KVPS Institute of Pharmaceutical Education, Boradi, Tal-Shirpur.Dist-Dhule. 425428 (MH) India and 2Department of
Pharmaceutics, College of Pharmacy, IPS Academy, Indore. 452 012 (MP), India PDA, Inc. 2012
ABSTRACT: The present work comprises the formulation and evaluation of losartan potassium with a view to
developing and preparing a losartan potassium releasing system for transdermal applications. The aim of the study
was to prepare the transdermal patch of drug using different blends of polymers. Transdermal patches of losartan
potassium were prepared using ethyl cellulose (EC): polyvinyl pyrrolidone (PVP), Eudragit RL-100: Eudragit RS-100
and polyvinyl alcohol (PVA): polyvinyl pyrrolidone (PVP) using different ratios by the solvent casting technique.
Physicochemical parameters like flexibility, thickness, smoothness, moisture content, hardness, and tensile strength
were studied. The in vitro permeation study was carried out using a modified Keshery diffusion cell, and the
formulation followed the Higuchi diffusion mechanism. The blood pressure lowering response of all formulations was
studied using hypertension-induced rats by the chronic renal hypertension method. The formulation containing
Eudragit RL-100: Eudragit RS-100 as polymers showed satisfactory drug release pattern (hydrophobic polymers)
compared to combination of hydrophobic and hydrophilic polymers (EC: PVP) and PVA: PVP (hydrophilic
polymers). The amount of drug release from formulations containing hydrophilic polymers and combination of both
hydrophobic and hydrophilic polymers were found to be less in comparison to the patches of hydrophobic polymers.
KEYWORDS: Losartan potassium, Transdermal patch, In vitro permeation, Hypertension, Eudragit
LAY ABSTRACT: The aim of the present study was to prepare and evaluate the transdermal patch of drug using
different polymers such as hydrophobic, combination of hydrophobic: hydrophilic, and hydrophilic. Losartan
potassium (hydrophilic) is the antihypertensive drug used for lowering increased blood pressure. Transdermal patches
of losartan potassium were prepared using different ratios of polymers by the solvent casting technique. The prepared
patches were evaluated for their flexibility, thickness, smoothness, moisture content, hardness, and tensile strength.
The in vitro permeation study was carried out using a diffusion cell. The blood lowering response of all formulations
was studied using hypertension-induced rats. The formulation containing hydrophobic polymers showed a satisfactory
drug release pattern compared to the combination of hydrophobic: hydrophilic polymers and the hydrophilic
polymers. Hence, the present study reveals that formulation of hydrophilic drug (losartan potassium) withhydrophobic
polymers exhibit good release properties as compared to that of hydrophilic polymers and combination of both
hydrophobic and hydrophilic polymers.
1. Introduction
Delivery ofdrug into systemic circulation at a predetermined rate using skin as a site of application is a
126
Figure 1
Formulation of transdermal patch: (a) casting solution in glass mould; (b) prepared transdermal
film.
TABLE I
Formulation of EC and PVP Combination
Code
Polymer
Ratio
EC/PVP
EC
(mg)
PVP
(mg)
Propylene
Glycol
(mL)
Losartan
K (mg)
F1
4:1
400
100
350
0.1
F2
3:2
300
200
350
0.1
EC, ethyl cellulose; PVP, polyvinyl pyrrolidone, DMSO, dimethyl sulfoxide.
DMSO
(mL)
Chloroform
(mL)
0.1
0.1
10
10
TABLE III
Formulation of PVA and PVP Combination
Code
Polymer
Ratio
PVA/PVP
PVA
(mg)
PVP
(mg)
Losartan
K (mg)
Propylene
Glycol
(mL)
F5
2:1
333
167
350
0.1
F6
1:1
250
250
350
0.1
PVA, polyvinyl alcohol; PVP, polyvinyl pyrrolidone; DMSO, dimethyl sulfoxide.
DMSO
(mL)
Water
Upto
(mL)
0.1
0.1
10
10
TABLE II
Formulation of Eudragit RL-100 and RS-100 Combination
Code
Polymer
Ratio
Eudragit
RL/RS100
F3
1:1
F4
2:3
DMSO, dimethyl sulfoxide.
128
Eudragit
RL 100
(mg)
Eudragit
RS 100
(mg)
Losartan
K (mg)
Propylene
Glycol
(mL)
DMSO
(mL)
Ethanol:
Acetone
(mL)
125
100
125
250
350
350
0.1
0.1
0.1
0.1
10
10
2.1.3.4. Thickness: A film thickness tester (Mitutoyomodel 4026F, Tokyo, Japan) was used to measure the
thicknesses of the prepared patches. The thickness was
measured at five different points of individual film and
the average of five readings with the standard deviation (SD) and standard error from the mean was calculated and recorded (16, 17).
2.1.3.5. Folding Endurance: Folding endurance was
measured manually for the prepared films. Each film
was repeatedly folded at the same place till it broke.
The number of times the film could be folded at the
same place without breaking gave the exact value of
folding endurance (18).
2.1.3.6. Tensile Strength: Tensile strength was evaluated using Instron Universal testing instrument (model
4206, Instron Ltd., Kawasaki, Japan) with a 2 kg load
cell. Films of a specific dimension and free from air
bubbles or physical imperfections were held between
two clamps positioned at a distance of 3 cm. For each
film, measurements were run in triplicate. Tensile
strength was calculated applying the following equation (19):
Tensile strength Force at break N/
Initial cross-sectional area of the sample mm2 .
2.1.3.7. Drug Content Uniformity: The patch (1 cm2)
was transferred into a graduated flask containing 100
mL of phosphate buffer pH 6.8. With mechanical
shaker the flask was shaken for 4 h. Then the solution
was filtered and, after suitable dilutions with phosphate buffer pH 6.8, the absorbance was measured at
249 nm using the placebo patch solution as blank and
the drug content was calculated (15, 20).
2.1.4. In Vitro Drug Release Studies: In vitro drug
release profiles were carried out by using modified
Keshery-Chein diffusion cell with the cellophane
membrane. The cellophane membrane was soaked
in 100 mL of phosphate buffer of pH 7.4 and then
cut into pieces of 7 cm 2 area (21). The receptor
phase was maintained at 370.5 C (20). It was
mounted on the diffusion cell and equilibrated with
receptor fluid for 15 min and used for the drug release
studies. The volume of diffusion cell was 10 mL. The
cell consists of two compartments, the donor and the
receptor compartments. The donor compartment was
in contact with the ambient conditions of the atmosphere. The receptor compartment was in contact with
Vol. 66, No. 2, MarchApril 2012
Figure 2
IR spectra of losartan potassium, F2, F4, and F6 formulations.
Blood pressure was measured 4 5 weeks after clipping, and rats with values higher than 150 mm Hg
were selected for the experiments. Blood pressure
readings were taken on each of 3 days prior to application of patch by the tail cuff method. Patches were
applied for 3 days and predrug and 24 h postdrug
blood pressure readings were taken. Changes in systolic blood pressure were expressed in mm Hg. Com130
Figure 3
DSC Thermograms of (A) losartan potassium (LP),
(B) losartan potassiumEudragit RL100,(C) losartan potassiumEudragit RS100, and (D) losartan
potassiumethylcellulose (EC).
TABLE IV
Physicochemical Properties of the Prepared Transdermal Patches
Formulation
Code
Flexibility
Smoothness
Transparency
F1
Flexible
Smooth
Opaque
F2
Flexible
Smooth
Opaque
F3
Flexible
Smooth
Opaque
F4
Flexible
Smooth
Opaque
F5
Flexible
Smooth
Opaque
F6
Flexible
Smooth
Opaque
* Average of three determinations. AM (average mean).
Vol. 66, No. 2, MarchApril 2012
Stickiness
Folding
Endurance*
Weight* (mg)
AM SD
Non-sticky
Non-sticky
Non-sticky
Non-sticky
Non-sticky
Non-sticky
160200
160200
200245
200240
170210
170210
28.001 0.067
30.967 0.099
27.767 0.012
26.913 0.023
31.571 0.064
33.456 0.019
131
TABLE V
Physiochemical Properties and Drug Content of the Prepared Transdermal Patches
Percentage
Formulation Hardness* (kg) Moisture
Code
AM SD
Absorption
Thickness*
(mm) AM
SD
F1
0.294 0.019
3.01
0.279 0.019
F2
0.328 0.023
3.18
0.323 0.017
F3
0.388 0.026
3.45
0.325 0.023
F4
0.403 0.022
3.66
0.248 0.014
F5
0.352 0.027
4.48
0.293 0.021
F6
0.438 0.031
4.29
0.364 0.026
* Average of three determinations. AM (average mean).
Tensile
strength*
(kg/mm) AM
SD
Amount in 1
cm2* (mg)
Percentage
Drug Content
in cm2
0.397 0.053
0.435 0.047
0.534 0.068
0.513 0.061
0.468 0.059
0.492 0.071
13.00 0.0324
11.95 0.0196
13.00 0.0421
12.90 0.0312
13.35 0.0358
12.92 0.0316
93.60 0.7345
92.88 0.4015
93.08 0.3439
95.32 0.7852
95.40 0.5714
93.24 0.5127
Figure 4
Comparison of in vitro percentage drug release of
all formulations.
PDA Journal of Pharmaceutical Science and Technology
TABLE VI
Kinetic Release (R2) Values of All the Patches
Code
F1
F2
F3
F4
F5
F6
Zero order
First order
Higuchi model
0.9443
0.9724
0.9873
0.9071
0.9456
0.9928
0.9427
0.9816
0.9878
0.9244
0.9630
0.9901
0.9346
0.9615
0.9852
0.9472
0.9674
0.9755
the patches. After collection of blood pressure readings, it was found that all the formulations, F1 to F6,
reduced blood pressure significantly. But the reduction
in blood pressure caused by F3 was remarkable. The
data was analyzed by one-way ANOVA with Dunnetts multiple comparision post-test for comparison
of antihypertensive response of all other formulations
with F3. One way ANOVA revealed significant reduction in blood pressure of rats treated in all groups (P
0.05). The data was further analyzed by Dunnetts
multiple comparison test to determine the hypotensive
effect of F3 with all other groups. It was found that
hypotensive effect of F3 was significantly greater than
all groups [F1, F(5, 48) 2.938, (P 0.05); F2, F(5,
48) 3.186, (P 0.05); F5, F(5, 48) 3.633, (P
0.05); F6, F(5, 48) 3.582, (P 0.05)] except F4.
Hence formulation F3 was found to be optimum because the blood pressure levels were close to normal
and stable over the period of 9 to 24 h (Figure 5).
4. Conclusion
The aim of the study was to study the effect of various
hydrophilic and hydrophobic polymers by in vitro
release rate and in vivo antihypertensive activity from
transdermal patches of losartan potassium. Propylene
glycol was used as plasticizer at a concentration of 1%
v/v for all patches, which exhibited good flexibility,
tensile strength, hardness, and handling property. The
TABLE VII
Stability Study of Transdermal Patches at Various Temperature and Humidity
Formulation
Code
F1
F2
F3
F4
F5
F6
Initial
Percentage
Drug
Content
15
Days
30
Days
60
Days
15
Days
30
Days
60
Days
93.60
92.88
93.08
95.32
95.40
93.24
93.59
92.70
92.99
94.97
95.37
93.22
93.57
92.65
92.95
94.92
95.35
93.18
93.54
92.58
92.91
94.89
95.29
93.11
93.58
92.68
92.98
94.95
95.32
93.20
93.55
92.61
92.94
94.90
95.28
93.15
93.53
92.55
92.88
94.86
95.22
93.09
133
3. Kydonieus, A. F.; Berner, B. Transdermal Delivery of Drugs; R.C. Press: Boca Raton, FL, 1987;
pp 69 77.
4. Blank, I. H. Cutaneous barrier. J. Invest. Dermatol. 1965, 45, 240 256.
5. Barry, B. W. Dermatological Formulations: Percutaneous Absorption; Marcel Decker: New York
and Basel, 1983; pp 261262.
Figure 5
In vivo antihypertensive study of losartan potassium transdermal patches.
24. Landgraf, W.; Li, N.-H.; Benson, J. R. New polymer enables near zero-order release of drugs.
Drug Delivery Technol. 2005, 5 (2), 48 55.
18. Stoughton, R. B.; Fritsch, W. Influence of dimethyl sulfoxide on human percutaneous absorption. Drug. Dev. Ind. Pharm. 2003, 29 (4),405
407.
19. Gupta, P. S.; Jain, S. K. Effective and controlled
transdermal delivery of metoprololtratarate. Indian J. Pharm. Sci. 2005, 67 (3), 346 350.
20. Kulkarni, R. V.; Mutalik, S.; Hiremath, D. Effect
of plasticizers on the permeability and mechanical
properties of eudragit films for transdermal application. Indian J. Pharm. Sci. 2002, 64 (1), 28 31.
21. Rao, R. P.; Divan, P. V. Influence of casting
solvent on permeability of ethyl cellulose free
films for transdermal use. East Pharma. 1997, 40,
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135