ISSN: 2277- 7695

CODEN Code: PIHNBQ

ZDB-Number: 2663038-2
IC Journal No: 7725

Vol. 1 No. 7 2012

Online Available at www.thepharmajournal.com

THE PHARMA INNOVATION

Formulation and Evaluation of Buccal Patches of

Simvastatin by Using Different Polymers
Shalini Mishra1* , G. Kumar1, P. Kothiyal1

1. Division of pharmaceutical sciences, S.G.R.R.I.T.S. Patel Nagar, Dehradun, Uttarakhand-248001, India

The objective of this study was to develop mucoadhesive buccal tablets of Simvastatin using
mucoadhesive polymers. Simvastatin has short biological half-life (3hr), high first-pass
metabolism and poor oral bioavailability (5%), hence an ideal candidate for buccal delivery
system. From the present study carried out on simvastatin buccal patches prepared from 1%
eudragit-RS100 and variable amount of different polymer composite, PVP, PVA, HPMC and
EC. The buccal patches prepared using 50% glycerine w/w of polymer weight were found to
have good physical characteristics. The mean thickness of buccal polymeric patches increased
with an increase in the amount of polymer percent. Eudragit RS-100 HPMC (1:2) containing
50% glycerine w/w of polymer weight had is maximum thickness. Percent swelling index
determined at 5, 10, 30 and 60 minutes increased with time and with an increase in hydrophilic
polymer. Eudragit-RS100-HPMC buccal patches better swelling index, , folding endurance
followed by Eudragit-RS100-HPMC, Eudragit-RS100-PVA and Eudragit-RS100-PVP buccal
patches. . The increase in the amount of polymer retarded the release of simvastatin. F1
(eudragit-RS100-PVP) showed the maximum and faster release. Simvastatin was incorporated in
the selected polymeric patches and these were then evaluated for content uniformity and in vitro
release. Higher drug release was obtained.
Keyword: Buccal Mucosa, Transmucosal Drug Delivery, Buccal Patches, Simvastatin, Polymers, Bio
Adhesion, In Vitro release.

INTRODUCTION: Historically, the oral route The reasons for this preference are obvious
of drug administration has been the one used because of the ease of administration and
most for both conventional as well as novel drug widespread acceptance by patients. Major
delivery. limitations of oral route of drug administration
are Some drugs irritate the gastrointestinal tract
Corresponding Author’s Contact information: and this is partially counteracted by coating. Oral
Shalini Mishra * route may not be suitable for drugs targeted to
Department of Pharmaceutical Sciences, S.G.R.R.I.T.S., specific organs.The conventional type of buccal
Patel Nagar, Dehradun, India. dosage forms are buccal tablets, troches and
E-mail: diya.anacool@gmail.com
lozenges, and mouth washers. Amongst the

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Shalini Mishra*, G. Kumar, P. Kothiyal

various routes of administration tried so far in the name Zocor, as well as generically. The primary
novel drug delivery systems, localized drug uses of simvastatin is for the treatment of
delivery to tissues of the oral cavity has been dyslipidemia and the prevention of cardiovascular
investigated for the treatment of periodontal disease. It is recommended to be used only after
disease, bacterial and fungal infection. Over the other measures such as diet, exercise, and weight
decades mucoadhesion has become popular for its reduction have not improved cholesterol levels.
potential to optimize localized drug delivery, by All statins act by inhibiting 3-hydroxy-3-
retaining a dosage form at the site of action (e.g. methylglutaryl coenzyme A HMG-CoA
within the gastrointestinal tract) or systemic reductase, the rate-limiting enzyme of the HMG-
delivery by retaining the formulation in intimate CoA reductase pathway, the metabolic pathway
contact with the absorption site (e.g. buccal responsible for the endogenous production of
cavity)[1]. Well defined bioadhesion is the ability cholesterol. Statins are more effective than other
of a material (synthetic or biological) to adhere to lipid-regulating drugs at lowering LDL-
a biological tissue for an extended period of time. cholesterol concentration but they are less
The biological surface can be epithelial tissue or effective than the fibrates in reducing triglyceride
it can be the mucus coat on the surface of a concentration. However, statins reduce
tissue. If adhesion is to a mucous coat, the cardiovascular disease events and total mortality
phenomenon is referred to as mucoadhesion. The irrespective of the initial cholesterol
use of mucoadhesive polymers in buccal drug concentration. The t1/2 for simvastatin is 2 to 4
delivery has a greater application. Various hrs and bioavailablity is 5% and efficiency of
mucoadhesive devices, including tablets, films, protein binding is 95%.[4,5]
patches, disks, strips, ointments and gels, have
recently been developed. However, buccal patch
offer greater flexibility and comfort than the other MATERIALS AND METHOD :-
devices. In addition, a patch can circumvent the Materials:-
problem of the relatively short residence time of
Simvastatin was a gift sample from Ind swift
oral gels on mucosa, since the gels are easily
pharmaceutical pvt. lmtd.Chandigarh (India)
washed away by saliva. Buccal route of drug
Hydroxy propyl methyl cellulose,Ethyl cellulose
delivery provides the direct access to the systemic
and Eudragit RS 100 were obtained from Central
circulation through the jugular vein bypassing
drug house pvt. Ltd. And other chemicals used
the first pass hepatic metabolism leading to high
were of analytical grade and produced from
bioavailability. Other advantages such as
central drug house (New Delhi,India)
excellent accessibility, low enzymatic activity,
Concentrations of simvastatin were measured
suitability for drugs or excipients that mildly and
with a uv-vis spectrometer And polymers was
reversibly damage or irritate the mucosa,
verified using FTIR,and UV-VIS spectrometric
painless administration, easy withdrawal, facility
methods
to include permeation enhancer/ enzyme
inhibitor or pH modifier in the formulation, Methods
versatility in designing as multidirectional or Preparation of polymeric solution:-
unidirectional release system for local or Accurately weighed quantity of PVP was
systemic action .[3] dispersed in 5% ethanol aqueous solution.
Required amount of eudragit RS 100 was then
Simvastatin is a Hypolipidemic used to control dissolved in the solution. This polymeric solution
elevated cholesterol, or hypercholesterolemia. It
was then kept for 24 hours in a sonicator and
is a member of the Statin class of then it was filtered through a muslin cloth.
pharmaceuticals. Simvastatin is a synthetic
Glycerine (plasticizer) was then added to the
derivate of a fermentation product of Aspergillus polymeric solution in the desired ratio 10 ml of
terreus. The drug is marketed under the trade
the resultant

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Shalini Mishra*, G. Kumar, P. Kothiyal

mixture was poured into each fabricated glass Drug content uniformity of the patches[8]:-
ring placed on a mercury substrate. Drying was The patches were tested for the content
carried out at 45ºC for 24 hours in hot air oven, uniformity. A patch of size 1×1 cm2 was cut and
resultant polymeric patches had a diameter of 6.2 placed in a beaker. Ten ml of a 0.1 N
cm. The patches obtained were used as such or hydrochloric acid solution was added. The
cut into a diameter of 1 cm² for different contents were stirred in a cyclo-mixer to dissolve
evaluation studies. Similar procedure was carried the film. The contents were transferred to a
out for the preparation of eudragit-PVA, eudragit- volumetric flask (10 ml). The absorbance of the
HPMC, eudragit-EC polymeric patches. The solution was measured against the corresponding
glycerine was used as plasticizer in percent of blank solution at 248 nm.
20%, 30% and 50% w/w of polymer weight.:-
Swelling studies of the patches[9]]
Weight and area increase due to swelling were
Method of Preparation: measured (Gua and Cooklock, 1995). Weight
Calculated amount of simvastatin (30 mg/cm²) increase due to swelling: A drug-loaded patch of
was dispersed in the polymeric solution, after the 1x1 cm2 was weighed on a preweighed cover
drug is completely dispersed, glycerine slip. It was kept in a petridish and 50 ml of
(plasticizer) was added and stirred to form a phosphate buffer, pH 6.6 was added. After every
uniform dispersion. The dispersion was casted five min, the cover slip was removed and
onto the mercury substrates kept in the hot air- weighed upto 30 min. The difference in the
oven at 45ºC for 24 hours. The patches thus weights gives the weight increase due to
formed were removed and stored between butter absorption of water and swelling of patch.Area
paper in a dessicator. increase due to swelling: A drug loaded patch
size of 1x1 cm2 was cut and placed in a petridish.
A graph paper was placed beneath the petridish,
EVALUATION OF BUCCAL PATCHES: to measure the increase in the area. Fifty ml of
phosphate buffer, pH 6.6, was poured into the
Thickness uniformity of the patches[6]:- petridish. An increase in the length and breadth of
The thickness of each patch was measured using screw
the patch was noted at five min intervals for 60
gauge at five different positions of the patch and the
min and the area was calculated. The percent
average was calculated. swelling, %S, was calculated using the following
equation:
Folding endurance[7]:-
Folding endurance of the patches was determined
(Khanna et al., 1997) by repeatedly folding one
patch at the same place till it broke or folded upto where Xt is the weight or area of the swollen
300 times manually, which was considered patch after time t and Xo is the original patch
satisfactory to reveal good patch properties. The weight or area at zero time.
number of times of patch could be folded at the
same place without breaking gave the value of the
folding endurance. This test was done on five Tensile strength of the patches[10]:-
patches. Tensile strength of the patch was determined with
Digital Tensile Tester (DY-20, Adamulthomargy,
France 1986).

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Shalini Mishra*, G. Kumar, P. Kothiyal

Table No:1 : Composition of different buccal mucoadhesive formulations containing Simvastatin

Ingridient F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

Simvastatin(mg) 20 20 20 20 20 20 20 20 20 20 20 20

Eddragit RS-100 1% 1% 1% 1% 1% 1% 1% 1% 1% 1% 1% 1%

PVP 1% 1.5% 2% - - - - - - - - -

PVA - - - 1% 1.5% 2% - - - - - -

HPMC - - - - - - 1% 1.5% 2% - - -

EC - - - - - - - - - 1% 1.5% 2%

Ethanol 5% 5% 5% 5% 5% 5% 5% 5% 5% 5% 5% 5%

Glycerine(percent 50 50 50 50 50 50 50 50 50 50 50 50
w/w of polymeric
weight)

Table 2: Characteristics of buccal mucoadhesive patches containing Simvastatin

Formulation Thickness Folding Content Percentage swelling index in time Tensile

code endurance uniformity (min) strength
(mm)
(mg) 5 10 30 60

F1 0.2048 96.55 0.5217 3.57 9.49 22.06 27.46 1.4168

F2 0.220 96.00 0.5225 3.68 9.87 23.37 27.97 1.7068

F3 0.227 104.80 0.5209 5.45 9.89 23.47 28.49 1.8568

F4 0.256 105.35 0.5231 5.94 12.63 23.80 31.18 1.9368

F5 0.291 106.88 0.5224 6.10 13.55 24.65 34.70 2.047

F6 0.2968 109.88 0.5254 6.77 13.96 27.67 34.78 2.118

F7 0.3295 115.00 0.5223 7.16 17.64 33.46 42.0 1.889

F8 0.34488 125.00 0.5215 8.49 18.85 33.89 44.54 1.9635

F9 0.3565 132.88 0.5242 8.80 19.30 37.89 53.68 2.128

F10 0.3585 155.35 0.5242 10.12 19.60 39.70 45.69 2.1935

F11 0.3686 162.55 0.5231 12.83 22.80 44.80 50.68 2.26

F12 0.390 16 7.00 0.5250 15.88 24.98 44.89 54.74 2.495

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Shalini Mishra*, G. Kumar, P. Kothiyal

The sensitivity range of the machine is 1 to 10 Figure no:1 Calibration curve of Simvastatin
Newtons. It consisted of two load cell grips. The
lower one was fixed and upper one was movable. 1
The test patch of size (5×3 cm2) was fixed 0.9 y = 0.086x + 0.057 0.8924
between these cell grips and force was gradually 0.8
R² = 0.9869
applied till the film broke. The tensile strength of 0.7392
0.7
the patch was taken directly from the dial

Absorbance
reading in Newtons, which was converted into 0.6 0.5913 Series1
kilograms. 0.5
0.4 0.427 Linear
In vitro release studies of simvastatin patches (Series1)
0.3 0.2735
in phosphate buffer (pH 7.2)[11]:- 0.2
A patch of 1x1 cm2 size was cut and attached to a
0.1
glass slide with a few drops of phosphate buffer
(pH 7.2). This slide was kept at an angle of 45 o 0 0
in a 250 ml beaker containing 100 ml of 0 5 10 15
concentration(mg/ml)
phosphate buffer (pH 7.2) solution. The beaker
was kept in circulating water bath in which the From the present study carried out on simvastatin
temperature was maintained at 37oC. A non- buccal patches prepared from 1% eudragit-RS100
agitated system was selected to eliminate any and variable amount of different polymer
effect of turbulence on the release rate composite, PVP, PVA, HPMC and EC the
(Borodkin and Tucker, 1974). Samples were following points can be concluded. The buccal
withdrawn periodically after removing the slide patches prepared using 50% glycerin w/w of
from the beaker. The solution was stirred with a polymer weight were found to have good
glass rod and 5 ml of sample was withdrawn physical characteristics. The mean thickness of
using a graduated pipette, whose tip was attached buccal polymeric patches increased with an
to a tube with glass wool (as a filter). The slide increase in the amount of polymer percent.
was quickly reintroduced into the beaker. Five Eudragit RS-100 HPMC (1:2) containing 50%
ml of the buffer was replaced immediately and glycerine w/w of polymer weight had is
the beaker was kept covered with a petridish to maximum thickness. Percent swelling index
prevent evaporation of the fluid. The samples determined at 5, 10, 30 and 60 minutes increased
were taken after every 10 min upto 90 min. and with time and with an increase in hydrophilic
analyzed for drug content at 238 nm. The release polymer. Eudragit-RS100-HPMC buccal patches
studies were conducted for three times and better swelling index, folding endurance
average was determined. followed by Eudragit-RS100-HPMC, Eudragit-
RS100-PVA and Eudragit-RS100-PVP buccal
RESULTS AND DISCUSSION patches.
Calibration curve of simvastatin in 0.1 N HCl and Simvastatin was incorporated in the
phosphate buffer (pH 7.2) solutions were selected polymeric patches and these were then
obtained at λmax 238 nm with a UV-VIS evaluated for content uniformity and in vitro
spectrometer (UV-1601PC, Shimadzu release.in fig 2. Higher drug release was obtained
Corporation, Tokyo, Japan). Beer’s law obeyed from eudragit-RS100-PVP patches followed by
to construct the calibration curve was in the eudragit-RS100 -PVA, eudragit-RS100 -HPMC
concentration range of 2-10 μg/ml. Analyses were and - eudragit-RS100- EC F1 (chitosan-PVP 1:1)
done in triplicate which shown in fig 1. showed the maximum and fastest release t50%
1.7 hours, D8 hrs 99.95%. In vitro release
characteristics of Simvastatin buccal patches
showed

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Shalini Mishra*, G. Kumar, P. Kothiyal

Figure no-2 Percentage cumulative drug release of with time and with an increase in hydrophilic
various formulations of simvastatin by using different
polymers:-
polymer. Thus, one may conclude that these
polymer systems of eudragit-RS100 along with
120
F1 PVP, PVA, HPMC and EC have potential for
consideration for drug delivery as buccal dosage
100 F2
forms.
F3
80
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maximum thickness. Percent swelling index
determined at 5, 10, 30 and 60 minutes increased

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