Design, Development, Physicochemical and In Vitro Evaluation of Transdermal Patches Containing Verapamil Hydrochloride in Ethyl Cellulose - Povidone Matrices

 

Chakraborty Prithviraj*1, Dey Biplab K.2,  Bahadur Sanjib3, Thakkar Suresh1 and Das Sudip1

1S.D. College of Pharmacy, Barnala, Punjab, PIN 148101

2Dept.of Pharmaceutics, Himalayan Pharmacy Institute, Majhitar, Rangpo, East Sikkim, PIN-737136

3Oriental College of Pharmacy, Thakral Nagar, Raisen Road, Bhopal 462021

*Corresponding Author E-mail:  prithviraj.in@gmail.com

 

ABSTRACT

An attempt has been made to develop transdermal patches of Verapamil HCI by using ethyl cellulose and polyvinyl pyrrolidoneK30 as polymer matrix, dibutyl phthalate as plasticiser and polyvinyl alcohol as backing membrane. The present study has revealed the designing and in vitro evaluation of transdermal patches containing verapamil hydrochloride in ethyl cellulose - povidone matrices. After preparation of patches several physicochemical properties were examined i.e. thickness, percent moisture content, percent moisture uptake, percent flatness, water vapour transmission rate, tensile strength and weight variation to satisfy the suitable criteria’s.  In vitro skin permeation study was performed taking rat skin using modified Keshary -Chien diffusion cell. After the graphical examination conclusion was drawn that in formulation with higher concentration of hydrophobic polymer, patches releases drug extending 24hrs whereas with higher amount of hydrophilic polymer drug release occurred less than above. Drug- polymer interactions were studied by FTIR spectroscopy and surface morphologies of the films were investigated using SEM

 

KEY WORDS:  Verapamil hydrochloride, Transdermal patch, Ethyl cellulose, Povidone

 


INTRODUCTION:

During the last decade, transdermal delivery has received increasing attention in the face of growing awareness that drugs administered by conventional means are frequently excessively toxic and sometimes ineffective. Thus, conventionally administered drugs in the form of pills, capsules, injectable and ointments are introduced in to the body as pulses that usually produce large fluctuation of drug concentration in the bloodstream and tissues and consequently, shows unfavorable pattern of efficacy and toxicity. Improved patient compliance and effectiveness are inextricable aspects of a delivery system now a days. Thus a number of drug molecules have been or are being developed to be given in the transdermal drug delivery system (TDDS).

 

Transdermal delivery offers several biomedical advantages over conventional routes including avoidance of pre-systemic and systemic first pass metabolism and controlled release over extended period besides providing a convenient non-invasive and easily terminable means

 

for systemic as well as topical drug delivery hence also improves patient compliance, safety and efficacy of the drug.1 The first drug delivered through the skin was dimethyl sulfoxide in 1900 and nitro-glycerine ointment was introduced for the management of angina in 1954.2

 

Verapamil hydrochloride is a calcium ion influx inhibitor, which is used widely in the treatment of angina pectoris, hypertension and supraventricular tachyarrhythmia’s and used as conventional and sustained release dosage form. It was the first amongst the calcium-channel blockers (CCBs). It has been used since 1962 in Europe, then in Japan for its antiarrhythmic and coronary vasodilator effects.3,4 Verapamil hydrochloride is the drug of choice for controlled delivery as the drug is reported to have a terminal plasma half life of 2 to 8 hours following single oral dose or intravenous administration but is subject to very considerable first-pass metabolism in the liver and the bio-availability is only about 20%.5, 6, 7

 

MATERIALS AND METHODS:

Verapamil hydrochloride was obtained as gift sample from Torrent Pharmaceuticals Ltd; Ahmedabad. Ethyl cellulose, Polyvinyl alcohol were procured from S.D. Fine Chemicals Ltd. Mumbai. Povidone (Polyvinyl pyrrolidone K30) was procured from Thomas Baker, Mumbai. Aluminium foil used were purchased from S.R. Industries; New Delhi. All other materials used in the study were of analytical grade.

 

Preparation of the patches:

Transdermal patches of verapamil hydrochloride were prepared using different combinations of EC and PVP K30 by solvent evaporation technique 8,9 in cylindrical both side opened glass moulds. The bottom of the mould was wrapped with aluminium foil on which the backing membrane was cast by pouring 4% (w/v) PVA solution followed by drying at 60° C for 6 hours.10 The two polymers were weighed in requisite ratio and they were then dissolved in Chloroform as a solvent. Dibutyl phthalate 30% (w/w) of polymer composition was used as a plasticizer. The drug was added 20% (w/w) of the total weight of polymer, in the homogeneous dispersion, by slow stirring with a magnetic stirrer. The uniform dispersion (2 ml each) was casted on the PVA backing membrane casted earlier and dried at 40° C for 6 hours. After drying patches were removed from the mould, wrapped with aluminium foil and kept in desiccators until they were used for further study. All the patches obtained from this compositions were smooth, elastic and were easily removed from glass moulds. The formulation design is shown in Table I

 

Fig.1: (%) Moisture content and (%) moisture uptake profile of the prepared Verapamil hydrochloride transdermal patches

 

Evaluation of polymeric transdermal patches:

Uniformity of thickness:

The thickness of the patch at five different points was measured with micrometer (Mitutoyo) and the average of five readings with the standard deviation was calculated11. The procedure was followed for all the formulation batches.

 

Percent moisture content (% MC):          

The patches were weighed individually and kept in a desiccator containing 10 gm of calcium chloride as desiccant at 37°C for 24 hour. The patches were weighed again and again individually until it showed a constant weight. The final weight was noted when there was no further change in the weight of individual patch. The percentage of moisture content was calculated12 as a difference between initial and final weight with respect to final weight.

 

% Moisture content = [(x-y)/y] * 100, where, x =   initial weight, y = finial weight

 

Fig.2: In vitro permeation profile of transdermal patches composed of EC and PVP K30 through albino rat skin

 

Table I: Formulation design of transdermal patches of Verapamil hydrochloride

Sl. No.

Formu

Lation

code

Ratio

of EC

: VP

Total

Weight

Of EC and PVP

Solvent

(Chlor

oform)

 

Plasticizer(% w/w)

Of total polymer

Drug

(% w/w)

total polymer

1.

EP1

8:1

500 mg

10 ml

30

20

2.

EP2

6:1

500 mg

10 ml

30

20

3.

EP3

4:1

500 mg

10 ml

30

20

4.

EP4

2:1

500 mg

10 ml

30

20

5.

EP5

1:8

500 mg

10 ml

30

20

6.

EP6

1:6

500 mg

10 ml

30

20

7.

EP7

1:4

500 mg

10 ml

30

20

8.

EP8

1:2

500 mg

10 ml

30

20

 

The results of moisture content studies for different formulations are shown in Figure 1. Each result is mean of three replicates.                       

 


 

Fig.3: FTIR Spectrum of pure verapamil hydrochloride and drug loaded patches of EC and PVP K30

 


 

TABLE II: Thickness, percent flatness, water vapour transmission rate, tensile strength, weight variation profile of the prepared Verapamil hydrochloride transdermal patches

Formulation code

Ratio of EC :PVP

Thickness**(In cm.)± S.D. n= 5

% Flatness n=5

WVTR (gm/cm/h)

Tensile strength

(gm / cm2) n=3

Weight in gm

± S.D. n=5

EP1

8:1

0.00200 ±0.00070710

100

1.33853 x10 -4

267 ± 0.60

0.143 ±0.0035

EP2

6:1

0.00198 ±0.00083666

100

1.90409 x 10 -4

259 ± 0.52

0.134 ± 0.0032

EP3

4:1

0.00176 ±0.00054772

100

1.47524 x 10-4

242 ± 0.81

0.131 ± 0.0058

EP4

2:1

0.00174 ±0.00054772

100

1.85419 x 10-4

239 ± 0.63

0.134 ± 0.0025

EP5

1:8

0.00190 ±0.00012247

100

1.75309 x 10-4

215 ± 0.59

0.126 ± 0.0020

EP6

1:6

0.00178 ±0.00013038

100

1.90838 x 10- 4

228 ± 0.32

0.133 ± 0.0030

EP7

1:4

0.00188 ±0.00016431

100

1.67355x 10 -4

231 ± 0.29

0.126 ± 0.0045

EP8

1:2

0.00174±0.00016733

100

1.79766 x 10 -4

238 ± 0.34

0.130 ± 0.0026

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

n = number of repeated observation; ± S.D. is the standard deviation

 

Percentage moisture uptake (% MU):

The patches were weighed accurately and placed in a desiccator where a humidity condition of 75 % RH was maintained by using saturated solution of sodium chloride. The patches were taken out periodically and weighed for a period of 72hours. The percentage of moisture uptake was calculated12 as difference between

final and initial weight of the patch with respect to initial weight.

 

% Moisture uptake = [(y-x)/x] * 100, Where, x =   initial weight, y = finial weight.

 

The results of moisture content studies for different formulations are shown in Figure 1. Each result is mean of three replicates.

 

Percent flatness study:

Longitudinal strips were cut out from each transdermal patch, one from the centre and two from the either side. The length of each strip was measured and the variation in the length because of non-uniform in flatness was measured by determining % constriction, considering 0 % constriction is equivalent to 100 % flatness.12                         

 

 

% constriction = [(l1 – l2)/l2] *100, Where, l1 = initial length of each strip,l2 = final length of each strip. 

 

Water vapour transmission (WVT) rate:  

For this study glass vials of equal diameter (1.4mm) were used as transmission cells. These cells were washed thoroughly and dried in a oven. The transdermal patch of known thickness was fixed over the edge of the glass vial containing 3 g of fused calcium chloride as a desiccant by using an adhesive. Then the transmission cells were weighed accurately and initial weight was recorded. The cells were then kept in a desiccator containing saturated solution of potassium chloride (200ml). The humidity inside the desiccator was to be 80-90% RH. The cells were taken out periodically and weighed for a period of 72 hrs. The experiment was performed and values were calculated by the method of using the formula13            

 

      WVT rate = WL/ S where;

      W             = water vapour transmitted in gm.

      L              = Thickness of the transdermal patch in cm.

      S              = Exposed surface area in cm2

 

Fig.4: SEM Photograph of Drug loaded Transdermal patch before skin permeation study

 

Tensile strength:

The tensile strength measurement was made using an instrument assembled in the laboratory and following the method used by Sadhna et al.14 The films were fixed individually to the assembly, the required weights to break the films were noted and calculated according to the formula given below

 

Tensile strength= (break force/a x b) x (1+ L/I )

Where a, b, L and I are the width, thickness, length and elongation of the films.

 

Weight variation study:

This test provides a means for measuring uniformity in terms of the weight within a batch as well as batch to batch. The weight of each patch was taken using single pan balance with sensitivity of 0.001 mg. 15

 

In vitro skin permeation study using albino rat skin:   

Invitro skin permeation study was performed taking albino rat skin. Young albino rat weighed between (200 gm- 250 gm) were taken and sacrificed by excess chloroform inhalation. The abdominal hairs were removed with marketed hair removers. The abdominal skin was carefully separated from the body, with the dermis part remaining intact. Subcutaneous tissues were surgically removed. The inner part of the skin was washed with distilled water thoroughly to separate the adhering fat. The skin, so obtained, was examined microscopically for the presence of any possible damage. The full thickness skin thus obtained was kept in normal saline solution and stored at 4 ± 1°C until used for the experiment.

 

The drug permeation from the transdermal patches through the skin was determined using modified Keshary – Chien diffusion cell16.   The contents of the donor and receptor compartments were separated by placing the excised skin in between two compartments. The skin was mounted in such a way that the stratum corneum side of the skin continuously remained in an intimate contact with the transdermal patch in the donor compartment. The receptor compartment contained 100ml distilled water at 37 ± 2°C. The content of the diffusion cell was stirred using a teflon coated bead at a constant speed (100 rpm). Samples were withdrawn (1 ml) at predetermined time intervals and replaced with same amount of distilled water to maintain the sink condition. After suitable dilution the samples were analyzed for drug content using UV spectrophotometer at λ max 229.5 nm. The permeation study was carried out for 24 hours.

 

Fourier transforms infrared spectroscopy (FTIR) study:

Drug- polymer interactions were studied by FTIR spectroscopy. The spectra were recorded for verapamil hydrochloride, physical mixture of polymers and drug loaded patches without plasticizer using FTIR – spectrophotometer (FTIR 8400S; SHIMADZU, Japan) from KBr pellets. The scanning range was 400-4000cm­-1 ­­ and the resolution was 1 cm-1

 

 

Scanning Electron Microscopy: 17, 18

The surface morphologies of the films were investigated by using a JEOL JSM 6360 Scanning electron microscope at 7 kV. Prior to examination, samples were gold coated to make them electrically conductive.

 

Fig. 5: SEM Photograph of exhausted Transdermal patch after Skin permeation study

 

RESULTS AND DISCUSSION:

In the present study transdermal patches of Verapamil hydrochloride were prepared as monolithic matrices by solvent casting technique employing glass moulds of known diameter. Transdermal patches were prepared using polymers ethyl cellulose with PVP K30 in different combinations (Table I).

 

The different physicochemical characteristics of different patches along with their release characteristics were studied. The thickness of the patches prepared with ethyl cellulose and PVP K30 were found between 0.00174cm to 0.00200 cm (Table II). Low standard deviation values in the patch thickness measurement ensure uniformity of the patches prepared by solvent casting technique.

 

The percent moisture content and the percent moisture uptake of the patches  showed (Fig 1)  that the moisture content and moisture uptake increases gradually with the increase of hydrophilic polymer concentration for different formulations containing PVP K30 with ethyl cellulose. Again little moisture content of the formulations helps them not to become completely dried and brittle. Again low moisture uptake value protects microbial contamination of the formulations. Formulation EP1   and EP2 were found to be the best amongst all the formulations prepared of ethyl cellulose with combination PVP K30 in this respect. The uniformity in flatness of the prepared patches (Table II) indicates that the formulation by solvent evaporation technique is reproducible and the formulations can maintain satisfactory surface smoothness. It was observed from the tensile strength measurement study, that with the increase of PVP K30 concentration, the tensile strength of the patches gradually decreased (Table II).  The Water vapour transmission rate is good for all the patches which indicate that they are permeable to water vapour.  All the patches prepared showed uniformity in weight which is indicative of efficiency of solvent casting process.

The in vitro permeation of drug from the prepared patches were carried out in modified Keshary-Chien diffusion cell through albino rat skin using 100 ml distilled water as diffusion media for a period of  24 hours. The graphical representation of Cumulative % drug release as a function of time (Figure 2) showed that the patches releases drug over an extended period of 24 hrs where hydrophobic ethyl cellulose concentration is higher. Formulation like EP1 release only 61% of total drug present, where as EP4 releases near about total amount of drug. Again in case of formulations that contain a higher amount of hydrophilic polymer like PVP K30 like EP5 and EP6, the drug release was found more earlier than 24 hrs. A burst release was observed in case of all formulations containing higher proportion of hydrophilic polymer. No significant drug-polymer interaction is observed in IR spectrum of the drug loaded patch (Figure 3).  The scanning electron microscopic examination of drug loaded patches composed of ethyl cellulose and PVP K30 in 2:1 ratio shows good film formation superficially (Figure 4). After skin permeation study the drug release from the patches can be evidenced by the pore formation in the film (Figure 5).

 

CONCLUSION:

From the results obtained from all the evaluation, it is evident that transdermal formulation can be prepared by suitable incorporation of ethyl cellulose and povidone in a suitable proportion to form a matrix from which sustained release and prolong release of drug can be obtained by controlling the ratio of ethyl cellulose and povidone. 

 

ACKNOWLEDGEMENT:

The authors wish to thank Torrent Pharmaceuticals Ltd. for the gift sample of drug. The authors also wish to thank The Authority, Himalayan Pharmacy Institute, Majhitar; East Sikkim, for providing laboratory facilities to carry out the present work.

 

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Received on 08.11.2008           Modified on 24.11.2008

Accepted on 16.12.2008          © RJPT All right reserved

Research J. Pharm. and Tech. 2(1): Jan.-Mar. 2009; Page  168-172