FORMULATION AND EVALUATION OF BUCCAL FILM OF …

www.wjpps.com Vol 6, Issue 9, 2017.

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Shivani et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND EVALUATION OF BUCCAL FILM OF

ROSUVASTATIN

Shivani Saxena* and Dr. Sobhna Singh

M.J.P. Ruhilkhand University Bareilly, U.P., India.

ABSTRACT

For systemic drug delivery, the buccal region offers an attractive route

for drug administration. The main objective of the study is to formulate

buccal films of rosuvastatin. Rosuvastatin is a HMG Co-A inhibitor

used for the treatment of hyperlipidaemia, atherosclerosis disease. It’s

oral bioavailability is 20% due to extensive first pass metabolism.

Rosuvastatin films were prepared using HPMC, CMC and PVA,

Tragacanth in various proportions and combinations using Glycerine as

a plasticizer. Citric acid was used to enhance the penetration of buccal

film. The surface pH of films ranged between 6 and 7. The thickness of

medicated patches was ranged between 0.24 and 0.39 mm. The tensile

strength of all films was varied from 0.90 to 1.49kg/mm2. All formulations showed folding

endurance more than 300.The results of drug contents showed that there is enough amount of

drug is present in the films which varied from 69.75 to 72.29%. The swelling index for all

formulations was varied from 41.75 to 50.91%. The prepared 7 films of rosuvastatin were

also evaluated for percentage drug release at various time intervals in simulated saliva fluid.

The results are shown that F3 formulation was best for drug content and drug release. Data of

in vitro release from films were fitted to different kinetic models such as zero order, first

order, Higuchi and Korsmeyer–Peppas models to explain the release profile. Formulations F9

was observed best fitted to Higuchi model.

KEYWORDS: HPMC, CMC, PVA, Tragacanth (polymers), Buccal film, Hyperlipidaemia,

Atherosclerosis, Rosuvastatin.

INTRODUCTION

Amongst the various routes of drug delivery oral route is perhaps the most preferred to the

patient and the clinicians. On the basis of biochemical and physiological aspects of

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.647

Volume 6, Issue 9, 1800-1812 Research Article ISSN 2278 – 4357

Article Received on

18 July 2017,

Revised on 07August 2017, Accepted on 28 August 2017,

DOI: 10.20959/wjpps20179-10098

*Corresponding Author

Shivani Saxena

M.J.P. Ruhilkhand

University Bareilly, U.P.,

India.


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absorption and metabolism, many drugs cannot be delivered successfully through the oral

route. The reason of this problem is that after the administration of drug, drug are subjected to

extensive presystemic clearance. This presystemic clearance leads to a lack of significant

correlation between membrane permeability, absorption and bioavailability. The buccal route

is capable to maintain the delivery of drug for an extended period of time. Thus buccal route

has a great appeal for both local as well as systemic drug bioavailability. The buccal mucosa

is relatively permeable with a rich blood supply. The absorption occurring from buccal

mucosa is efficient. This route also provides rapid drug transport to the systemic circulation

and avoids degradation of drug by gastro-intestinal enzymes as well as first pass hepatic

metabolism. Oral route is an attractive alternative to the oral and parenteral routes for

systemic drug delivery because of the rich vascularization of the oral mucosa and its

permeability for many drugs. The drug delivery system by the buccal route offers a novel

route of drug administration. This route has been used successfully for the systemic delivery

of many drug candidates.[1]

Buccal films release topical drugs in the oral cavity at a

predetermined rate. This will provide distinct advantages over traditional dosage forms for

treatment of many diseases.[2]

Extensive efforts have been focused on delivering the drugs to a particular region of the body

for a long period of time. Hence targeted drug delivery system maximizes availability of drug

and minimizes dose dependent side effects.[15]

Recent advances in buccal drug delivery

system have been attempted to enhance safety and efficacy of drug. This is achieved by

formulating a dosage form for convenient administration and to achieve good patient

compliance. Formulation of buccal film (containing drugs) is one of the approaches for

treatment of various diseases whose medication undergoes extensive first pass metabolism.[1]

A buccal delivery is suitable for administration of retentive dosage form because of excellent

accessibility which occurs with the aid of the smooth muscle. It involves the administration

of the desired drug through the buccal mucosal membrane lining of the oral cavity. Drug

absorption through buccal mucosa has gained significant attention. Drug absorption through

the buccal mucosa occurs by passive diffusion into the lipoidal membrane. A suitable buccal

drug delivery system should possess good bioadhesive property so that it can be retained in

the oral cavity for the desired time duration.[3]

As buccal films are intended for attachment to

the buccal mucosa, hence buccal film can be formulated to exhibit local as well as systemic

action.[4]

It is also possible to administer therapeutic agent to patient who cannot swallow due


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to accident. Hence buccal film has gained importance as efficacious and novel drug delivery

systems and is cost effective with a good patient compliance.[5]

Hyperlipidaemia leads to a disease atherosclerosis which is responsible for coronary heart

disease, stroke and myocardial infarction. Atherosclerosis (also known as Arteriosclerotic

Vascular Disease or ASVD) is the condition in which an artery wall thickens as the result of a

build-up of fatty materials such as cholesterol. It is a syndrome affecting arterial blood

vessels, a chronic inflammatory response in the walls of arteries, in large part due to the

accumulation of macrophage, white blood cells and promoted by low density (especially

small particle) lipoproteins (plasma proteins that carry cholesterol and triglycerides) without

adequate removal of fats and cholesterol from the macrophages by functional high density

lipoproteins (HDL) is commonly referred to as a hardening or furring of the arteries.

Arteriosclerosis is a condition in which medium or large arteries become hard (and loss of

elasticity). From the Greek Arterio, meaning artery, and sclerosis, meaning hardening);

arteriosclerosis can also be defined as any hardening (and loss of elasticity) of arterioles

(small arteries) or atherosclerosis is a hardening of an artery specifically due to the formation

of atheromatous plaque.[6]

Rosuvastatin is a statin prescribed in patients having hyperlipidaemia, stroke or CHD. Statins

(or HMG-CoA reductase inhibitors) are a class of drugs used in the treatment of elevated

cholesterol levels. Rosuvastatin competitively inhibit conversion of 3hydroxy-3methyl

glutaryl coenzyme A (HMG-COA) to mevalonate (rate limiting step in cholesterol synthesis)

by the enzyme HMG-COA reductase. The raised level of cholesterol has been associated with

cardiovascular diseases (CVD). Statins have rare but severe adverse affects particularly

muscle damage and some doctors believe they are overprescribed.[7]

MATERIAL AND METHOD

Material

Rosuvastatin was obtained as a gift sample from Intas Pharmaceutical Limited. Polymers like

Hydroxypropyl cellulose, Carboxymethyl cellulose, Tragacanth, Polyvinyl alcohol were

obtained from SD fine Chemical Limited, Pesi Bex 2850, Himedia lab. Limited, Central drug

house (P) Limited respectively. Citric acid and methanol were obtained from Merck Pvt Ltd.

All the reagents were of analytical grade.


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Methods

Preformulation study was carried out to check the compatibility between drug and different

polymers (such as HPMC, CMC, PVP, Tragacanth). Melting point was determined by

capillary tube method.[11]

Partition coefficient and solubility studies were also carried out.

FTIR Spectra of rosuvastatin was measured and it was compared with the standard FTIR

spectra.[12]

UV spectrophotometer (UV 2450 Shimadzu Scientific) was used for the

estimation of rosuvastatin. The absorbance was measured at 244 nm.

Preparation of mucoadhesive buccal patches

Matrix type buccal films containing rosuvastatin were prepared by solvent casting method.[15]

The required proportion of polymers (Hydroxypropyl cellulose, Carboxymethyl cellulose,

Polyvinyl alcohol, Tragacanth) were weighed and dispersed in 20 ml of casting solvent (10

ml of water and 10 ml of methanol) by continuous stirring for 5 to 6 hrs. Then glycerin (2 to

4 drops) was incorporated as a plasticizer and citric acid (0.25%) was incorporated as a

penetration enhancer in the mixture. After stirring of 5 to 6 hrs the solution was poured in the

petri dish which was greased with a single layer of mixture of liquid paraffin and bees wax.

Then the mixture in petri dish was allowed to dry with an inverted funnel over petri dish at

room temperature. Each film contained 100mg of rosuvastatin and the proportions of

ingredients in the film which were taken are as following.

Table 1: formulation table.

Ingreidient F1 F2 F3 F4 F5 F6 F7

Hydroxypropyl cellulose (mg) 200 200 200 200 200 200 200

Carboxymethyl cellulose(mg) 200 250 300 - - - - -

Tragacanth(mg) - - - 250 300 - -

Polyvinyle alcohol(mg) - - - - - 250 300

Glyycerin (ml) 2 ml 2 ml 2 ml 2 ml 2 ml 2 ml 2 ml

Citric acid 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25%

Rosuvastatin(mg) 100 100 100 100 100 100 100

Evaluation of Prepared Buccal Films

Surface pH

Buccal films were allowed to swell for 2 hours on the surface of an agar plate. The surface

pH was measured by using pH paper which was placed on the surface of the swollen film.[8]

Thickness

The thickness of each film was measured using a micrometer.[8]


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Measurement of tensile strength

Tensile strength is the maximum stress applied to a point at which the film breaks. Film strip

with the dimension of 60mm x10 mm and without visual defects was cut and positioned

between two clamp separated by a distance of 3cm. Clamps were designed to secure the film.

The lower clamp was held stationary and the strips were pulled a part by the upper clamp

moving at a rate of 2mm/sec until the strip broke. The force at the point when the strip got

broke was recorded. The tensile strength is calculated using the formula.[14]

m=mass in gram, g=acceleration, b=breath of specimen, t= thickness of specimen, T=tensile

strength.

Folding endurance

The folding endurance was measured manually. A small strip of film 2cm2 of each

formulation was taken and folded at the same place until it breaks. The number of time a film

folded at the same place until broken will give the value of folding endurance. Average of 3

was determined,[9]

Drug content

The amount of drug contained in the buccal film was determined by dissolving the patch by

stirring in 100 ml of simulated saliva (pH 6.8) for 5 h by magnetic stir without heating. The 2

ml solution was taken and diluted with isotonic phosphate buffer pH 6.8 up to 10 ml and the

resulting solution was filtered through a whatman filter paper. The drug content was then

determined after proper dilution by UV spectrophotometer (Shimadzu-1700 Japan) at λmax

of 244 nm. The experiments were carried out in triplicate.[10]

Swelling index

Buccal film (1.5cm2) was weighed individually (W1) and placed in 7 percent agar gel plates.

All films were placed in separate agar gel plate. After 4 hour films were examined for any

physical changes. Films were removed from the agar gel plates and excess water on the

surface of the film was removed by using the filter paper. The swollen film was then be

weighed (W2). Then the swelling index was calculated using the following formula.[2]

W1 = weight before swelling, W2 = weight after swelling


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In-vitro drug release

The USP rotating paddle method was used to study the drug release from the patches. The

dissolution medium consisted of phosphate buffer pH 6.8. The release rate was determined at

37±0.8ºC with a rotation speed of 50 rpm. The buccal patch was attached to the glass disk

with instant adhesive material such that the diffusion layer was exposed to dissolution fluid.

The disk was placed at the bottom of the dissolution medium. Samples (2 ml) were

withdrawn at predetermined interval and replaced with fresh medium. The samples were

filtered and analyzed for drug content after appropriate dilution.[10]

RESULT AND DISCUSSION

Melting point was found to be 121ºC and that reported is 122ºC. Partition coefficient of the

drug when studied in chloroform and water in ratio 1:1 was found to be 0.13.

The solubility of rosuvasatin was studied in various solvent at room temperature. The

solubility order was found to be acetone>acetonitrile>ethanol>methanol>water.

Solvent of solubility study Solubility assessment

Acetone Freely soluble

Methanol Soluble

Ethanol Soluble

Actonitrile Slightly soluble

Water Soluble

FTIR studies were done to confirm the identity of pure drug and to detect the interaction of

drug with excipient used in the preparation of buccal film of rosuvastatin. Formulation F3

containing polymer hydroxypropylmethylcellulose and carboxymethylcellulose (200+300mg)

was analysed for FTIR scanning.


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Figure 1: FTIR of rosuvastatin.

Figure 2: FTIR of F3 formulation (HPMC+CMC+RSV).

Standard curve of the drug was prepared so as to set up a standard analytical method of drug

by U.V. spectrophotometry. The absorbance versus concentration was plotted. The curve was

linear showing R2 value 0.999 and the drug obeyed Lambert’s law from 0µg/ml to 30µg/ml

concentration range.


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Table 2: Calibration reading.

Concentration (µg/ml) Absorbance

0 0

1 0.029

2 0.059

3 0.087

4 0.120

5 0.151

6 0.180

Figure 3: Standard curve of rosuvastatin.

The buccals films of rosuvastatin were evaluated for characterization. The buccal films of

rosuvastatin were successfully prepared by solvent casting method as per described in the

formulation table. By this method seven films were prepared containing different ratio of

polymer and drug. All the films were evaluated for surface pH, thickness, swelling index,

water absorption capacity, folding endurance, tensile strength and % drug content. The results

of all 7 buccal films are given in table no.3.

Table 3: Evaluation of buccal patches.

Parameters F1 F2 F3 F4 F5 F6 F7

Surface pH 6 6 6 7 6 6 7

Thickness(mm) 0.37±0.01 0.39±0.02 0.41±0.017 0.31±0.015 0.29±0.005 0.24±0.03 0.24±0.04

Tensile trength

(kg/mm) 0.90±1 1.34±2.08 1.47±2.5 1.39±1 1.02±1.7 1.49±2 1.16±0.57

Folding endurance 311± 3 316± 2.5 317± 2.5 327± 2.6 331± 1.5 346± 1 354± 1.1

Drug content (%) 72.42 69.75 73.84 70 71.83 71.24 72.29

* All values are expressed as mean ± SD, (n= 3)

The surface pH of all formulation complied with the pH of mouth that is 6 to 7. All the

formulation had low standard deviations which indicate that all films were generally similar.

The thickness of all films varied from 0.24 to 0.39mm which were thin and had a good

patient compliance. Low standard deviation value of all the films showed that these films


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were uniform in thickness for buccal cavity. The thickness of all films was found to be in

ascending order as given below.

F3>F2>F1>F4>F5>F6,F6

The tensile strength of all 7 buccal film of RSV was done. This parameter was studied to

determine breaking level of all films. The tensile strength varied from 0.90 to 1.49kg/mm,

which indicate good strength of film. The values of tensile strength were good enough to

provide strength against breaking of film.

The buccal film of rosuvastatin was also studied for folding endurance. Folding endurance of

all films was found to be more than 300 folds. All the films were 100% flat and uniform. The

result indicate that the prepared film had good tensile strength and folding endurance

indicating that preparation had good stability against breaking.

The drug content of all 7 films was performed to determine the percentage of drug that is

present in the formulations. The result showed that there is enough amount of drug is present

in the films which varied from 69.75 to 72.29%. The quantity of drug present was close to the

dose. The swelling index of all buccal films was studied at various time intervals i.e. 0 to 4

hrs. The each buccal film was cut into the desired size (1.5cm2) and then subjected to swell in

agar plate. The swelling index was found to be in order F3>F7>F2>F5>F1>F6>F4 with

appreciable amount of water in them so as to aid release of drug from matrix.

The swelling index for all formulations was performed at various time intervals at room

temperature. All buccal films were subjected for swelling index upto 240min. The swelling

index varied from 41.75 to 50.91%.

Table 4: Swelling Index After 4hrs.

Formulations Weight before

swelling ( ) (mg)

Weight after

swelling ) (mg) Swelling

index Mean±S.E

F1 91 129 41.75±1

F2 90 133 47.7±2.08

F3 90 138 55.5±0.57

F4 80 108 35±1.05

F5 90 131 45.77±23

F6 81 112 38.75±1.15

F7 89 134 50.91±2

* All values are expressed as mean (n= 3).


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Figure 4: Swelling index of Rosuvastatin films.

The cumulative percentage drug release at each time interval were calculated and plotted

against time. The drug release from the formulations F1 to F7 which have varying proportion

of HPMC, CMC, PVA and tragacanth. The drug release showed that formulation F3

(containing CMC and HPMC) showed highest drug releas. Around 76% drug got release in

300 minutes. The drug release was found in order F3>F7>F2>F5>F1>F6>F4.

Table 5: Percent drug release of all formulation

Time(min.) F1 (%) F2 (%) F3 (%) F4 (%) F5 (%) F6 (%) F7 (%)

0 0 0 0 0 0 0 0

15 24.73 20.6 21.94 19.61 17.28 22.82 18.94

30 31.63 30.74 32.11 22.73 36.91 35.61 26.55

60 37.57 41.79 47.29 29.77 40.87 43.52 35.22

120 41.72 52.94 58.58 35.89 45.73 50.53 41.22

180 48.73 57.03 65.11 42.06 51.2 58.6 47.22

240 54.85 62.93 68.7 57.01 56.78 63.88 52.05

300 64.83 65.32 71.41 63.41 64.34 68.25 64

360 73.02 67.76 76 68.84 71 70.77 72.22

* All values are expressed as mean (n= 3).

Combined graph of drug release of all formulation is given in figure 5.

Figure 5: Drug releases.


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Data of the in-vitro release was fit into different equations and kinetic models to explain the

release kinetic of RSV from the prepared buccal film. The kinetic models were close Higuchi

release model. The best fit with highest correlation value was shown by the Higuchi models.

Thus as per kinetic analysis, the film showed release pattern of matrix type. Formulation F3

was best in the term of release rate, drug content and had highest swelling index and water

absorption capacity. The release pattern of this formulation was close to Higuchi model (R2=

0.946).

Table 6: Kinetics oF Drug Release.

Formulation Zero order First order Higuchi Kores peppas

R2

K T50 R2

K T50 R2

K T50 R2

K T50

F3 0.777 0.173 151 0.905 0.001 184 0.946 3.88 10.61 0.906 0.693 71

Figure 6: Zero order kinetic. Figure 7: First order kinetic.

Figure 8: Higuchi kinetic. Figure 9: Korsmeyer kinetic.


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CONCLUSION

Rosuvastatin buccal film were formulated successfully and evaluated with the objective of

providing maximum therapeutic efficacy, patient compliance by decreasing the dosing

frequency and other problem associated with conventional, parenteral formulation. From the

results of evaluation study it was found that all formulated film exhibited certain satisfactory

characterstic regarding integrity and dispersion of drug.

All the films were uniform in thickness, had good folding endurance and had good tensile

strength indicating good stability against wear and tear. The formulation had good swelling

index and water absorption capacity which will provide good patient compliance by

providing softness on getting wet by saliva and releasing drug for absorption after absorbing

water. The release profile of all formulation except F1 and F5 was close to Higuchi model

indicating matrix type drug release. Formulation F3 showed maximum release (76%) in 300

minutes. Formulation F3 was best not only in terms of drug release but also had highest drug

content, swelling index and water absorption capacity. Hence films made up of polymer

HPMC and CMC were better than films made up of tragacanth and HPMC polymer, PVA

and HPMC polymer. Formulation F3 can be further taken for in depth studies.

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