International Journal of PharmTech Research

CODEN (USA): IJPRIF ISSN : 0974-4304

Vol.4, No.2, pp 757-764, April-June 2012

Formulation Development and Evaluation of

Transdermal Patches of Losartan
Jain D. K.*, Darwhekar G. N., and Chaurasia S.

College of Pharmacy, IPS Academy, Rajendra nagar, A.B. Road,

Indore - 452012 (M.P.) India

Corres.author : [email protected]
Phone: (O) +91-731-4041627, (M) +91-9826059042

Abstract: The purpose of this research was to develop matrix type transdermal therapeutic system containing
losartan with different ratios of hydrophilic and hydrophobic polymeric concentration by the solvent evaporation
technique. The prepared patched showed satisfactory physiochemical characteristics of weight uniformity,
thickness, folding endurance, moisture absorption for stability of the formulation and drug content were uniform in
all patches. In vitro study done by using Franz diffusion cell having cellophane membrane to determine the amount
of drug present in the formulated patch. In different formulation on the basis of present study formulation F5 show
satisfactory drug release pattern.
Keywords: Losartan potassium; Transdermal patches; In vitro skin permeation.

INTRODUCTION release liner and with/without rate controlling

membrane.
Novel drug delivery is geared towards developing
friendly dosage forms of various formulations with
Desirable features for transdermal patches
the ultimate aim of increasing their dosing
1. Composition relatively in variant in use.
convenience to the patient. The NDDS may
2. System size reasonable.
involve a new dosage form e.g., from thrice a day
3. Defined site for application.
dosage to once a day dosage form or developing a
4. Application technique highly reproducible.
transdermal patch in place of injections. Today,
5. Delivery is (typically) zero order.
about 74% of drugs are taken orally and are
6. Delivery is efficient3.
found not to be as effective as desired. Thus,
Losartan Potassium is a novel multiple action
various forms of NDDS such as transdermal
cardiovascular drug. This drug is currently approved
delivery systems, controlled release systems,
in India. The decrease in the blood pressure is
transmucosal delivery systems etc. emerged. In
produced by competitive antagonist action of AT1
addition, because transdermal patches are user-
receptor and release of aldosterone and adrenaline
friendly, convenient, painless, and offer multi-day
from adrenal gland, renal action promoting salt and
dosing, it is generally accepted that they offer
water re-absorption.
improved patient compliance1,2. Transdermal patch
Losartan Potassium is less absorbed from the
is a device for delivering the therapeutic
gastrointestinal tract and the bioavailability is only
substances through the skin for systemic effect at
33% due to first pass metabolism in liver (cytochrome
predetermined and controlled rate; comprising of
p450 enzyme). It has half life of 2.1 ± 0.7 hrs.
backing membrane, drug incorporated into matrix,
Jain D. K. et al /Int.J. PharmTech Res.2012,4(2) 758

Losartan Potassium was chosen as a model drug for

study since it posses near ideal characteristics that drug
must have in formulating drug delivery system such as
low molecular weight, high lipid solubility, effective in
low plasma concentration as well as high degree first
pass effect. It also means multiple administrations with
subsequent lack of patient compliance4.

MATERIALS AND METHODS

Drug-Excipient interaction study
MATERIAL The drug–excipient interaction study was performed
Losartan was obtained as a gift sample from IPCA labs using silica gel coated TLC (Thin Layer
Ratlam (M.P.). EC (Ethyl- Cellulose), PVP, PEG-400 Chromatography) plates and a mixture of given
and Tween 80, Span 80 other excipient used in the volume of chloroform-methanol-acetone-formic acid
processing of manufacture of the patches, is purchased (7.5:1.5:0.5:0.03) as a mobile phase. The TLC plates
from S.K. Traders Indore (M.P.). All the other reagents were prepared using slurry of silica-G. The prepared
or solvents used were of analytical grade. plates were activated at 110oCfor 30 min. On the
activated plates, 2µL of each solution in methanol of
METHODS losartan potassium containing different experimental
Preparation of drug containing polymer matrices ratio of excipient, that is, PVP, EC, were applied. The
Drug loaded polymer patches were prepared by solvent plates were dried in a stream of warm air for 10 min
evaporation technique. The drug matrix was prepared and then placed in contact with iodine vapours. The
by PVP: EC in different ratio. The polymer in different plates were heated at 110oC for 15 min. The Rf values
ratios was dissolved in chloroform. Losartan dissolved were calculated from the chromatogram obtained7.
in ethanol and slowly added in polymer solution and
mixed thoroughly to obtain a uniform solution, PEG- Permeation study of pure drug
400 as a plasticizer was added and mixed. Films were The In vitro drug release experiment was carried out
casted by placing this solution on desired size flat by using fabricated Franz diffusion cell. The treated
Teflon plates allow to evaporate the solvent for 24 rat skin was cut into desired size and clamped between
hrs.5 the receptor and donor compartments. The receptor
compartment was filled with 13.2 ml of diffusion
EXPERIMENTAL medium (Phosphate buffer pH 7.4) through sampling
Preformulation port taking care to remove all the air bubbles. The
Partition coefficient determination contents were stirred at about 500 rpm by externally
Partition coefficient is a measurement of drug’s driven, teflon coated small magnetic bead to keep them
lipophilicity and its ability to cross cell membrane. well mixed.
Partition coefficient of losartan was determined at 37 ± In order to attain 32 ± 0.5oC at the skin surface,
0.5oC by taking 10 ml of octanol which was saturated receptor compartment was maintained at 37.5oC.
with 10 ml of phosphate buffer (pH7.4) by stirring Accurately weighed 10 mg of losartan (with suitable
with externally driven magnetic stirrer. After stirring solvents and permeation enhancers) was placed on the
the system remain undisturbed for half an hour. About membrane. At suitable intervals, aliquots 3ml were
10 mg of drug was added to this solution and was collected at preset time , then determined by
shaken on wrist action mechanical stirrer. measuring the absorbance at 248 nm using a double
Two layers were separate through separating funnel beam UV spectrophotometer (Shimadzu 1601-A). The
and filterer through Whatman grade filter, and the diffusion medium of the same volume 3ml, which was
amount of losartan solubilized, was determined by pre warmed at 37oC, was then replaced into the
measuring the absorbance at 248 nm against reagent diffusion cell. Duration of the experiment was 24 hrs.
blank through double beam UV/Vis spectrophotometer The experiments were performed in triplicate (n=3)
(Shimadzu 1601-A) in both the solution. Partition and mean value was used to calculate the permeability
coefficient was determined as ratio of concentration of coefficient. The amount of drug diffused was
drug in octanol to the concentration of drug in calculated from absorbance8.
phosphate buffer (pH 7.4) and the value were reported
as log P6.
Jain D. K. et al /Int.J. PharmTech Res.2012,4(2) 759

EVALUATION humidity levels. Little moisture uptake indicates the

stability of the formulation. A good amount of
1. PHYSICAL EVALUATION OF
moisture uptake indicates bulkiness of the
TRANSDERMAL PATCH
formulation and the chance of microbial growth6.
A. Thickness measurement Percentage moisture uptake=
The thickness of the drug containing polymer matrix Initialweight-Final weight x 100
was determined by measuring the thickness of the Final weight
whole patches. The average thickness of drug
containing polymer matrix was determined at four F. Drug contents uniformity
points using vernier caliper9. A specified area of patch was dissolved in a
suitable solvent in specific volume. Then the
B. Weight uniformity solution is to be filtered through a filter medium
The prepared patches dried at 60°C for 4 hrs. before and analyze the drug contain with UV method
testing. A specified area of patch was cut in different (11,12)

parts of the patches and weight in digital balance. The

average weight and standard deviation values G. Percentage elongation break test
calculated from the individual weights9. The percentage elongation break test was
determined by noting the length just before the
C. Folding endurance break point, the percentage elongation can be
A strip of specific area was cut and repeatedly folded determined from the below mentioned formula: (12)
at the same place till it broke. The number of times the Elongation percentage = L1-L2 x 100
film could be folded at the same place without L2
breaking gave the value of the folding endurance9. Where, L1 is the final length of each strip and L2
is the initial length of each strip.
D. Moisture content
The prepared films were weighed individually and In vitro drug permeation study with different
kept in a desiccators containing activated silica at formulation
room temperature for 24 hrs. The films were weighed The In vitro permeation studies were conducted using
again and again individually until it showed a constant fabricated Franz diffusion Cell. The treated rat skin
weight. The percentage of moisture content was was cut into desired size and placed between the
calculated as a difference between initial and final receptor and donor compartments the diffusion cell.
weight with respect to final weight. The fabricated patch was placed over the membrane.
The donor compartment was placed on the receptor
A small amount of moisture in patch type formulations compartment containing phosphate buffer pH 7.4
helps maintain stability and prevents the formation of a maintaining at 37 ± 0.50C. The entire assembly was
dried and brittle film. A greater amount, however, can kept on magnetic stirrer. The solution in the receiver
lead to microbial contamination during storage. The compartment was continuously stirrer with magnetic
moisture content is determined by variations in the beads with about 500 rpm during the experiment.
water content of the dried film and un-dried film.
Percent moisture content is determined as follows6. The amount the drug permeated through membrane
Percentage moisture content= was determined by with drawing 2 ml of sample at
Initialweight-Final weight x 100 predetermined time interval and replacing them with
Final weight an equal volume of buffer. The withdrawal samples
were diluted 10 times and filtered through filter paper
E. Moisture uptake (WhatmanR 41). Absorbance of the sample was
A weighed film was kept in desiccators at normal measured at 248 nm taking phosphate buffer as the
room temperature for 24 hrs was taken out and blank. Drug absorbance were determined by the
exposed to 84% relative humidity (saturated standard curve of losartan in phosphate buffer (pH
solution of potassium chloride) in desiccators until a 7.4). The amount of drug permeated per square
constant weight for the film was obtained. The centimeter at each time interval was calculated
percentage of moisture uptake was calculated as from the calibration curve. The mean cumulative
the difference between final and initial weight percentage of the drug permeation through total
with respect to initial weight. patch area was plotted against time10.

This study can predict the moisture-absorbing

capacity of a particular type of patch at various
Jain D. K. et al /Int.J. PharmTech Res.2012,4(2) 760

TABLE 1: Formulation of transdermal patches

Ingredient F-1 F-2 F-3 F-4 F-5
Losartan 30 30 30 30 30
Ethyl Cellulose 500 400 300 200 100
PVP K30 100 200 300 400 500
Tween-80 6ml 6ml 6ml 6ml 6ml
PEG 400 0.3ml 0.3ml 0.3ml 0.3ml 0.3ml
Chloroform: Alcohol 10ml 10ml 10 ml 10ml 10ml

TABLE 2: Partition coefficient of drug in PBS 7.4

Partition coefficient of drug Solvent system Log p Values

Losartan potasium Phosphate buffer: n-octanol 3.87 ± 0.03

TABLE 3: Partition coefficient of drug in skin

Partition coefficient of drug Solvent system Log p Values
Losartan potasium Phosphate buffer: skin 3.85±0.04

TABLE 4: Rf value of losartan alone and with excipient

S. No Sample Initial Rf value Rf value after 2 week
1 Drug 0.74±0.03 0.75±0.025
2 Drug+EC 0.72±0.13 0.74±0.09
3 Drug+PVP 0.73±0.06 0.74±0.10
4 Drug+All excipient 0.74±0.12 0.73±0.15

TABLE 5: Physiochemical characterization of transdermal patches

Parameter F1 F2 F3 F4 F5
Thickness(μm) 52±10 61±10 54±10 65±10 55±15
Weight variation 115±2.13 105±3.06 111±2.53 109±3.0 95±2.07
(mg) 5
Folding Endurance 59±2.8 55±3.6 41±4.4 49±3.2 45±2.8
Percentage Moisture 1.035±0.32 1.113±0..35 1.096±0.14 1.252 ±0.22 1.481±0.24
Content (%)
Percentage Moisture 1.112±0.25 0.994±0.15 1.028±0.27 1.118±0.22 1.124±0.23
Uptake (%)
Drug Content 89.21±0.24 84.61±0.19 79.44±0.34 88.92±0.16 94.21±0.21
Percentage 92.4 92.3 85.5 87. 1 113.1
Elongation break (%)
Percentage 68.57 74.19 69.86 84.92 90.28
cumulative amt.
permeation (%)
Jain D. K. et al /Int.J. PharmTech Res.2012,4(2) 761

TABLE 6: Curve fitting data for the release rate profile of formulation F5
Model r 2 value
Krosmeyers – peppas 0.4278
Zero order 0.7221
First order 0.3437
Higuchi matrix 0.9981
Hixson Crowel 0.1501

Fig 1: Percentage moisture content

Fig 2: Percentage moisture uptake

Jain D. K. et al /Int.J. PharmTech Res.2012,4(2) 762

Fig 3: Percentage drug content

Drug permeation of different formulation with

pure drug
%Cumulative amt of drug

100
permeation

80 Pure drug
60 F1
40 F2

20 F3
F4
0
0 10 20 30 F5

Time (hrs.)
Fig 4: In vitro drug permeation profile of different formulation.

RESULTS AND DISCUSSION carried out in phosphate buffer (pH 7.4) for 24
hours. The partition coefficient of the Losartan
In the present work efforts have been made to prepare potassium was found to be 3.87. After 24 hrs. 71.25 %
transdermal drug delivery system of Losartan drug was permeated through skin.
potassium EC and PVP, using polyethylene glycol as a
The thickness of the patches varied from 52 to 65μm.
plasticizer by solvent casting technique. The selection
The minimum standard deviation values assumed that
of polymer combinations produces clear, smooth,
the process used for preparing the drug delivery
uniform, substantive, flexible and desired thickness
system is capable of giving reproducible result.
film for the transdermal drug delivery systems of
Losartan potassium. The prepared formulation were As the concentration of PVP and Ethyl cellulose
evaluated for different physico-chemical increase, moisture content of patches was also
characteristics such as thickness, folding endurance, increase. Formulation F5 (1.481±0.24) absorbed
drug content, percent moisture absorption, percentage highest amount of moisture which also revealed its
moisture loss and weight uniformity. The release high hydrophilicity and formulation F1 (1.096±0.14)
characteristics of the formulation were studied in In absorb least amount of moisture.
vitro conditions. In vitro permeation studies were
Jain D. K. et al /Int.J. PharmTech Res.2012,4(2) 763

The folding endurance was measured manually; films formation of pores and thus a decrease in the mean
were folded 59 times maximum in formulation F1and diffusion path length of drug molecules to release
if the film shows any cracks it was taken as end point. into the dissolution medium the result is higher
The folding endurance was better in F1 formulation. dissolution rates. Substances such as PVP act as
As the concentration of PVP and Ethyl cellulose antinucleating agents that retard the crystallization of a
increase, moisture uptake of patches was also increase. drug. Thus they play a significant role in improving
The highest moisture absorption was found in the the solubility of a drug in the matrix by sustaining the
formulation F5 and lowest value of moisture drug in an amorphous form so that it undergoes rapid
absorption was found in the formulation F1. solubilization by penetration of the dissolution
The drug content uniformity of the prepared medium.
formulation have shown that the process used to
prepared the transdermal film in this study was capable
CONCLUSION
of giving film with uniform drug content. The result
of drug content indicates that drug is uniformly The prepared transdermal drug delivery system of
dispersed in formulation. Losartan potassium using different ratios of
In vitro drug permeation studies were carried out for polymers such as EC and PVP had shown good
the different formulations using Franz diffusion cell. promising results for all the evaluated
The medicated films showed drug release study in % parameters. Based on the In vitro drug release and
cumulative release. The relationship can be established drug content result, formulation F5 was concluded
as F5 >F4 > F2>F3>F1 Thus, by varying amount of as an optimized formulation, which shows its
polymer in film, percent release can be varied. Drug- higher percentage of drug release.
polymer affinity can be major factor that control
release of drug from formulation. ACKNOWLEDGEMENTS
Maximum percentage of drug release (i.e. 90.28%) The authors are thankful to College of Pharmacy,
was observed with formulation F5 and the minimum IPS Academy Indore for providing all the facilities
(i.e. 68.57%) was found with formulation F1. The to carry out this research work and also thankful
addition of hydrophilic components such as PVP into to IPCA laboratories Ratlam for providing gift
the formulation tends to enhance its release-rate sample of Losartan potassium for research purpose.
constants. This outcome can be attributed to the
leaching of the soluble component, which leads to the

REFERENCES
1. Chong S. and Fung H.L., Transdermal Drug 6. Arora P., Mukherjee B., Design, Development,
Delivery Systems: Pharmacokinetics, Clinical Physicochemical, and In Vitro and In Vivo
Efficacy, and Tolerance Development, In: Evaluation of Transdermal Patches Containing
Hadgraft, J., Guy and R.H. Eds.; Transdermal Diclofenac Diethylammonium Salt, J. Pharm. Sci.,
Drug Delivery: Developmental Issues and 2000,91,2076-2089.
Research Initiatives, Marcel Dekker, New York, 7. Banker G.S., Rhodes C.T., Modern pharmaceutics,
1989, 135-240. New York, Marcel Dekker INC, 1990, 213-245.
2. Walter Kennath A. Dermatological & transdermal 8. Jayaprakash S., Mohamed Halith S., Mohamed
formulations, Marcel Dekker INC New York, 2000, Firthouse M.U. and Yasmin Nagarajan M.,
411, 318. Preparation and evaluation of celecoxib
3. British Pharmacopoeia, 2004.212. transdermal patches. Pak. J. Pharm. Sci., 2010, 23,
4. Clark S., Analysis of Drugs and Poisons, 279-283.
Pharmaceutical Press, 2004,1190 9. Vijayan V., Sumnath M.H., Suman L., Vinay T.
5. Ubaidulla U., Reddy Molugu V.S., Ruckmani K., and Kumar Jayaraj K., Development and
Ahmad Farhan J. and Khar Roop K., Transdermal Physiochemical, In-Vitro Evaluation of
Therapeutic System of Carvedilol: Effect of Antihypertensive Transdermal Patches,
Hydrophilic and Hydrophobic Matrix on In Vitro J.pharm.Sci., Res., 2010, 3, 170-177.
and In Vivo Characteristics. AAPS Pharm SciTech 10. Mukherjee B., Mahapatra S., Gupta R., Patra B.,
2007, 81, E1-E8. Tiwari A. and Arora P., A comparison between
povidone-ethyl cellulose and povidone-eudragit
Jain D. K. et al /Int.J. PharmTech Res.2012,4(2) 764

transdermal dexamethasone matrix patch based on Crvedilol transdermal patches. Int. Res. J. Pharm.
in-vitro skin permeation, European journal of 2011, 2, 237-248.
Pharmaceutics and Bio Pharmaceutics., 2005, 59, 12. Patel J.H., Patel J.S., Desai B.G., Patel, K.D.,
475-483. Design and Evaluation of Amlodipin Besilate
11. Sanjoy M., Thimmasetty J., Ratan G.N. and Transdermal Patches Containing Film Former.
Kilarimath B. H., Formulation and evaluation of Int. J. Pharm. Res., Dev. 2009; 7, 1-10.

*****