8 CF 3
8 CF 3
8 CF 3
DOI: 10.7897/2230-8407.09454
ABSTRACT
The present investigation was done based on the many frequencies of drug taken orally per single day so, for altering the dose frequency of the drug delivery
for the colonic diseases diclofenac sodium was loaded with the microsponges. The colonic targeted microsponges are prepared by acid resistant polymers
such as eudragit L100, eudragit RS 100, eudragit EPO 100. These acid resistant polymers release the drug for controlled manner and site specific action.
Diclofenac sodium was incorporated into microsponges which help in controlled release of the diclofenac sodium. The polymer used for the preparation of
microsponges was useful in forming sponges in which drug was entrapped. FT-IR studies were performed and from the FT-IR spectra it was evident that
there were no interactions between the diclofenac sodium and polymer. Formulations of microsponges were prepared by quasi-emulsion solvent diffusion
technique using eudragit L100, eudragit RS 100 and eudragit EPO 100 in various ratios such as (1:0.5, 1:1, 1:2 and 1:2). By using the 3 polymers 12
formulations were prepared from the 12 formulations 3 formulations were selected as optimized formulations based on the production yield(%),drug
loading(%), encapsulating efficiency and in vitro drug release studies (90.4.7%). Hence, it was proposed that diclofenac sodium microsponges having porous
structure and drug release is controlled by predetermined rate. By comparing these three formulations (L2, S3, EPO1) L2 formulation containing EL100
gives the best results.
Keywords: Microsponges, patient compliance, Eutragit S 100, Eutragit L100, Eutragit EPO 100.
This approach for the new drug delivery designs has been termed as MDS can provide increased efficacy for topically active agents
lamentation. Most drug compounds are not inherently long-lasting with enhanced safety, extended product stability and improved
in the biological system and require multiple daily dosing to achieve aesthetic properties in an efficient manner. [5] To control the delivery
10
S.Janakidevi & K.V.Ramanamurthy. Int. Res. J. Pharm. 2018, 9 (4)
rate of active agents to a pre determined site in the human body has Drug content: 100 mg of diclofenac sodium loaded microsponges
been one of the biggest challenges faced by pharmaceutical was taken and mixed with 100 mL of 6.8 pH phosphate buffer.
scientists.[6, 7]. Stirring was carried out for four hours then the mixture was filtered,
then filtrate was taken for absorbance.
MATERIALS AND METHODS
Encapsulation efficiency (%)
Diclofenac sodium, Eudragit S100, Eudragit L100, Eudragit EPO
100, were gift samples from Hetero labs, Hyderabad. Polyvinyl The loading efficiency (%) of the microsponges was calculated
alcohol purchased from Loba Chemie Pvt. Ltd. According to the following equation:
Fourier Transform Infrared (FTIR) Spectroscopy Encapsulation efficiency = Actual drug content in microsponge /
Theoretical drug content × 100
The Fourier transform infrared (FTIR) spectra of samples were
obtained using FTIR spectrophotometer (Perkin Elmer). Pure drug, Surface Morphology – SEM
individual polymers and optimized formulations were subjected to
FTIR study. About 2–3 mg of sample was mixed with dried Morphology scanning electron microscopy (SEM), SEM is used
potassium bromide of equal weight and compressed to form a KBr widely for which prepared Microsponges are coated with gold–
disk. The samples were scanned from 500 to 4000 cm−1. palladium under an argon atmosphere at room temperature and then
the surface morphology of the microsponges is studied.
Construction of calibration curve for diclofenac sodium
In-vitro drug release study
Preparation of stock solution
In vitro dissolution of diclofenac microsponges was studied in USP
100 mg of the drug was weighted and dissolve in small amount of XXIII dissolution apparatus (Electro lab) rotated at 100 rpm.900 ml
ethanol and then made up to 100 mL with distilled water. This was of standard buffer pH 1.2 for two hours, followed by pH 6.8 for the
noted as stock I. From stock I, 10 mL of solution was taken and next 4 hours and pH 7.4 phosphate buffer solutions for remaining
made up to 100 mL with distilled water this was noted as stock hours were used as dissolution medium. The temperature of
II.From this 0.2 mL, 0.4 mL, 0.6 mL, 0.8 mL, and 1.0 mL and dissolution medium was maintained at 37± 0.50C throughout the
solutions was taken and made up to 10 mL with methanol to obtain experiment. One tablet was used in each test. Samples of dissolution
2 µg, 4 µg, 6 µg, 8 µg, and 10 µg concentrations respectively. The medium (5ml) were withdrawn by means of syringe fitted with pre-
absorbance of the samples was seen at 275 nm in UV filter at known intervals of time and analyzed for drug release by
spectrophotometer (8).A calibration curve was constructed by measuring the absorbance at 275 nm. The volume withdrawn at
plotting the absorbance against the concentration of diclofenac each time interval was replaced with fresh quantity of dissolution
sodium. A regression equation was derived from the plot. medium. The dissolution studies were carried out in triplicate.
Cumulative percent drug released was calculated and plotted against
Microsponge preparation time [11].
The microsponges containing Diclofenac sodium were prepared by Dissolution test parameters
quasi emulsion solvent diffusion method using the different Rpm : 100
polymers amounts. In this method internal phase containing Time : 60min interval.
polymer such as Eudragit which is dissolved in ethyl alcohol. Then, λ : 288 nm
max
the drug is slowly added to the polymer solution and dissolved, then
Temperature : 370 C ± 0.50 C
plasticizer such as glycerin was added in order to aid the plasticity.
The inner phase is then poured into external phase containing
In-vitro Release kinetics
polyvinyl alcohol and distilled water with continuous stirring for 2
hours. Then, the mixture was filtered to separate the microsponges.
Dissolution data of above formulations was fitted in Zero order,
The product (microsponges) was washed and dried in an air- heated
First order equations.
oven at 40°C for 12 hr (9).Micro sponges were prepared as per
Zero-Order Kinetics:Zero order as cumulative amount of drug
formula in table 1.
released vs. time,
C = K0 t
Evaluation of micro sponge [10]
Where K0 is the zero-order rate constant expressed in units of
concentration/time and t is the time in hours. A graph of
The prepared microsponges evaluated for production yield (%),
concentration vs. time would yield a straight line with a slope equal
drug content (%), encapsulating efficiency (%) was determined.
to K0 and intercept the origin of the axes [12].
First order kinetics: First order as log cumulative percentage of drug
Production yield (%)
remaining vs. time,
The production yield of the micro particles was determined by
L o g C = L o g C0− k t / 2.303
calculating accurately the initial weight of the raw materials and the
last weight of the microsponge obtained.
Where C0 is the initial concentration of drug, k is the first order
constant, and t is the time [12].
Production yield = Practical mass of microsponges / Theoretical
mass (polymer + drug) ×100
11
S.Janakidevi & K.V.Ramanamurthy. Int. Res. J. Pharm. 2018, 9 (4)
Higuchi Model:Higuchi’s model as cumulative percentage of drug EPO 4 (55.99±0.57) In this, L2, S3 and EPO 1 showed higher
released vs. square root of time product yield as shown in the Table-3.
Where K is the constant reflecting the design variables of the system Drug loading of the formulations were found to be L1 (43.85±0.11),
and t is the time in hours. Hence, drug release rate is proportional to L2 (47.52±0.85), L3 (40.85±0.37), L4 (38.25±0.64), S1
the reciprocal of the square root of time [13]. (35.25±0.720), S2 (40.85±85), S3 (43.85±73) S4 (39.52±0.92),
EPO 1 (40.89±0.34), EPO 2 (35.52±0.46), EPO 3(32.35±0.67) and
Korsmeyer Peppas equations: EPO 4 (29.85±0.61). In this, L2, S3 EPO 1 showed higher drug load,
in these 3 formulations S3 was found to be less then L2, EPO 1 was
To evaluate the mechanism of drug release from dosage form, data less then S3, are show on the Table-3.
for the first 60% of drug release were plotted in Korsmeyer et al’s
equation log cumulative percentage of drug released vs. log time, Encapsulating efficiency (%)
and the exponent n was calculated through the slope of the straight
line. The entrapment efficiency was found to be L1 (60.53±0.10), L2
(54.52±0.45), L3 (48.65±0.56), L4 (39.85±0.81), S1 (52.45±0.34),
Mt/M∞=Ktn S2 (49.52±0.91), S3 (59.62±0.27) S4 (48.52±0.13), EPO 1
(60.52±0.67), EPO 2 (52.86±0.51), EPO 3(45.42±0.24) and EPO 4
Where Mt/M∞ is the fractional solute release, t is the release time, (43.12±054). In this, L2, S3, EPO 1 showed higher encapsulating
K is a kinetic constant characteristic of the drug/polymer system, efficiency, in these 3 formulations L3 was found to be higher
and n is an exponent that characterizes the mechanism of release of encapsulating then S3, and EPO 1 are show on the Table-3.
tracers. For cylindrical matrix tablets, if the exponent n = 0.45, then
the drug release mechanism is Fickian diffusion, and if 0.45 < n < Drug release profiles of microsponges
0.89, then it is non-Fickian or anomalous diffusion. An exponent
value of 0.89 is indicative of Case-II Transport or typical zero-order Drug release studies indicated that microsponge formulations L1,
release [14]. L2, L3, L4, S1, S2, S3, S4, EPO1, EPO2, EPO3, and EPO4 released
drug for about 12hrs. During this period, the amount of drug
RESULTS AND DISCUSSION released by L2 is 90.15±0.49 at 12 hrs; S3 is 62.05±0.95 at 12 hrs,
EPO1 59.51±0.54 is at 12hrs, among these 12 formulations, L1, S3,
Diclofenac sodium was selected as the drug for the preparation of EPO 1 shows the maximum release for about 12hr and these are
microsponges tablets using ethanolic solutions of eudragit, L100, selected for the formulation of tablets.
eudagit RS 100, eudragit EPO which act as internal phase and 5 %
w/v PVA as external phase for the preparation of microsponge Keeping the view of drug load (%), product yield (%) and
tablets. encapsulating efficiency the microsponges are optimized and
further preparation of tablets formulation. Results were shown in
Calibration curve of diclofenac sodium table no-4 to7 and figure no-2 to 9 From the above 12 formulations,
from each polymer one optimized formulation were selected based
In the present investigation the calibration of diclofenac sodium was on production yield, drug content , encapsulating efficiency. From
carried by using UV-spectrophotometry by measuring the the above tables, the drug release was observed to be about 12 hrs.
absorbance at 275 nm. The results of absorbance vs. concentration Release kinetics followed zero order kinetics and the Release
are shown in Table 2 and the calibration curve is shown in Fig. 1. mechanism was observed as diffusion mechanism also the type of
The absorbance vs. concentration obeyed the Beer’s law in the range diffusion was super case –II transport, hence the prepared
of 2-10 µg/mL. Good correlation was observed between the microsponge (L2, S3, and EPO1) could extend drug release as
absorbance and concentration and the coefficient of determination expected. When compared these three formulations L2 formulation
was found to be 0.9979. release maximum % of the drug 82.17%.
The microsponges were prepared in drug-polymer ratios of The FT-IR spectra of pure drug diclofenac sodium, pure polymer
L1(1:0.5), L2 (1:1), L3 (1:1.50), L4 (1:2), S1 (1:0.5), S2 (1:1), S3 eudragit L 100 and diclofenac sodium and eudragit L100 are shown
(1:1.50), S4 (1:2) and EPO 1 (1:0.50), EPO2 (1:1), EPO 3 (1:1.50) in Fig. 10 , 11, and 12.The FT-IR spectrum of diclofenac sodium
and (1:2) by using eudragit L100, eudragit RS100 and eudragit EPO showed characteristic C–H stretch at 2998 cm-1, aliphatic C=C at
100 as ethanolic solutions which acts as internal phase for 1658 cm-1.The FT-IR spectrum of eudragit L100 showed
diclofenac sodium and 5 % w/v PVA solution as external phase. characteristic C-O stretch at and C=O at 1041 cm-1.The FT-IR
spectrum of both drug and polymer showed similar characteristics
Production yield (%) with minor shifts. The major peaks for the pure drug and the
polymer are well in support with the theoretical prediction with
Product yield of all the formulations were found to be L1 respect to the functional groups. This indicates that there is no
(62.85±0.12), L2 (80.59±0.18), L3 (63.44±0.68), L4 (60.05±0.64), interaction between drug and the polymer used in the study. Hence
S1 (60.95±0.28, S2 (60.58±0.64), S3 (65.86±0.75) S4 (55.49±.98), FTIR spectral analysis proved the compatibility of the drug and
EPO 1 (70.49±85), EPO 2 (64.94±0.85), EPO 3(63.94±0.29) and polymer used in the study.
12
S.Janakidevi & K.V.Ramanamurthy. Int. Res. J. Pharm. 2018, 9 (4)
TABLE.3: PRODUCT YIELD (%), DRUG LOADING (%) AND ENTRAPMENT EFFICIENCY (%)
Formulation code Product Yield (%) Drug loading (%) Entrapment efficiency (%)
L1 62.85±0.12 43.85±0.11 60.53±0.10
L2 80.59±0.18 47.52±0.85 54.52±0.45
L3 63.44±0.68 40.85±0.37 48.65±0.56
L4 60.05±0.64 38.25±0.64 39.85±0.81
S1 60.95±0.28 35.25±0.720 52.45±0.34
S2 60.58±0.64 40.85±85 49.52±0.91
S3 65.86±0.75 43.85±73 59.62±0.27
S4 55.49±.98 39.52±0.92 48.52±0.13
EPO 1 70.49±85 40.89±0.34 60.52±0.67
EPO 2 64.94±0.85 35.52±0.46 52.86±0.51
EPO 3 63.94±0.29 32.35±0.67 45.42±0.24
EPO 4 55.99±0.57 29.85±0.61 43.12±054
All the values are expressed mean±SD, (n=3)
Time (mins) L1 L2 L3 L4
15 0.099±0.75 0.204±0.54 0.188±0.78 0.799±0.58
30 3.894±0.34 3.278±0.16 2.63±0.28 4.368±0.18
60 11.756±0.85 20.52±0.45 18.76±0.19 8.796±0.37
120 18.641±0.64 26.8±0.65 20.58±0.18 25.11±0.48
180 32.046±0.42 46.22±0.37 34.65±0.25 36.31±0.28
240 42.498±0.35 56.37±0.18 41.98±0.45 44.9±0.75
360 48.498±0.75 63.75±0.34 44.98±0.27 47.19±0.18
480 50.625±0.19 71.46±0.48 45.05±0.29 60.2±0.48
540 53.152±0.85 76.62±0.19 57.95±0.37 68.6±0.27
720 70.75±0.75 90.15±0.49 71.40±0.67 71.5±0.27
All the values are expressed mean±SD, (n=3)
13
S.Janakidevi & K.V.Ramanamurthy. Int. Res. J. Pharm. 2018, 9 (4)
Time (mins) S1 S2 S3 S4
15 0.54±0.75 0.126±0.16 0.155±0.48 0.044±0.18
30 3.014±0.79 2.76±0.18 2.89±0.64 2.8±0.48
60 6.37±0.85 6.17±0.20 13.85±0.24 7.2±0.19
120 15.07±0.83 13.7±0.64 18.52±0.59 15.64±0.54
180 24.24±0.18 22.16±0.85 30.52±0.34 29.42±0.34
240 31.33±0.48 29.27±0.48 35.65±0.75 30.44±0.47
360 35.83±0.48 30.86±0.18 40.58±0.95 36.30±0.58
480 42.84±0.49 42.44±0.85 45.85±0.34 44.05±0.18
540 49.50±0.49 49.26±0.45 50.58±0.82 50.6±0.15
720 57.85±0.75 56.38±0.64 62.05±0.95 57.3±0.24
0.25
0.2
Absorbance
0.15
y = 0.0195x + 0.0259
0.1
R² = 0.9977
0.05
0
0 2 4 6 8 10 12
Concentration µg/ml
FIG.1: CALIBRATION CURVE OF DICLFENAC SODIUM
14
S.Janakidevi & K.V.Ramanamurthy. Int. Res. J. Pharm. 2018, 9 (4)
100
90
70
60
Cummulative % of drug remained
50
40 S1
30 S2
S3
20
S4
10
0
0 200 400 600 800
-10
Time (min)
15
S.Janakidevi & K.V.Ramanamurthy. Int. Res. J. Pharm. 2018, 9 (4)
70
60
40 EPO 1
30 EPO 2
EPO 3
20
EPO 4
10
0
0 200 400 600 800
-10
Time (mins)
16
S.Janakidevi & K.V.Ramanamurthy. Int. Res. J. Pharm. 2018, 9 (4)
120
100
% of drug remained 80
60
L1
40 S3
EPO 1
20
0
0 200 400 600 800
-20
Time (mins)
Fig .6: ZERO ORDER PLOT FOR OPTIMIZED MICROSPONGES L2, S3, EPO1
2.5
Log % of drug remained
1.5
L2
1 S3
EPO 1
0.5
0
0 200 400 600 800
Time (mins)
FIG .7: FIRST ORDER RELEASE OF OPTIMIZED FORMULATIONS (L2, S3, EPO1)
17
S.Janakidevi & K.V.Ramanamurthy. Int. Res. J. Pharm. 2018, 9 (4)
100
Cummulative % of drug
80
60
L2
release
40
20
S3
0
0 10 20 30 40
-20
-40
√ Time (mins)
3905.87
3787.90
3634.55
3250.64
3067.13
3032.19
2970.68
2905.21
2609.14
2538.71
2296.89
2191.20
1917.23
1857.36
1799.78
1763.92
1577.06
1501.15
1450.47
1380.70
1305.60
1249.02
1195.32
1154.22
1088.66
1043.42
947.38
916.43
890.76
865.71
843.11
768.02
745.57
715.05
691.11
635.73
615.64
586.71
22/08/2016
C:\Program Files\OPUS_65\MEAS\.946 D1 SOLID
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S.Janakidevi & K.V.Ramanamurthy. Int. Res. J. Pharm. 2018, 9 (4)
100
100
80
80
Transmittance [%]
Transmittance [%]
60
60
40
40
20
20
0
0
3904.50
3247.63
3067.20
3002.98
2956.65
2607.10
1916.84
1855.98
1725.24
1577.05
1555.57
1497.73
1450.86
1382.84
1275.51
1195.31
1156.43
1100.39
1044.50
3904.50
3247.63
3067.20
3002.98
2956.65
2607.10
1916.84
1855.98
1725.24
1577.05
1555.57
1497.73
1450.86
1382.84
1275.51
1195.31
1156.43
1100.39
1044.50
964.04
949.89
917.51
891.86
865.48
841.61
767.70
746.59
715.20
690.92
669.15
635.57
614.31
586.44
964.04
949.89
917.51
891.86
865.48
841.61
767.70
746.59
715.20
690.92
669.15
635.57
614.31
586.44
4000 3500 3000 2500 2000 1500 1000 4000 3500 3000 2500 2000 1500 1000
Wavenumber cm-1 Wavenumber cm-1
22/08/2016 22/08/2016
C:\Program Files\OPUS_65\MEAS\.945 D2 SOLID C:\Program Files\OPUS_65\MEAS\.945 D2 SOLID
FIG.11: STRUCTURE OF EUDRAGIT L100 FIG.12: SPECTRA OF DICLOFENAC SODIUM AND EUDRAGIT
L100
CONCLUSION 5 . D’souza JI, Harinath NM. The microsponge drug delivery
system: for delivering an active ingredient by controlled time
The present work was focused on development of colon targeted release. Pharma. info. net. 2008;6(3):62.
diclofenac sodium loaded microsponges which serve the purpose of 6. Nanda S, Kaur M, Sood N, Nagpal S. Microsponge drug delivery
increasing the drug release by the use of ethanol and eudragit as system: an overview. World Journal of Pharmacy and
internal phase and 5% w/v PVA as external phase. Among 12 Pharmaceutical Sciences. 2013 Mar 2;2(3):1032-43.
formulations 3 formulations were optimized formulations among 7. Kaity S, Maiti S, Ghosh AK, Pal D, Ghosh A, Banerjee S.
the three formulations L2 gives best release rate of the drug, so it Microsponges: A novel strategy for drug delivery system. Journal
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work, I could conclude that microsponges can be used as efficient 8. Joshi Y, Kumar R, Teotia UV, Sade S. Evaluation of Release
means of formulation to enhance drug delivery thus helping to Modifying Potential of Artocarpus Heterophyllus (Jackfruit)
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ACKNOWLEDGEMENTS specific drug delivery system containing flurbiprofen
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The author is thankful to DST, Women scientist-A program for 2;318(1):103-17.
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gastro retentive drug delivery system of curcumin: Optimization
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http://dx.doi.org/10.7897/2230-8407.09454
Source of support: DST, Women scientist-A program, Conflict of interest: None Declared
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