
• Dr. Sateesh Kumar Vemula: Is an accomplished researcher, eminent teacher in Pharmaceutical Sciences.
Presently working as Associate Professor in Department of Pharmacy, College of Medical & Health Sciences,
Wollega University, Ethiopia. He has 9 yrs teaching experience and an extensive research experience in Colon-
specific drug delivery systems, Fast dissolving tablets, Solid dispersions, and Liquisolid tablets. He has more than 45
research publications in several international and national journals, 20 poster/oral presentations as presenting author
in several national and international conferences and guided 18 M. Pharm students.

382 Journal of Young Pharmacists  Vol 7 ● Issue 4 ● Oct-Dec  2015

 Sateesh Kumar : Flurbiprofen colon specific matrix tablets

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