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RESEARCH ARTICLE
Formulation and Evaluation of Matrix-Type Transdermal Delivery System
of Ondansetron Hydrochloride Using Solvent Casting Technique
Farsiya Fathima1, Vijaya Kumar B1*, Shashi Ravi Suman Rudrangi2, Satish Kumar Vemula1,
Prasad Garrepally1, Swathi Chilukula1 and Samatha Rudrangi3
1
Department of Pharmaceutics, Jangaon Institute of Pharmaceutical Sciences, Kakatiya University,
Yeshwanthapur, Jangaon-506167, Andhra Pradesh, India
2
Department of Pharmaceutical Sciences, School of Science, University of Greenwich, Chatham Maritime, Kent,
United Kingdom ME4 4TB
3
Department of Pharmaceutics, Talla Padmavathi College of Pharmacy, Kakatiya University, Urus, Kareemabad-
506002, Andhra Pradesh, India
*Corresponding Author E-mail: suman_rudrangijips@yahoo.com
ABSTRACT:
The purpose of this research was to develop a matrix-type Transdermal therapeutic system containing drug
Ondansetron hydrochloride (OSH) with different ratios of hydrophilic and hydrophobic polymeric systems by the
solvent evaporation technique by using 25 % w/w of di-butyl phthalate to the polymer weight, incorporated as
plasticizer. 5% menthol was used to enhance the Transdermal permeation of OSH. Formulated transdermal patches
were physically evaluated with regard to thickness, weight variation, drug content, flatness, folding endurance,
percentage of moisture content and water vapour transmission rate. All prepared formulations indicated good physical
stability. Ex vivo permeation studies of formulations were performed by using Franz diffusion cells. Formulation
prepared with combination of hydrophilic polymers containing permeation enhancer showed best ex vivo skin
permeation through rat skin (Wistar albino rat) as compared to all other formulations. The release profile of OSH
followed zero-order kinetics in all formulations. However, the release profile of the optimized formulation F17 (r2 =
0.999 for Higuchi) indicated that the permeation of the drug from the patches was governed by a diffusion mechanism.
Formulation F showed highest flux among all the formulations in drug permeation. These results indicate that the
formulations containing menthol as the penetration enhancer (5%) giving better penetration of OSH through rat skin
were considered as suitable for large scale manufacturing with a backing layer and a suitable adhesive membrane.
KEYWORDS: Transdermal drug delivery, penetration enhancers, hydrophilic and hydrophobic polymers,
Ondansetron hydrochloride.
INTRODUCTION:
Transdermal drug delivery systems are topically Patient satisfaction has been realized through decreased side
administered medicaments in the form of patches that are effects, reduced dosing frequency, and improved plasma
mainly used for non-invasive “intravenous infusion” of profiles as compared with conventional oral dosing or
drugs for systemic effects at a predetermined and controlled painless administration as compared with injection therapy.
rate.1 In the last two decades, among the greatest successes in CR
drug delivery is the commercialization of transdermal
Transdermal systems are designed to deliver the therapeutic dosage forms 2-7
for the systemic treatment of a variety of
agent at a controlled rate from the device to and through the diseases.
skin into the systemic circulation. This route of
administration avoids unwanted presystemic metabolism To date, nearly 20 drugs alone or in combination have been
(first-pass effect) in the GI tract and the liver. launched into transdermal products worldwide. Additional
drugs are in the late development phases (phase II to
registration). Matrix based transdermal formulations have
been developed for a vast number of drugs that include
ephedrine, ketoprofen, metoprolol, labetolol hydrochloride,
Received on 21.02.2011 Modified on 12.03.2011 triprolidine, nitrendipine, lercanidipine, and propranolol. 8-14
Accepted on 24.03.2011 © RJPT All right reserved
Research J. Pharm. and Tech. 4(5): May 2011; Page 806-814
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Research J. Pharm. and Tech. 4(5): May 2011
Ondansetron is a potent antagonist of Serotonin (5 HT3) Preparation of standard solution: Firstly, stock solution-1
receptor which has been proved effective in prevention of of OSH was prepared by dissolving 10 mg of drug in 100
chemotherapy and radiotherapy-induced nausea and ml of PBS pH 7.4, so as to get a solution of 1 mg/ml
vomiting. It can control diarrhoea and nausea in up to 100% concentration. Then stock solution -2 was prepared by
of patients and occasionally ameliorate the flushing. In this taking 10 ml from the previous stock solution and
work an attempt was made to formulate and evaluate TDDS dissolving in 100 ml of PBS pH 7.4, so as to get a solution
for sustained release OSH by solvent casting method. Low of 100 mg/ml concentration. Accurately measured aliquot
molecular weight, good permeability, poor bioavailability portions of standard drug solution, like 0.4 ml, 0.6 ml, 0.8
(60%) and shorter half-life (5-6 h) of OSH made it a ml, 1.0 ml, 1.2 ml, 1.4 ml and 1.6 ml were taken from stock
suitable drug candidate for the development of Transdermal solution-2 and were transferred in to 10 ml volumetric
patches. The main objective of formulating the Transdermal flasks and were diluted up to the mark with PBS pH 7.4.
system was to prolong the drug release time, reduce the Absorbance of each solution was measured at max of 310
frequency of administration and to improve patient nm against PBS pH 7.4 as the blank, by using UV-
compliance. spectrophotometer. A graph of concentration of drug vs.
absorbance was plotted.
MATERIALS AND METHODS:
Materials: Ondansetron hydrochloride was obtained as a Formulation of Transdermal Patches16, 17
generous gift from Sun Pharmaceuticals (Baroda, India). Preparation of blank patches: Polymers of single or in
Eudragit RL100 and Eudragit RS100 were procured from combination were accurately weighed and dissolved in
Aurobindo Pharmaceuticals (Hyderabad, India). Di-butyl respective solvent and then casted in a Petri-dish with
phthalate, menthol, hydroxypropyl methylcellulose, ethyl mercury as the plain surface. The films were allowed to dry
cellulose, cellulose acetate phthalate were purchased from overnight at room temperature.
SD Fine Chemicals (Mumbai, India). All the polymers
received were of pharmaceutical grade and were used as Development of Transdermal Patches: Mercury substrate
received. Other materials and solvents used were of method was employed in preparing transdermal patches of
analytical grade. OSH.
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Research J. Pharm. and Tech. 4(5): May 2011
entrapped air and was then transferred into a previously membranes (in weight %) was calculated in terms of
cleaned Petri plate (70.00 cm2) and kept aside for solvent percentage increase in weight of membrane over the initial
evaporation. The rate of solvent evaporation was controlled weight of the specimen. The experiments were carried out
by inverting a glass funnel over the Petri plate. After 12h, in triplicate and the average values were used for the
the dried films were taken out and stored in a desiccator. calculation. The percentage degree of swelling (DS) was
The composition of the patches is given in Table 1. calculated as
until further use. The skin was allowed to equilibrate with Table 3: Standard graph of OSH in PBS pH 7.4
room temperature prior to use and was mounted between CONCENTRATION(µG/ML) ABSORBANCE
donor and receptor compartment of cell. It was clamped in 0 0.00
2 0.129
such a way that the dermal side was in contact with receptor 4 0.231
23
medium . 6 0.359
8 0.482
Method: PBS pH 7.4 was used as receptor solution. The 10 0.591
volume of diffusion cell was 15 ml and stirred with 12 0.697
14 0.837
magnetic beads. The temperature was maintained at 37 ± 16 0.982
1°C with the help of hot plate. The diffusion was carried out Slope 0.06
for 10 h and 3 ml sample was withdrawn at an interval of 1 R2 0.998
h. The same volume of PBS pH 7.4 was added to receptor
compartment to maintain sink conditions and the samples
were analyzed at 310 nm.
Kp =J / C
Where, J= flux (µg/cm2/hr) and C= concentration of drug
in the patch Fig.1: Standard curve of OSH
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Research J. Pharm. and Tech. 4(5): May 2011
Table 4: Physical evaluation data of OSH Transdermal patches. Results are the mean of triplicate observations ± SD
Formul Weight Thickness Folding (%)Moistur (%) Moisture WVT Rate Drug Swellability
ation variation (mm) endurance e uptake content (g.cm2/day content (%)±SD
code (mg) ±SD ±SD ±SD ±SD ±SD X10-4 ±SD (%)±SD
F1 65.34±1.6 0.025±1.6 71±0.9 2.96±0.95 3.08±0.97 2.36±0.14 97.24±0.2 12.73±0.43
F2 65.87±1.6 0.025±1.6 72±1 3.27±0.62 3.11±0.83 2.48±0.15 97.36±0.2 13.25±0.36
F3 66.12±1.8 0.024±1.6 71±0.9 3.89±0.86 3.28±0.75 2.62±0.16 97.45±0.2 14.28±0.38
F4 66.45±1.8 0.026±1.6 72±1 4.85±0.91 3.32±.058 2.93±0.16 98.41±0.3 16.34±0.42
F5 65.34±1.6 0.026±1.6 72±0.9 4.55±1.14 3.98±1.17 3.07±0.17 98.58±0.3 18.94±0.48
F6 66.39±1.8 0.025±1.6 71±1 4.75±1.08 4.63±0.67 3.14±0.17 98.34±0.3 20.67±0.46
F7 65.48±1.6 0.025±1.6 71±0.9 4.27±1.17 4.92±1.38 3.35±0.18 101.17±0.3 22.01±0.38
F8 67.28±1.7 0.045±1.8 77±1 4.93±0.6 3.12±0.3 3.66±0.13 99.38±0.4 38.59±0.61
F9 67.91±1.7 0.045±1.7 77±1 4.68±0.6 3.26±0.3 3.82±0.12 96.75±0.4 35.48±0.45
F10 68.08±1.7 0.047±1.9 80±2 4.86±0.8 3.53±0.6 3.91±0.13 96.81±0.4 32.87±0.46
F11 68.36±1.8 0.046±1.8 79±2 4.53±0.8 3.34±0.3 4.15±0.11 96.84±0.5 30.13±.055
F12 68.94±1.8 0.046±1.8 77±1 4.37±0.7 3.47±0.3 4.28±0.13 96.48±0.5 28.63±0.54
F13 64.86±1.8 0.045±1.5 78±2 4.48±0.5 4.39±0.5 4.12±0.26 98.28±0.7 42.15±0.62
F14 64.53±1.5 0.036±1.3 78±2 4.65±0.4 4.62±0.5 4.16±0.28 98.46±0.7 44.86±0.64
F15 64.21±1.4 0.037±1.4 77±2 4.83±0.6 4.92±0.8 4.28±0.24 98.74±0.3 46.38±0.39
F16 64.83±1.5 0.037±1.3 77±1 4.96±0.4 4.87±0.6 4.38±0.21 98.83±0.7 48.34±0.42
F17 64.46±1.4 0.036±1.3 79±2 5.03±0.5 5.01±0.7 4.48±0.21 100.15±0.8 48.92±0.64
WVT=Water Vapour Transmission; SD=Standard Deviation.
Table 5a: In vitro drug release from F-1 to F-7
Cumulative % drug released
Time F1 F2 F3 F4 F5 F6 F7
0 0.00 0.00± 0.00 0.00 0.00 0.00 0.00
1 6.81±0.45 7.06±0.54 7.91±0.71 8.50±0.86 8.94±0.94 9.31±0.96 9.75±1.01
2 13.80±0.46 14.29±0.56 16.33±0.74 16.89±0.89 17.32±0.97 17.77±0.98 18.45±1.07
3 20.98±0.49 22.74±0.58 23.63±0.76 24.30±0.92 24.93±0.99 25.92±1.01 26.34±1.11
4 28.49±0.51 30.61±0.61 32.23±0.77 33.49±1.02 34.37±1.01 35.34±1.05 36.44±1.15
5 34.58±0.53 37.16±0.63 38.19±0.82 41.56±1.05 42.53±1.05 43.85±1.12 45.11±1.18
6 41.73±0.55 44.38±0.66 47.01±0.85 50.68±1.06 53.89±1.08 55.33±1.16 57.16±1.23
12 76.31±0.57 79.76±0.69 84.07±0.87 88.47±1.07 90.38±1.13 92.98±1.18 96.79±1.29
Release profile data with mean ±SD
Table 5b: In vitro drug release from F-8 to F-12
Time F8 F9 F10 F11 F12
0 0.00 0.00 0.00 0.00 0.00
1 8.94±0.41 8.16±0.48 7.75±0.53 7.22±0.65 6.69±0.77
2 16.63±0.41 15.94±0.51 15.33±0.54 14.82±0.66 13.99±0.79
3 24.82±0.43 24.31±0.52 23.93±0.56 23.03±0.68 21.93±0.81
4 33.89±0.45 32.86±0.54 32.01±0.58 31.31±0.71 29.79±0.83
5 41.95±0.46 40.43±0.56 39.64±0.59 38.74±0.74 37.13±0.86
6 50.27±0.48 49.01±0.58 47.91±0.62 46.81±0.76 44.58±0.89
12 93.19±0.49 88.40±0.61 85.99±0.63 80.30±0.79 76.63±0.91
Release profile data with mean ±SD
Table 5c: In vitro drug release from F-13 to F-17
Time F13 F14 F15 F16 F17
0 0.00 0.00 0.00 0.00 0.00
1 7.06±0.21 7.94±0.31 8.63±0.42 8.78±0.52 9.09±0.61
2 14.91±0.22 15.93±0.33 16.66±0.46 16.91±0.54 17.23±0.63
3 22.99±0.24 23.86±0.35 24.81±0.49 25.16±0.57 25.78±0.66
4 30.67±0.27 31.74±0.37 33.29±0.51 33.61±0.59 34.11±0.67
5 38.57±0.28 39.61±0.39 41.11±0.52 41.59±0.61 42.61±0.68
6 46.67±0.29 47.93±0.42 49.89±0.55 50.99±0.62 51.76±0.69
12 90.22±0.35 93.79±0.45 94.54±0.56 96.66±0.64 98.43±0.75
Release profile data with mean ±SD
Table 6a: Ex vivo diffusion release data for F1-F7
Cumulative % drug permeated
Time F1 F2 F3 F4 F5 F6 F7
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00
1 4.19±0.45 4.29±0.53 4.36±0.68 4.41±0.77 4.54±0.83 4.43±0.87 4.28±0.93
2 7.32±0.46 7.41±0.57 7.54±0.69 7.67±0.79 7.83±0.86 7.63±0.89 7.50±0.95
3 9.82±0.51 10.12±0.59 10.23±0.72 10.38±0.81 10.91±0.89 10.43±0.92 10.27±0.98
4 12.06±0.49 13.13±0.62 13.99±0.75 15.02±0.84 16.12±0.91 14.96±0.94 14.21±1.01
5 16.18±0.53 17.65±0.66 18.32±0.76 19.38±0.89 21.64±0.93 20.20±0.96 19.16±1.06
6 20.10±0.55 21.78±0.68 23.59±0.79 25.14±0.92 27.09±0.96 25.78±0.99 24.92±1.08
12 50.69±0.57 51.35±0.71 52.26±0.82 54.81±0.94 56.64±0.99 57.42±1.02 58.60±1.13
Release profile data with mean ±SD
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Research J. Pharm. and Tech. 4(5): May 2011
Fig.2c: In vitro release profile of F13-F17 Fig.3b: Ex vivo release profile of F8-F12
Fig.3a: Ex vivo release profile of F1-F7 Fig.3c: Ex vivo release profile of F13-F17
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Research J. Pharm. and Tech. 4(5): May 2011
Table 7: Ex vivo skin permeation steady state flux, permeability coefficients of Transdermal patches
Formulation code Flux (µgcm-2h-1) Permeability coefficient (Kp)
F1 4.266 0.533
F2 4.336 0.542
F3 4.433 0.554
F4 4.676 0.584
F5 4.851 0.606
F6 4.928 0.616
F7 5.041 0.630
F8 4.686 0.585
F9 4.824 0.603
F10 5.035 0.629
F11 5.268 0.658
F12 5.355 0.669
F13 5.203 0.65
F14 5.388 0.673
F15 5.779 0.722
F16 5.683 0.710
F17 5.937 0.742
Table 8: Ex vivo skin permeation kinetics followed by formulations of OSH Transdermal patches
Formulation code Zero order model First order model R2 Higuchi model Peppas model
R2 R2
n R2
F6 0.990 0.847 0.958 0.992 0.989
F8 0.994 0.771 0.971 0.703 0979
F17 0.971 0.970 0.972 0.766 0.991
Table 9: Physical evaluation data of OSH Transdermal patches before and after 3 months
Formulation Weight Thickness Folding (%)Moisture (%)Moist WVT Drug Swellability
code variation (mm) endurance uptake ure Rate(g.cm2/ content (%)±SD
(mg) ±SD ±SD ±SD ±SD content day X10-4 (%)±SD
±SD ±SD
F6 Before 66.39±1.8 0.025±1.6 71±1.8 4.75±1.08 4.63±0.67 3.14±0.17 98.34±0.3 21.67±0.46
After 66.58±1.6 0.027±1.6 72±2.1 4.97±1.17 4.82±1.38 3.25±0.18 99.17±0.3 22.01±0.38
F8 Before 67.28±1.7 0.045±1.8 77±1 4.93±0.6 3.12±0.3 3.66±0.13 99.38±0.4 38.59±0.61
After 67.91±1.7 0.046±1.7 78±1 4.98±0.6 3.26±0.3 3.82±0.12 99.75±0.4 39.48±0.45
F17 Before 64.46±1.5 0.036±1.3 79±1 5.03±0.4 5.01±0.6 4.38±0.21 98.83±0.7 48.34±0.42
After 64.83±1.4 0.037±1.3 80±2 4.98±0.5 4.99±0.7 4.48±0.21 99.15±0.8 48.92±0.64
Table10: In vitro drug release data of optimized formulations before and after 3 months
OPTIMIZED Before stability After stability
FORMULATION
CODE 0 month 1st month 2nd month 3rd month
F6 92.98±1.18 93.06±1.19 93.13±1.20 93.21±1.21
F8 93.19±0.49 93.38±0.51 93.45±0.52 93.49±0.54
F17 98.43±0.75 98.56±0.76 98.62±0.77 98.71±0.79
SIMILARITY FACTOR 80.23
Table 11: Ex vivo skin permeation steady state flux, permeability coefficient, kinetics followed by optimized formulations of transdermal
patches
Formulation Flux (µgcm-2h-1) Permeability Zero order First order Peppas model
code coefficient (Kp) model R2 model R2 HiguchimodelR2
n R2
F6 4.968 0.636 0.987 0.849 0.921 0.993 0.991
F8 4.716 0.592 0.999 0.781 0.976 0.711 0981
F17 5.981 0.761 0.999 0.975 0.977 0.774 0.992
Standard graph of OSH in PBS pH 7.4: Standard graph The physical evaluation of Transdermal patches for all
of drug was plotted as per the procedure in experimental formulations was performed. Weight variation was found in
method and its linearity was shown in table 3 and graph. the range of 64.21±1.4 to 68.94±1.8 and thickness was
The standard graph showed good linearity with R2 of 0.998 found to be between 0.024±1.6 to 0.047±1.9. The results of
which indicates that it obeys “Beer-Lambert’s” law. flatness study showed that none of the formulations had the
difference in the strip lengths before and after longitudinal
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Research J. Pharm. and Tech. 4(5): May 2011
cut, indicating 100% flatness, thus they could maintain a the slope (0.992) indicated that the drug released by zero
smooth surface when applied to the skin. The folding order type as shown in Table 8.
endurance was found to be in the range of 71±0.9 to 80±2
which indicated that the patches would not break and would Stability: After storage, the formulations were subjected to
maintain their integrity with general skin folding when drug content, physical evaluation and in vitro release
used. The folding endurance of Eudragit patches was higher studies. The statistical analysis of these parameters after
than patches containing Ethyl cellulose and PVA-PVP. storage at 45 °C and 75% RH for three months showed no
Drug content was found to be in the range of 96.48±0.5 to significant change Table 9-11.
101.17±0.3 indicating that the drug was uniformly
distributed throughout the patches and evidenced by the low ACKNOWLEDGEMENTS:
values of SD. Hydrophilic polymers showed considerable We would like to express our deepest gratitude towards
swelling, as they increased the surface wettability and Prof. Stephen. R. Wicks, University of Greenwich, U.K.,
consequently water penetration within the matrix varied Prof. D. Rambhau and Prof. Shashank Apte, Natco
between 12.73 to 48.92%. Research Centre, Hyderabad for their noble guidance
throughout the project.
Patches containing higher amount of PVP showed good
water vapour transmission (4.48±0.21) than that of Eudragit CONCLUSION:
and Ethyl cellulose patches. The enhancement of water Seventeen formulations were prepared using different
vapour permeation with increase of PVP is due to the polymers in different ratios and combinations, along with
irregular arrangement of molecules in the amorphous state, plasticizers and penetration enhancer. Mercury was used as
which causes the molecules to be spaced further apart than a substrate for pouring the polymeric solution. The films
in crystal. Hence the specific volume is increased and the were evaluated for uniformity of thickness, weight
density decreased compared to that of crystal, which leads variation, drug content, folding endurance, % elongation, %
to the absorption of vapour into their interstices. All the moisture absorption, moisture content, water vapour
formulations were permeable to water vapour. transmission study, in vitro release and ex-vivo diffusion
studies using Franz diffusion cell. The formulations
Diffusion Studies: followed the Higuchi’s model for the drug diffusion study.
In vitro Release: The in vitro release studies were Since the formulations follow Higuchi’s model, thus they
conducted for all the formulations and the data was indicate diffusion mechanism. The Peppa’s plot showed the
represented in tables 5a, b and c. The in-vitro release n value of 0.766 for formulation F17, thus indicating non-
profiles for all the formulations were shown in fig.2a, b and fickian diffusion. There is scope for the further study and
c. The percentage release was found to be highest (98.43%) development of the Ondansetron Hydrochloride
for formulation carrying PVA: PVP in ratio 2:8 because of Transdermal patches.
the hydrophilic nature of the polymer.
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