ujjawal nautiyal* , devendra singh · 2018-12-29 · ujjawal nautiyal* 1, devendra singh 2....

INDIAN JOURNAL OF PHARMACEUTICAL & BIOLOGICAL RESEARCH (IJPBR), Vol. 1(1); March, 2013

*Corresponding Author: Ujjwal Nautiyal, Department of Pharmacy, Siddartha Institute of Pharmacy, Dehradun,

Uttarakhand, India. E-Mail Id: [email protected]

44

P

1Department of Pharmacy, Siddartha Institute of Pharmacy, Dehradun, U.K, (India)

2Cipla Limited, Paonta Sahib, Sirmour, H.P, (India)

……………………………………………………………………………………………..

Abstract

Administration of drugs through skin has received great attention through the last decade.

Hence this study aims to formulate an anti-hypertensive drug losartan as transdermal

patch using different bioadhesive polymers such as ethyl cellulose, cellulose acetate, and

polyvinyl pyrrolidon,hydroxyl propylemethylcellulose with plasticizers propylene glycol

(PG). Patches were prepared though solvent evaporation method, The backing membrane

was a non permeable aluminium foil laminated with polyethylene and evaluated for

thickness uniformity, Uniformity of weight, Scanning Electron Microscopy, Surface pH,

Swelling studies, Drug content uniformity Effect on agingn, skin irritation potential, and

In vitro release study.Patches exhibited controlled release over more than 2 hr.It was

concluded that patches containing 30 mg of losartane with HPMC (formulation F2)

,showed moderate swelling, surface pH and controlled drug release, thus can be selected

for the development of transdermal patches for effective uses.

Keywords: Transdermal patch, losartan, polymers, bioadhesive

Keywords: Cardiovascular diseases, antioxidant, cardioprotective, phytoconstituents.

………………………………………………………………………………………………

1. INTRODUCTION

Transdermal drug delivery is the non-

invasive delivery of medications from

the surface of skin-the largest and most

accessible organ of human body-

through its layers, to the circulatory

system. TDDS offers many advantages

over conventional injection and oral

methods. It reduces the load that the oral

route commonly places on the digestive

tract and liver. It enhances patient

compliance and minimizes harmful side

effects of a drug caused from temporary

overdose. Another advantage is

convenience, especially notable in

patches that require only once weekly

Formulation and Characterization of Transdermal Patches of

Losartan

Ujjawal Nautiyal*1, Devendra Singh

2

Nautiyal et al., 1(1); 2013

Available online on www.ijpbr.in 45

application. Such a simple dosing

regimen can aid in patient adherence to

drug therapy. A transdermal patch is a

medicated adhesive patch placed on the

skin to deliver a time-released dose of

medication through the skin for treating

topical or systemic illness. Since early

1990, this dosage form of transdermal

therapeutic system has been available in

the pharmaceutical market. Such a

system offers a variety of significant

clinical benefits over others, such as

tablet and injection1,2,3

.Trans dermal

drug delivery that meets all the stringent

needs that are specific to the drug

molecule (physicochemical and stability

factors), the patient (comfort and

cosmetic appeal), the manufacturer

(scale up and manufacturability) and

most important the economy4.

Also, for the transdermal route of

administration, peak plasma levels of

drug are reduced leading to decreased

side-effects and it avoids presystemic

and systemic first pass metabolism and

eliminates the need for intravenous

access5,6,7

. Transdermal route is a

potential mode of delivery of lipophilic

drugs in the systemic circulation8. It

controls of the area of application,

amount applied, release kinetics and

prolongation of applicationtime9.

Low turnover rate of transdermal

products from pharmaceutical research

and development departments could be

attributed to the disadvantages

encountered with this route of

administration including the outermost

stratum corneum layer of the epidermis

as a significant barrier to penetration

across the skin8. Skin irritation

associated with some drugs10

. Limitation

of dose that could be incorporated in the

patch, lag time for drug absorption and

onset of action, and metabolism of some

drug in the skin11

.

2. Materials and Methods

2.1Material

LOSARTAN was obtained as gift

sample from cipla,sikkim.

Polyvinylpyrrolidone (PVP) was

obtained from ipca lab.Dehradun and

hydroxypropylmethylcellulose acetate

phthalate (HPMCP) from Shasun Drugs

and Chemicals, Cuddalore. Cellulose

acetate phthalate (CAP), ethyl cellulose

(EC) and propylene glycol were

purchased from CDH (P) Ltd. and 1,8-

cineole from mankind Company. The

cadaver skin was procured from

Department of forensic medicine,

AIIMS, New Delhi 110049. The drug



samples were characterized by means of

UV, IR methods along with

determination of solubility and pH for

their authentication.

2.2 Preparation of drug containing

polymer matrices:

Films composed of different polymers

(CAP, EC and HPMC) with PVP were

prepared in methanol/acetone mixture

[Table - 1]. Propylene glycol (40%w/w

of dry weight of polymers, used as a

plasticizer) and 1,8-cineole (penetration

enhancer) were added with continuous

stirring using Teflon-coated magnetic

bead placed in magnetic stirrer. Drug

(30% w/w) was added to the polymer

solutions and stirred continuously for an

hour and the solutions were casted on

the backing mambrane (aluminum foil)

and dried in a dessiccator at room

temperature. Backing membrane was

prepared by wrapping aluminum foil

over the Teflon mold. The films were

then packed in aluminum foil and stored

in a dessiccator until further evaluation.

3. Evaluation of the prepared films

3.1Thickness uniformity of the films

The thickness of each transdermal patch

was measured using screw gauge at five

different positions of the transdermal

patch and the average was calculated.

3.2Uniformity of weight of the films

Transdermal patches sizes of 10x10

mm2 were cut. The weights of 10 film

were taken and the weight variation was

calculated.

3.3Scanning Electron Microscopy

To detect the surface morphology of the

Transdermal patches, SEM of the

patches was performed at IIT Roorkee

by Scanning Microscope-Joel of Japan

Model No 5600. SEM photograph of

different formulations is shown in

(Figure-1,2 and 3)

3.4Surface pH

Transdermal patches were left to swell

for 1 h on the surface of the agar plate,

prepared by dissolving 2% (w/v) agar in

warmed isotonic phosphate buffer of pH

6.8 under stirring and then poured the

solution into the petridish allowed to

stand till gelling at room temperature.

The surface pH was measured by means

of pH paper placed on the surface of the

swollen film.

3.5 Swelling studies of the films

Weight and area increase due to swelling

were measured.



Weight increase due to swelling: A drug-

loaded patch of 10x10 mm2 was

weighed on a preweighed cover slip. It

was kept in a petridish and 50 ml of

phosphate buffer, pH 6.6was added.

After every five min, the cover slip was

removed and weighed upto 30 min. The

difference in the weights gives the

weight increase due to absorption of

water and swelling of film. The percent

swelling, % S, was calculated using the

following equation: percent swelling (%

S)=(Xt–Xo/Xo)×100, where Xt is the

weight of the swollen film after time t,

Xo is the initial film weight at zero time.

3.6 Drug content uniformity of the

films

The transdermal patches were tested for

the content uniformity. A film of size

10×10 mm2 was cut and placed in a

100ml volumetric flask. 100ml of a

6.8pH buffer was added. The contents

were stirred in a magnetic stirrer for 24

hr. After 24hr. take 1ml from this and

made volume upto 10ml by addition of

6.8 pH buffer. The absorbance of the

solution was measured against the

corresponding blank solution at 256nm.

3.7 In vitro release study

The release study was carried out in a

USP 24 dissolution apparatus type 1

(six-station dissolution apparatus,

Hanson research, USA), slightly

modified in order to overcome the small

volume of the dissolution medium. The

dissolution medium was 100 mL IPB,

pH 5.5, maintained at 37±0.5 ºC and

kept in a glass beaker fixed inside the

USP dissolution flask. The film was

fixed to the central axis, which rotated at

50 rpm. Filtered samples (5 mL) were

manually collected at different intervals.

The samples were compensated with an

equal volume.

The concentration of drug released in the

medium was assayed

spectrophotometrically at 256 nm after

suitable dilution with the dissolution

medium when necessary. The

experiment was carried out in triplicate.

3.8 Effect on aging

The effect of aging on physical

appearance was studied by packing the

polymeric films in properly sealed

aluminum foil and then stored in a

dessiccator at ambient conditions for 30

days.

3.9 Evaluation of skin irritation

potential of polymeric matrices:

The primary skin irritation studies were

done using modified Draize test. The



hair of rabbits were removed by shaving

from the dorsal area on both sides 24 h

before test, one side of the back of each

rabbit i.e. untreated skin area serves as

the control for the test. Medicated patch

was secured on experimental side using

adhesive tape and the non-medicated

patch was adhered on the control side of

six rabbits. These patches were covered

with occlusive covering to approximate

the condition of use. The medicated

patches were changed after 48 h. and the

fresh patches were secured at the same

site. However the patches on the control

side were not changed. The patches were

secured on the back for seven days.

After removal of patch after a week each

of the areas were examined for any sign

of erythema or oedema.

4. Results and Discussion

Transdermal pathes were prepared by

solvent casting technique using polymers

such as PVP, HPMC, EC, and CAP. The

prepared transdermal pathes were

evaluated for different physicochemical

tests such as weight variation, thickness,

content uniformity, swelling index,

surface pH, and in vitro drug release

studies.

All the transdermal pathes showed

uniform thickness throughout. The film

thickness were observed to be in the

range of 529±0.91µm to 540±1.1 µm.

And average thickness found was about

534.66 µm. The weights of different

formulation were found to be in the

range of 98.87±0.97% to 91.07±1.11%.

The acidic or alkaline pH may cause

irritation to skin and may affect the drug

release, degree of hydration of polymers,

therefore the surface pH of patches was

determined to optimized both drug

release and adhesion. The surface pH of

all formulations was within ±0.5 units of

the neutral pH and hence no skin

irritations were expected and ultimately

achieve patient compliance.

The swelling of the films were observed

in phosphate buffer solution (pH 5.5).

The comparative swelling in different

formulations are in order to F2 > F1> F3.

Swelling was more pronounced in films

F2 which containing HPMC due to

presence of more hydroxyl group in

HPMC molecules. These results were in

agreement with the increase in area due

to swelling.

As the drug was uniformly dispersed in

the matrix of the polymer, a significantly



good amount of drug was loaded in all

the formulations. The drug content was

found to be in the range of 14.78 ± 1.11

(F3) to 13.87 ± 1.53 (F1). The order of

drug content was found to be F3 > F2 >

F1. The results of content uniformity

indicated that the drug was uniformly

dispersed.

The physical appearance of the patches

and the effect on ageing indicated that

the patches need to be stored in properly

sealed air tight packing to keep them

protected from extremes of moisture that

may alter their appearance, thus, the

properties were found to be within limits

and satisfactory.

In vitro release studies of various

formulations were performed using pH

5.5 phosphate buffer as dissolution

medium. The drug concentration was

determined spectrophotometrically at

256nm. Significant difference was

observed in the release pattern of

LOSARTANE transdermal patches

containing PVP, HPMC, EC and CAP

(Fig. 4). During dissolution, HPMC

containing films swelled forming a gel

layer on the exposed film surfaces. The

loosely bound polymer molecules in

these films were readily eroded,

allowing the easy release of

LOSARTAN as compared to CAP. After

two hr the release was found to be in the

range of 92.96 to 96.35 %. The rank

order of drug release after 2hr was found

to be 96.35 > 95.06 > 92.17 % for

formulations F2 > F1> F3 respectively.

Scanning Electron Microscopy showed

that the surface of F2, F3 seems to be

rough and non-uniform and formulation

F1 again shows rough but with structures

like crystals, which seems to be more

uniform. On the basis of SEM we can

concluded that irregular the surface or

rough the surface of transdermal patches,

more and easy release of drug, due to

lack of contact angle. So by surface

morphology, F2, F3, release drug more

easily in faster rate then F1.

The primary skin irritation studies of

formulation showed that formulation F1

causes slight irritation after 7 days of

application (modified Draize test).

Irritation subsided within few hours after

removal of patch. Formulation F2 was

not found irritant in primary skin

irritation studies.

The results of all the physical parameters

of all formulations (F1 – F3) were found

to be satisfactory and comply with

theoretical limits. The in vitro drug



release was found satisfactory. Hence

the development of bioadhesive buccal

formulations for Losartan may be a

promising one as the dose of Losartan

may be decreased, bioavailability may

be increased and hence side effects and

patient compliance may be reduced.

TABLE 1: COMPOSITION OF VARIOUS FORMULATIONS OF

TRANSDERMAL PATCHES OF LOSARTAN

Formulation

ingredient

F1

F2

F3

DRUG(%W/W) 30 30 30

(POLYMER)%W/W

PVP 80 80 80

EC 12

HPMC 12

CAP 12

(PLASTICIZER)(%W/W)

PROPYLINE GLYCOL 40 40 40

1,8 CINEOLE(%W/W) 20 20 20

METHENOL:ACETONE 8:1 8:1 8:1



TABLE 2: PHYSICAL EVALUATION OF TRANSDERMAL PATCHES OF

LOSARTAN

PHYSICAL

PROPERTIES

F1 F2 F3

DRUG

CONTENT(mg/

cm2±SD)

13.87±1.53

Translucent, Dry,

Nonsticky,

Flexible

14.38±1.23

Transparent,Moist

Sticky,Flexible

14.78±1.11

Transparent,Dry

Nonsticky,Flexible

WEIGHT

WARIATION(

%±SD)

92.05±1.02 98.87±0.97 91.07±1.11

THICKNESS(µ

m±SD)

540±1.1 535±0.88 529±0.91

(EFFECT OF

AGING IN

APPEARANCE

)IF LEFT

OPEN IN A

DESSICATOR

Translucent, Dry,

Flexible

Opaque, Dry, Brittle Transparent,Dry,

Brittle

IF STORED IN

PROPER

SEALED BAG

Translucent,

Dry,Nonsticky,Fl

exible

Opaque,Moist, Sticky,

Flexible

Transparent,Dry

Nonsticky,Flexible

SWELLING

INDEX(2hr)

17.13±1.22 21.24±1.32 21.33±1.23

SURFACE pH 5.23±1.08 5.52±1.07 5.72±1.11



Table 3: In-vitro Release of Losartan from Different Transdermal Patches

Time (Min) Cumulative percent drug release

Formulation F1 F2 F3

0 0 0 0

15 48.51 77.46 42.21

30 68.98 81.46 51.53

45 80.73 93.44 59.15

60 84.39 101.08 71.78

75 95.48 94.43 86.16

90 95.06 95.67 92.17

105 94.82 96.35 85.14

120 85.31 92.45 74.6

135 82.15 88.53 72.93

FIG 1: SEM of F1 fomulation





REFERENCES

1. Ranade VV. Drug delivery

systems: Transdermal drug

delivery. J Clin Pharmacol

1991;31:401-18.

2. Modamio P, Lastra CF, Marino

EL. A comparative in-vitro study

of percautaneous penetration of

betablochers in human skin. Int J

Pharm 2000;194:249-59.

3. Ke GM, Wang L, Xue HY, Lu

WL, Zhang X, Zhang Q, et al. In-

vitro and in-vivo characterization

of a newly developed clonidine

transdermal patch for treatment

of attention deficit hyperactivity

disorder in children. Biol Pharm

Bull 2005;28:305-10.

4. Kandavilli S, Nair V,

Panchagnula R. Polymers in

transdermal drug delivery

systems, Pharmaceutical

Technology 2002, 62-78.

5. Guy RH. Current status and

future prospects of transdermal

drug delivery. Pharm Res

1996;13:1765-9.

6. Tiwary AK, Sapra B, Jain S.

Innovations in transdermal drug

delivery: Formulations and

techniques. Recent Patents on

Drug Delivery and Formulation

2007;1:23-36.

7. Code G, Fischer W, Legler U,

Wolff HM. Proceedings of 3 rd

TTS symposium, Tokyo; 1987.

p. 3-8.

8. Heather AE. Transdermal drug

delivery: Penetration

enhancement techniques. Curr

Drug Deliv 2005;2:23-33.

0

20

40

60

80

100

120

1 2 3 4 5 6 7 8 9 10

%C

R

Time(hrs)

In-vitro drug release

F1

F2

F3



9. Tymes NW, Shah VP, Skelly JP.

In-vitro profile of estradiol

transdermal therapeutic systems.

J Pharm Sci 1990;79:601-2.

10. Zhai H, Maibach H. Occlusion

versus skin barrier function. Skin

Res Technol 2002;8:1-6.

11. Misra AN. Controlled and novel

drug delivery. In: Jain NK,

editors. Transdermal drug

delivery. New Delhi: CBS

Publishers;1997. p. 100-1.

Source of support: Nil, Conflict of interest: None Declared

ujjawal nautiyal* , devendra singh · 2018-12-29 · ujjawal nautiyal* 1, devendra singh 2....

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