Development and Evaluation of Lisinopril Transdermal Patches

 

Suja C.1*, Ramasamy C.2 and Narayanacharyulu R.3

1Research Scholar, Karpagam University, Eachanari (Post), Coimbatore,

2H.O.D,  Dept. of Pharmacy Practice, SRM College of Pharmacy, SRM University, Kattankulathur, Chennai.

3H.O.D,  Dept. of Pharmaceutics, NGSMIPS, NITTE University, Mangalore.

*Corresponding Author E-mail: sujajayan@rediffmail.com

 

ABSTRACT:

The present study was carried out to develop matrix type transdermal drug delivery system (TDDS) of Lisinopril using a combination of polymers i.e.,Eudragit RS100(ERS100),EudragitRL100(ERL100) and polyvinylpyrrolidone (PVP) . Propylene glycol was used as plasticiser and dimethylsulphoxide (DMSO) as penetration enhancer. IR and TLC studies were performed to follow drug carrier interactions. TDDS were prepared by solvent casting method employing methanol- water as solvent system. The physicochemical parameters like weight variation, thickness, folding endurance, drug content, tensile strength and stability were evaluated. An in vitro study was carried out using Modified Keshary Chien permeation cell. In vitro permeation profile of the formulated patches showed that formulations T4 (ERL100: PVP 2:3) and T9 (ERS100: PVP 2:3) showed highest permeation. The release of drug from all the formulations followed the diffusion controlled Higuchi Model and zero order release kinetics. The formulations were most stable at room temperature.

 

KEYWORDS: Lisinopril, transdermalfilms, PVP, ERL100, ERS100,

 

 


INTRODUCTION:

The basic goal of drug therapy is to achieve a steady state blood or tissue level that is therapeutically effective for an extended period of time. The therapeutic efficacy and safety of the drugs administered by conventional methods can be improved by more precise spatial and temporal placement within the body, thereby reducing both the size and number of doses through a controlled drug delivery system.  Lisinopril is an ACE inhibitor used in the treatment of hypertension and heart failure, prophylactically after myocardial infarction and in diabetic nephropathy. Lisinopril is slowly and incompletely absorbed following oral administration. On an average about 25% of the drug is absorbed after administration of a single dose.1  Thus a controlled drug delivery formulation of Lisinopril for transdermal absorption would be more advantageous and beneficial for improving the bioavailability and reducing the frequency of administration for long term treatment.

 

Lisinopril has a molecular weight of 441.52, poor bioavailability after oral administration and has dose of 20mg-80mg once daily in treatment of hyper tension and at doses of 2.5mg to 20mg once daily improves cardiac function.2This makes it an ideal candidate for transdemal delivery. A combination of hydrophobic (ERL100/ERS100) and hydrophilic (PVP) polymers are used to formulate the TDDS.

 

MATERIALS AND METHODS:

Materials:

Lisinopril was obtained as a gift sample from Dr.Reddy’s Laboratories,(Hyderabad,India) Eudragit RS100 and EudragitRL100 were obtained as gift samples from Evonik Degussa Ltd(Mumbai,India).PVP was procured from Loba Chemie Pvt.Ltd..All other chemicals used  in this study were of analytical grade.

 

Investigation of physicochemical compatibility of Drug and Polymer:3

The physicochemical compatibility between Lisinopril and the polymers used for formulation of patches were studied by using Fourier transform infrared spectroscopy.The IR  spectra were recorded using FTIR by the KBr pellet method and spectra was recorded in the wavelength region between 400-3800 cm-1 .The spectra obtained for lisinopril  and physical mixtures of lisinopril and polymers were compared.

Preparation of Trandermal films4-6:

Matrix type transdermal films of Lisinopril were prepared by solvent casting technique. Ten (10) formulations were prepared using ERL100 and PVP and ERS100 and PVP. All the formulations carried15%v/w of propylene glycol as plasticiser and 5%v/w of DMSO as penetration enhancers.

 

Polymer solution was prepared in methanol(10ml).Weighed quantity of lisinopril was added to the polymer solution with stirring until it dissolved .Plasticiser and penetration enhancer were then added and the mixture was stirred at 500rpm for 1 hour using a magnetic stirrer. After stirring 3.5ml of the resultant solution was poured in a petri-dish and a funnel was kept inverted over the petri-dish for air drying for 24hrs.Circular films of 4.9cm2 was then cut into films of 1cm2 size which were packed in aluminium foils and stored in a dessicator.

 

Table No.2:Formulation compositon

Formulation     code

Drug (mg)

Polymer ratio

ERL100:PVP

ERS100:PVP

T1

20mg

5:0

-------------

T2

20mg

4:1

--------------

T3

20mg

3:2

--------------

T4

20mg

2:3

-------------------------

T5

20mg

1:4

----------------

T6

20mg

------------

5:0

T7

20mg

------------

4:1

T8

20mg

------------

3:2

T9

20mg

-------------

2:3

T10

20mg

--------------

1:4

 

Physico chemical evaluation of the films :

Physical Appearance:13

All the prepared transdermal films were observed for colour, clarity, flexibility, and smoothness.

 

Thickness of the film:6

The thickness of patches was measured at three different places using screw guage and mean values were calculated.

 

Weight Variation:7

Three films of size 1cm2 from each batch was weighed individually and average weight determined.

 

Moisture content:8,9,13

3 films were weighed individually and kept in a dessicator containing calcium chloride at 370 c for 24hrs.The final weight was noted .The percentage of moisture content was calculated as a difference between initial and final weight with respect to final weight.

 

Moisture uptake:8,9,13

A weighed film was kept in a dessicator at room temperature and exposed to  2  different relative humidities 75% and 93% in 2 different dessicators for a period of 3 days. The percentage moisture uptake was calculated as the difference between final and initial weight with respect to initial weight.

 

 

Folding Endurance:9,10

A small strip of the film was folded repeatedly at the same place till it broke. The number of times the film could be folded at the same place without breaking is the folding endurance.

 

Tensile Strength and % Elongation:7

A strip of the film of 1*0.5cm was selected and attached  to a clip at one end of a flat wooden surface and was pulled by means of a pulley system. Weights were added to the pan to increase the pulling force till the film was broken. The elongation of the film at the point of break up was measured. The tensile strength was calculated as per the formula  given below,

               Tensile strength=break (force/a*b)*1+ΔL/L

Where, a=thickness of the film, b=width of the film, ΔL=length at breaking point, L=length of the film.

% Elongation was calculated using the formula,

% Elongation= (Lb –L0/L0)*100,

L0=original length of the film,Lb=length of the film when stress is applied.

 

Hardness:7

Hardness was determined using an apparatus designed in the laboratory. The film was placed  between the metal and sharp end of the rod of the apparatus. Weights were added gradually at an interval of 10 seconds for the stabilisation of the force till the bulb glows. The final weight was considered as the measure of hardness.

 

Drug Content:8,9

The patches (1cm2) were added to beaker containing 100ml of phosphate buffer(pH7.4).This was then stirred with Teflon coated magnetic bead for 2 hrs. The  contents were filtered  and the filtrate was analysed spectrophotometrically for drug content at 258nm.

 

Stability studies:12

The transdermal films were sealed in polyethylene coated aluminium foils and kept at 10C, room temperature, and 450 C for a period of 3 months. During this period the films were tested for any change in colour,texture and analysed periodically for its drug content.

 

In vitro Drug Release Studies :9,10,11

Modified Keshary-Chien apparatus was fabricated and used for the release study. The transdermal film was placed on cellophane membrane which was mounted on the donor compartment of the diffusion cell having a surface area of 1.76cm2. The donor compartment was kept in contact with the receptor compartment which was filled with phosphate buffer solution pH 7.4 at 370±10, in such a way that the membrane just touches the solution. The elution medium was stirred magnetically at 50rpm. The aliquots (5ml) were withdrawn at predetermined time intervals for 24hrs and replaced with the same volume of the buffer. The samples were analysed for drug content using UV spectrophotometer at 258nm.

 

 


Fig.1:IR Spectrum of pure drug -lisinopril

 

Fig.2:IR Spectrum of physical mixture of  pure drug and polymers

 

 


RESULTS AND DISCUSSION:

The FTIR spectra were recorded to find out if any interaction exists between the drug and polymers. The spectra showed no distinctive physical or chemical interaction between drug and polymer. However, some additional peaks were observed in the spectrum of physical mixture which may be due to the presence of polymers.As seen in (Fig.1 and Fig.2) FTIR results suggest that the drug and polymers are compatible.

 

All the patches prepared using different polymer concentrations were found to be uniform, smooth, flexible and homogeneous. There was no significant difference in the thickness and average weight of the prepared patches as seen in Table 2.The  thickness and average weight  of all the patches measured with low standard deviation values shows the uniformity of the films prepared. The mechanical properties i.e., tensile strength of the patches revealed that the formulations were found to be strong but not brittle. It is also seen that with the addition of PVP the tensile strength decreases. Moisture content was found to increase with increase in the concentration of PVP.All the strips contains more than 90% drug as per the content uniformity studies and exhibited more than 180 folding endurance.


Table 2: Physicochemical evaluation of the transdermal films of Lisinopril

Formulation

Weight (mg),SD

Thickness (mm), SD

Tensile strength (kg/cm2),

SD

Folding endurance, SD

% Elongation,SD

%Drug content,SD

% moisture content

% moisture uptake

75%

RHRT

93%

RHRT

T1

23±0.035

0.136±0.002

0.51±0.038

200 ±5.0

30.5±0.33

91.66±0.038

0.98

4.03

8.45

T2

32±0.022

0.202 ±0.004

0.66±0.208

210 ±6.5

65.05±0.45

95.09±0.025

1.05

3.85

10.86

T3

38±0.030

0.140 ±0.007

0.58±0.311

224 ±6.11

80.1±0.63

90.09±0.0375

1.44

3.66

13.66

T4

35±0.025

0.242 ±0.006

0.52±0.052

228 ±5.0

88.24±0.18

91.66±0.0345

2.21

3.45

15.05

T5

37±0.018

0.125 ±0.003

0.43±0.077

290 ±5.5

93.06±0.27

91.91±0.0144

2.02

4.12

15.87

T6

25±0.042

0.108 ±0.003

0.74±0.021

185 ±6.1

54.8±0.32

91.17±0.0275

0.89

3.99

8.86

T7

31±0.035

0.232 ±0.005

0.63±0.014

203 ±4.05

30.65±0.89

94.11±0.025

1.28

3.78

10.34

T8

42±0.022

0.145 ±0.004

0.54±0.047

231 ±6.55

87.58±0.67

91.42±0.0344

1.60

3.70

14.09

T9

40±0.025

0.195 ±0.004

0.49±0.051

245 ±4.8

90.15±0.20

92.64±0.0365

2.05

3.23

15.15

T10

38±0.015

0.155 ±0.005

0.41±0.091

284 ±5.6

93.76±0.43

91.66±0.0375

1.98

4.15

16.45

SD=Standard deviation,RT= Room temperature,RH=Relative humidity

 

Table3: Results of stability studies.

Formulation code

Drug content (mg/cm2)at 40C

Drug content (mg/cm2)at 250C

Drug content (mg/cm2)at 400C

15days

30days

60days

90days

15days

30days

60days

90days

15days

30days

60days

90days

T1

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

T2

3.88

3.88

3.88

3.88

3.88

3.88

3.88

3.88

3.88

3.88

3.88

3.88

T3

3.71

3.71

3.71

3.71

3.71

3.71

3.71

3.71

3.71

3.71

3.71

3.71

T4

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

3.74

T5

3.85

3.85

3.85

3.85

3.85

3.85

3.85

3.85

3.85

3.85

3.85

3.85

T6

3.72

3.72

3.72

3.72

3.72

3.72

3.72

3.72

3.72

3.72

3.72

3.72

T7

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

T8

3.73

3.73

3.73

3.73

3.73

3.73

3.73

3.73

3.73

3.73

3.73

3.73

T9

3.78

3.78

3.78

3.78

3.78

3.78

3.78

3.78

3.78

3.78

3.78

3.78

T10

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

3.84

 

 


Fig.3:In-Vitro drug permeation profiles from the transdermalfilms T1 to T5

 

In vitro drug permeation profiles (fig.3 and fig.4) indicated that formulations T4and T9 exhibited maximum %age of drug permeation. The rate of drug permeation was lowest in case of patches prepared from ERL100 (T1) and ERS100 (T6) alone. In vitro drug release increased with increase in concentration of PVP. It was also observed that as the concentration of hydrophilic polymer PVP increased in the formulations, the drug permeation rate increased substantially, with a nominal decrease in formulations T5 and T10. Addition of PVP increased the amount of drug permeated. The burst effect due to incorporation of PVP was because of the rapid dissolution of the surface hydrophilic polymer. The rapid leaching of hydrophilic fraction of film former results in the formation of pores and thus leads to decrease of mean diffusional path length of drug molecules to permeate into dissolution medium and hence higher permeation rates. The data from the in-vitro study was fitted to various kinetic models to determine the kinetics of drug release. Higuchi’s plot was found to be linear indicating matrix diffusion mechanism.

 

Fig.4: In-Vitro drug permeation profiles from the transdermal films T6 to T10

 

As shown in Table 3 the drug content in all the patches remained unchanged for a period of 90 days .Further there was no change in colour, texture and appearance of all the patches. Thus it can be concluded that all the patches were physically and chemically stable during the study period of 03 months .

CONCLUSION:

From the present study it can be concluded that matrix type transdermal patches of Lisinopril could be prepared by solvent casting technique having suitable mechanical properties and in-vitro permeation profiles.

 

ACKNOWLEDGEMENTS:

I sincerely thank Dr. Reddy’s Laboratories, Hyderabad for giving the gift sample of Lisinopril and Evonik (Degussa) Ltd. Mumbai for the gift samples of EudragitRL100 and EudragitRS100.

 

REFERENCES:

1.       Martindale. The Complete Drug Reference The Pharmaceutical Press, Great Britain (2005) 34th Ed.946-947.

2.       http://www.ncbi.nlm.nih.gov/pubmed/2844497.

3.       AnilKumar J Shinde,et al.” Design and evaluation of transdermal drug delivery system of  gliclazide” Asian J. Pharma. 2010 ;4(2) :121-129.

4.       Wongpayakul L,et al.”Effect of single and combined permeation enhancers on the skin permeation of ketoprofen transdermal drug delivery system”,CMU.Journal 2006:41-51.

5.       Jitendra Banweer et al.”Formulation, Optimisation and Evaluation of Matrix type Transdermal system of Lisinopril dihydrate using permeation enhancers”jpr.2008;1(1):16-22.

6.       Mohammed Gulzar Ahmed et al.”Polymeric Strips Containing Sparfloxacin for the long term treatmaent of Periodontitis”ijpr.2008;1(1) :48-53.

7.       Swamy N.G.M et al .”Study of film forming properties of hydroxy propyl guar and its use in preparation of medicated transdermal patches” ijper2008;42(3):147-152.

8.       Saxena M. Et al.”Formulation and evaluation of transdermal patches of metoclopramide hydrochloride”Ind.drugs2006;43(9):740-745.

9.       Suresh V Kulkarni et al.”Development and evaluation of Diltiazem hydrochloride transdermal patches by using glycerol and castor oil as plasticisers”Research J.Pharm.and Tech.2010;3(3):905-909.

10.     Tanwar et al.”Development and evaluation of carvedilol transdermal patches”Acta Pharm.2007;57:151-159.

11.     ShobhaRani et al.”Preformulation studies of methotrexate for assessing its suitability for transdermal vesicular drug delivery”Int J Pharma Excip.2006;93-98.

12.     H L Bhalla et al.”Transdermal films of isosorbide dinitrate” Ind.Drugs 1987;24(6):313-315.

13.     Hiremath S.P et al”Formulation, characterisation and evaluation of transdermal patches of Diltiazem Hydrochloride”Ind Drugs 2010;47(10):47

 

 

 

 

Received on 23.03.2011       Modified on 14.04.2011

Accepted on 10.06.2011      © RJPT All right reserved

Research J. Pharm. and Tech. 4(8): August 2011; Page 1260-1264