JDDR 127 PDF

JOURNAL OF DRUG DELIVERY RESEARCH
ISSN 2319-1074
RESEARCH ARTICLE
OPTIMIZATION OF TRANSDERMAL DELIVERY OF
SELECTED ANTIHYPERLIPIDAEMIC AGENTS-STATIN
Kusumdevi V*, Asha AN, Agadi SS, Mathew D
Dept. Of Pharmaceutics, Al-Ameen College of Pharmacy, Near Lalbagh

Main Gate, Hosur Road Bangalore- 560 027
ABSTRACT
A transdermal dosage form of Simvastatin has been developed using various polymers like Eudragit L100,
Eudragit S-100, HPMC, Ethyl cellulose, SCMC, Sodium alginate, Guar gum and Carbomer. Polymers like
Eudragit L-100 Eudragit S-100, Ethyl cellulose and HPMC exhibited good film forming properties. Propylene
glycol, Tween 80, Oleic acid and 4N- dibutyl phthalate were used as plasticizers to improve the film forming
properties of the polymer film. Among these 4N- dibutyl phthalate exhibited excellent results. The formulations
H20 and E20 containing HPMC and Ethyl cellulose showed excellent physico-chemical properties, drug content,
uniform content uniformity, but the permeability was not sufficient enough. Permeability enhancers such as
Tween 80, Oleic acid, Eucalyptus oil and DMSO were used to enhance the permeability. The final formulations
E20 and H20 were evaluated for their permeability coefficient, flux, and mechanism of drug release and kinetics
of drug release. The permeability coefficient and flux were found to be satisfactory. The mechanism of drug
release may be by diffusion and kinetics of drug release was first order. Finally the stability studies for one
month were studied at different temperatures.
Key words: Folding endurance, Transdermal, Permeability Coefficient, Plasticizer.
INTRODUCTION: triglycerides).In the management of

hyperipidaemia, statins are more effective
Cardiovascular diseases are the major than other classes of drugs. 1
concern of death in India. Cardiovascular The HMG-CoA reductase inhibitors
diseases (CVD) are the cause of more than (statins) are most affective and well known
30% of deaths, not only in the developed drugs for the management of
countries. The World Health Organization hyperlipidaemia. These efficiently act by
(WHO) estimates that low- and middle competitively inhibiting the HMG-CoA
income countries are disproportionately reductase, leading to inhibition of
affected. 82% of CVD deaths take place in cholesterogenesis in the liver2. However
low- and middle-income countries and the statins administered in conventional
occur almost equally in men and women. dosage forms have certain disadvantages
The WHO projects that by 2030, almost such as low oral bioavailability due to
23.6 million people will die from CVDs. extensive first pass metabolism.
One of the major causes of cardiovascular Simvastatin is a lipid-lowering agent that
disease is hyperlipidaemia an increased is derived synthetically from a
serum level of total cholesterol (low fermentation product of Aspergillus
density lipoprotein, cholesterol, terreus. After oral ingestion, simvastatin,
triglycerides or both cholesterol and which is an inactive lactone, is hydrolyzed
1 Volume 2 Issue 3 2013 www.earthjournals.org

ISSN 2319-1074
to the corresponding -hydroxyacid form. Eudragit S-100, Ethyl cellulose were

This is an inhibitor of HMG-CoA purchased from BDH Laboratory Mumbai.
reductase. Simvastain, because of its short METHODS
biological half life( t 1/2, 2 hours ) only 5%
of its dose reaches to the systemic 1.DETERMINATION OF PARTITION
circulation of the blood on oral CO-EFFICIENT OF SIMVASTATIN6
administration.. Hence Simvastatin is a For the determination of partition co-
suitable candidate for transdermal dosage efficient of Simvastatin, octanol/water
form .3 system was used. Equal volumes of
The skin is the most extensive and readily distilled water (10ml) and n-octanol
accessible organ of the human body. The (10ml) were taken in a separating funnel
medication through the skin can be used and shaken for 1 hour. 10mg of the
for dermatological local action within the Simvastatin was added to the separating
skin and circulating into blood stream for funnel and shaken for 2 hours. Then the
systemic action. The skin layers act as aqueous and n-octanol layers were
permeation barrier for the absorption of separated. From the aqueous layer 0.1mL
drugs into the systemic circulation. The solution was pipetted out and diluted to
transdermal route of administration has 100mL and absorbance was determined by
various advantages over oral route of UV spectrophotometer at a max of
administration; major one is bypassing the 247.5nm. The residue obtained after
first pass metabolism in the liver, and thus evaporation of n-octanol was dissolved in
extends the activity of drugs having short methanol and after appropriate dilution
half life. It also provides capacity to with distilled water the concentration of
terminate drug effect rapidly by removal of the solute was determined by UV
drug application from the surface of skin. spectrophotometric method. The partition
Therefore transdermal drug delivery co-efficient was calculated using the
system was chosen as an ideal dosage form following equation.
for Simvastatin.4,5 P o/w = (C oil/C water ) equilibrium.
In this project a transdermal drug delivery
system for Simvastatin was formulated 2. PERMEATION STUDIES OF
with optimization of polymer, plasticizer, SATURATED SOLUTION OF
permeation enhancer and their SIMVASTATIN THROUGH
concentrations. Such prepared CELLOPHANE MEMBRANE AND
formulations were evaluated for their RAT ABDOMINAL SKIN
physico-chemical characters, water vapor
transmission, stability, drug interaction Simvastatin is classified as a
and permeation study through rat Biopharmaceutics Classification System
abdominal skin. (BCS) Class-II compound with a poor
aqueous solubility and an acceptable
MATERIALS AND METHODOLOGY permeability through membranes.
MATERIALS Permeation studies of the pure simvastatin
Simvastatin was obtained as a generous were carried out using cellophane
gift from Biocon India Ltd, Bangalore. membrane and rat abdominal skin. The
Hydroxyl propyl methyl cellulose, abdominal skin was isolated from the body
Carbomer, Sodium alginate, Guar gum, of rat and was treated with dilute ammonia
2N- Dibutyl Phthalate and Dimethyl solution to remove the hairs and
sulfoxide were obtained from NR subcutaneous fat. The cellophane
chemicals, Mumbai. Eudragit L-100, membrane or rat skin was washed with
plenty of distilled water and trimmed into

ISSN 2319-1074
a circular section about 3 cm diameters. 5. FORMULATION OF

The modified Franz diffusion cell TRASNSDERMAL FILMS WITH
assembly having 100 ml capacity in DRUG
receptor chamber was used. Throughout The transdermal patch of Simvastatin was
the study the assembly was kept at prepared by simple solvent evaporation
temperature 37 20C. The studies were method. The polymer and drug
carried out using three different media, Simvastatin was dissolved in methanol
phosphate buffer (pH 7.4), distilled water separately and both were mixed together
and 20 % alcohol respectively with with vigorous stirring then the determined
continuous stirring on magnetic stirrer at quantity of plasticizers and permeation
70 RPM. The samples were withdrawn at enhancers were added. Prepared mixture
pre determined, regular time intervals for a was cast in a petri dish shaped alupoly of a
period of 24 hours and an equal amount of definite radius. After complete evaporation
fresh respecter medium was replaced. of the solvent the patch was removed and
Amount of drug in withdrawn samples was stored properly.The area of petri dish
determined spectrophotometrically at shaped alupoly was calculated as follows.
247.5 nm after suitable dilution. Diameter of alupoli was 5.14 cm. therefore
radius r = 2.57 cm.
Area of alupoli = r2
3. PREPARATION OF POLYMER = 3.142 (2.57)2 = 20.752 cm2
FILMS WITHOUT DRUG Formulation composition of films made
using ethyl cellulose and HPMC are given
Different polymers like Eudragit L-100, in Table No: 1.
Eudragit S-100, HPMC, Carbomer, Ethyl
cellulose, Guar gum, SCMC, Sodium 6. EVALUATION PARAMETERS
alginate were studied for their film FOR THE POLYMER FILM
forming property. Films were prepared The polymer films without drug were
using the above polymers in the evaluated for physico-chemical
concentration of 1%, 2%, 3%, 4% and 5% characteristics which include physical
w/v. appearance, weight variation, thickness,
The polymer film with various polymers in folding endurance and tensile strength.
different concentrations was then checked i.
for desired characteristics like physical ii. Appearance
appearance, tensile strength, folding iii. The physical appearance of the polymer
endurance by a set of experiments. film was observed.
iv.
4. SELECTION OF PLASTICIZER v. Weight variation
For proposed formulation of polymer film, The polymer film with the surface area
the plasticizers used were Propylene 6cm2 was cut at 3 different places in the
glycol, 4N-Dibutyl phthalate, Oleic acid cast film. The weight of each film strip
and Tween 80. The optimum concentration was taken and average weight variation
of plasticizers was determined by was calculated.
formulating transdermal patches with three vi.
different polymer concentrations 2%, 3%, vii. Thickness
4% with plasticizer concentrations at 10%, The thickness of the polymer film was
20%, 30%, 40%, and 50% respectively. determined by using screw gauge at
different positions and mean values were
calculated.
viii.

ISSN 2319-1074
found negligible. The study was carried

out at room temperature i.e. 37 20C with
continuous stirring on magnetic stirrer at
ix. Folding endurance 70 rpm. The sample was withdrawn at
The folding endurance is expressed as the predetermined regular time intervals and
number of folds (number of times a film is an equal amount of respective fresh
folded at the same plane) required to break medium was replaced. The amount of drug
the film or to develop visible cracks. This in the withdrawan sample was determined
gives an indication of brittleness of the spectrophotometrically at 237.5nm after
film. A strip of 6 cm2 was subjected to this suitable dilution.
test by folding the film at the same placexiii.
repeatedly several times until a visiblexiv. Selection of permeation enhancers
crack was observed. As the release rate of Simvastatin from the
x. Tensile strength formulations was not satisfactory,
Tensile strength was measured using permeation enhancers like Dimethyl
modified analytical two pan balance sulfoxide, Tween 80, Oleic acid and
method. The film of 6 cm2 wide was Eucalyptus oil in a concentrations of 1ml,
clamped between two clamps on one side; 2ml, 3ml and 4ml were used. The release
weights were added to the pan on other profile of the drug through the selected
side until the patch breaks. The weight transdermal patch with different enhancers
required for breaking the patch was taken of varying concentrations was used as a
as a measure of tensile strength of the tool for optimizing the permeation
patch. enhancer.
xi. Percentage elongation 7
Percentage elongation was calculated by xv. Drug content
measuring the increase in length of the The films were tested for drug content.
film after tensile measurement by using the Films of area 6 cm2 were cut, placed in 10
following formulae. ml volumetric flask and dissolved in
Percent elongation = [L L0] X 100 / L0 methanol; volume was made up to 10 ml
Where, L = Final Length, with methanol. 3ml of above solution was
L0 = initial Length. withdrawn and diluted up to 25 ml with
Further the selected formulations were 50% v/v of methanol. Form the above
subjected for permeation studies, drug solution 2 ml was diluted to 10 ml with
content, content uniformity and water methanol in 10 ml volumetric flask. The
vapor transmission as follows. absorbance of the solution was measured
xii. Permeation studies of formulation at 237.5 nm.
through rat abdominal skin
Permeation studies of the transdermalxvi. Content uniformity
patches which exhibited satisfactory The film was tested for content uniformity.
physico chemical parameters were carried Films of area 6 cm2 were cut from three
out using rat abdominal skin (treated with different places from the cast film. Each
dilute ammonia and distilled water). The film was placed in 10 ml volumetric flask
modified Franz diffusion cell assembly and dissolved in methanol and the volume
having 100ml capacity receptor chamber was made up to 10 ml with methanol. 3ml
was used. The media used in acceptor of above solution was withdrawn and
compartment was 20% alcohol and diluted up to 25 ml with 50% v/v of
distilled water, where as phosphate buffer methanol. From the above solution 2ml
(pH 7.4), solution was not used because; was diluted to 10 ml with methanol in 10
the drug release profile in this media was

ISSN 2319-1074
ml volumetric flask. The absorbance of the The kinetics of drug release was estimated
solution was measured at 237.5 nm. by comparing R2 values of first order
xvii. release kinetics (Wagners graph of log
xviii. amount of drug remained in the dosage
xix. form (AR v/s Time) and zero order release
xx. Water vapor transmission studies kinetics (zero order of CR v/s Time)
The water vapor transmission was graphs.
determined by placing films in open 5 ml
glass vials containing 2 gm of desiccant
(silica gel) and sealed with cellotape. The
xxiv. Mechanism of drug release 10
vials were conditioned in desiccators The mechanism of drug release of the final
containing silica gel for 12 hours. The formulations were determined by
vials were then placed in a Newtronic comparing the slope values of log CR Vs
humidity control oven (75% RH, 220 C). log time (Peppas Plot) with the standard
The moisture transmitted through films values and by plotting a graph of CR v/s t
was determined gravimetrically by (Higuchi plot)
weighing the vials initially and over 72xxv.
hours period (2,10,24 and 36 and 72 hours)xxvi. Compatibility studies
Compatibility studies of drug with
xxi. Flux calculation 8 different excipients were evaluated by
The flux was calculated by Fick`s law of following methods.
Diffusion. Flux is defined as the amount
(in mg) of the drug passing through a unit a) Fourier Transform Infra Red
cross sectional area S (in cm2) in unit time Spectroscopy (FTIR)
t (in hours). The equation for calculating Instrument used was Shimadzu FTIR-8700
the flux is spectrophotometer. In this studies
J=dm/S.dt potassium bromide disc method was
Where, m=Amount of drug passing employed. Both pure drug and its
through the rat abdominal skin formulations were subjected to IR studies.
S=Surface area of rat abdominal skin TDDS formulation was powdered and
t = total time of diffusion through the rat intimately mixed with dry powdered
abdominal skin. potassium bromide. The mixture was the
xxii. Permeability coefficient 9 compressed in to transparent disc under
Permeability coefficient is defined as the high pressure using special dies. The disc
amount of drug that would pass through was then placed in IR spectrophotometer
unit cross section area of rat abdominal using sample holder and the spectrum was
skin if the concentration in the donor recorded.
compartment remains relatively constant
through the time. b) Differential scanning calorimetric
If the concentration changes appreciably analysis (DSC)
with time the permeability coefficient may Differential scanning colorimeter was
be calculated according to following employed as a tool to investigate the
equation by calculating slope of log C v/s compatibility between the drug and
time as follows, number of commonly used excipients
which can affect the solubility of drug by
chemical or physical interaction thus
posing a threat to the drugs stability and
xxiii. Kinetics of drug release 8 bioavailability. DSC is a fast and reliable
method to screen any drug excipient

ISSN 2319-1074
interaction as compared to the time Polymer films without drug were prepared
consuming method of accelerated stability using the polymers in a concentration of
studies. 1%, 2%, 3%, 4% and 5% w/v. Polymer
films formulated using carbomer, guar
Procedure: The instrument used was gum, SCMC, and sodium alginate were
Perkin-Elmer DSC-7. Thermograms of tacky and sticky even after 48 hours, hence
formulations, excipients used and pure these polymers were not used for further
simvastatin were obtained. Samples were formulations of transdermal patch.
sealed hermetically in flat bottomed Polymer film formulated using eudragit L
aluminum cells (pans). These samples 100, eudragit S 100, HPMC and ethyl
were then heated over a temperature range cellulose in concentrations of 1%and 2%
320K to 420K in an atmosphere of were not possible to peel out from the
nitrogen (20 mm/min) at a constant rate of alupoly without breaking the film.
10K/min with alumina being reference Polymer films formulated using eudragit L
standard. 100, eudragit S 100, HPMC and ethyl
cellulose in a concentration of 3% were
RESULTS AND DISCUSSIONS very thin and broken during handling.
Polymer film formulated using eudragit L
Partition coefficient of Simvastatin 100, eudragit S 100, HPMC and ethyl
Partition coefficient of simvastatin was cellulose in a concentration of 5% were
found to be 4.68 thick and brittle. Finally polymers eudragit
L 100, eudragit S 100, HPMC and ethyl
Permeation studies of Simvastatin cellulose in a concentration of 4% were
through cellophane membrane and Rat selected for formulation of transdermal
abdominal skin patch. Results of different physical
evaluation parameters like appearance,
Permeation study of saturated solution of weight variation, folding endurance,
Simvastatin across cellophane membrane tensile strength of films with and without
and rat skin using distilled water, 20% drug are given in Table Nos: 4 and 5
alcohol and phosphate buffer (pH 7.4) respectively.
solution were carried out. The results
showed, the permeation of saturated Selection of plasticizer:
solution of simvastatin via rat abdominal For the formulation of polymer film
skin in distilled water as recipient vehicle without drug with selected polymers, the
was satisfactory for further study of plasticizers used were propylene glycol,
permeation of Simvastatin. The results of 4N-Dibutyl phthalate, Oleic acid and
permeation study of pure simvastatin is Tween 80. Polymer film without drug
given in Table Nos : 2 and 3 respectively. using 4N-Dibutyl phthalate as the
plasticizer was found to exhibit ease of
Selection of the polymer peeling and good appearance. The
The polymer film without drug using Optimum concentration of plasticizers was
different polymers of varying determined by formulating the film with a
concentrations was formulated. Such polymer concentration 4% w/v and
prepared polymeric films were subjected plasticizer concentrations of 10%, 20%,
to evaluation of their physico-chemical 30%, 40%, and 50% of the polymer
parameters in order to select the best respectively. It was found that 4N-Dibutyl
polymer. phthalate in a concentration of 30% was
found to be best platicizer.
Selection of best formula

ISSN 2319-1074
Dose calculation 3ml and 4ml) were subjected to

The total dose of drug (Dt), in a prolonged permeation studies through rat abdominal
action preparation comprises of the normal skin using distilled water as receptor
(prompt) dose (Dn), and the sustaining medium. It was found that the
dose (Ds) i.e. Dt = Dn+Ds formulations H20 and E20 with 3ml DMSO
If the first order elimination rate constant showed highest drug release, 3.258% and
is K 3.73% respectively at the end of the 27th
Then Dt = Dn(1+Kt) , Kt = t 1/2 hour. Results are shown in Table No: 7, 8
where t 1/2 is biological half life. and 9 respectively.
In case of Simvastatin the Normal dose Dn The formulations H20 and E20 were
is 10mg and its biological Half life Kt 1/2 is subjected for drug content, content
2 Hours uniformity and water vapor transmission
Therefore, Dt = 10(1+2) = 30mg studies as follows.
Drug content:
Permeation study of E20 and H20 The drug content was determined in
formulation. formulations H20 and E20. Simvastatin
The best two formulations E20 and H20 content in H20 and E20 was found to be
were subjected to permeation studies 99% 0.08and 99% 0.06 respectively.
through rat abdominal skin in distilled
water. 1cm2 of the prepared patch of 6cm2 Content uniformity:
was subjected to permeability studies. The drug content in each formulation of
Therefore the amount of drug available for H20 and E20 was found uniform within
permeation through rat abdominal skin each film respectively.
was only 17.33mg. It was found that the
release of Simvastatin from the Water vapor transmission studies:
formulation H20 and E20 was very less, The water vapor transmission was
1.34% and 1.190% respectively at the end determined by placing films in an open 5
of 27 hours. The results are shown in ml glass vials containing 2 gm of desiccant
Table no:6. (silica gel) and sealed with cello tape. The
vials were conditioned in desiccators
Selection of permeation enhancers. containing silica gel for 12 hours. The
As the release rates of simvastatin from the vials were then placed in a Newtonic
formulations were not satisfactory, humidity control oven (75% RH, 220 C).
permeation enhancers like Dimethyl The moisture transmitted through films
sulfoxide (DMSO), Tween 80, Oleic acid was determined gravimetrically by
and Eucalyptus oil were used. In order to weighing the vials initially and over a
select a best permeation enhancer 2ml of period of 72 hours. The water vapor
above permeation enhancers were transmission was found to be negligible.
incorporated into E20 and H20 formulations The data is tabulated in Table No: 10.
and the resultant films were subjected to
permeation studies through the rat Kinetics and Mechanism of drug release
abdominal skin using distilled water as of drug release
receptor medium. As shown in Table No: The results of in-vitro release profile
7 the formulations E20 and H20 with obtained for all the formulations were
DMSO as the permeation enhancer show plotted in kinetic models as follows,
a good release profile. Hence the
formulations E20 and H20 prepared with 1. Cumulative percent drug released versus
different concentrations of DMSO (1ml, time (zero order kinetic model).

ISSN 2319-1074
amorphous form. The DSC spectra for

2. Log cumulative percent drug remaining drug and polymer shows no change in the
to be absorbed versus time (First order spectrum which clearly indicating that the
model) drug remain in its original form i.e.
amorphous form, after incorporating it into
3. Amount of drug release or cumulative polymer.
amount of drug release versus square root
of
time (Higuchi model)
4. Log Mt / M versus log time (

Korsmeyer-Peppas model).
The kinetics of drug release can be
estimated by comparing R2 values of first
order release kinetics and zero order
release kinetics graphs. From the
estimation as given in table no:17 it is
clear that the R2 (0.991and 0.975) values
of Wagners graph was higher than the R2
(0.987 and 0.967 respectively) values of
Zero order graph; hence the release kinetic
follows First order for both the
formulations H20 and E20. The Higuchi
plot shows a straight line with R2
values0.967 and 0.967, which indicates
diffusion as drug release from both H20
and E20 formulations respectively.
The mechanism of drug release of the final
formulations were determined by
comparing the slope values of log CR v/s
log time (Peppas Plot) with the standard
values of korsmeyer peppas model and by
plotting a graph of CR v/s t (Higuchi
plot).
COMPATIBILITY STUDIES
FTIR SPECTRAL STUDIES:
The FTIR studies were carried out to study
the possible drug excipient interaction. By
comparing the FTIR spectra of pure drugs
and physical mixture, it was observed that
there was no significant difference in the
characteristic peaks of pure drug and
physical mixture revealing absence of any
interaction.
DSC STUDIES:
The DSC spectrum for pure drug shows
that the drug Simvastatin is in an

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Table No: 1 Simvastatin transdermal patch of different concentrations of Ethyl cellulose
and HPMC
SI FORMULATION
DRUG: POLYMER RATIO
NO CODE
1 E10 1:1
2 E20 1:2
3 E30 1:3
4 E40 1:4
5 E50 2:1
6 E60 2:3
7 H10 1:1
8 H20 1:2
9 H30 1:3
10 H40 1:4
11 H50 2:1
12 H60 2:3

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Table No: 2 Permeation study of a saturated solution of Simvastatin through cellophane
membrane using different receptor media
SI NO Time( hrs) %CPR
Water Alcohol Phosphate
20% buffer pH
7.4
1 0.2808 0.1872 0.2247
2 1 0.6367 0.4681 0.4494
3 2 1.3483 1.0486 1.1610
4 3 1.8539 1.6666 1.5916
5 4 2.2471 2.5093 2.0599
6 5 3.1460 2.9775 2.3970
7 10 3.6516 3.7078 3.0711
8 15 4.7003 3.9325 3.5393
9 27 6.4606 4.8314 3.9325
Fig No:1 Permeation study of saturated solution of simvastatin through cellophane membrane using
different receptor media

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Table No:3 Permeation study of a saturated solution of Simvastatin through rat
abdominal skin using different receptor media
SI NO Time( hrs) %CPR
Water Alcohol Phosphate

20% buffer pH
7.4
1 2.883895 2.41573 2.509363
2 1 3.707865 3.146067 3.2397
3 2 4.138577 3.40824 3.614232
4 3 5.486891 3.764045 4.007491
5 4 5.82397 4.382022 5.262172
6 5 7.172285 5.355805 5.842697
7 10 7.696629 6.554307 6.966292
8 15 9.213483 7.303371 7.921348
9 27 9.76779 7.883895 9.588015
Fig No:2 Permeation study of saturated solution of Simvastatin through rat abdominal skin using
different receptor media

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Table No: 4 Physical evaluation of polymer films containing different concentrations of

plasticizer
POLYMER PLASTICI- WEIGHT APPEARENCE THICKNESS FOLDING TENSILE
ZER (mg) (mm) ENDURANCE STRENGHT
(Kg/cm2)
Eudragit L- 982 Transparent 200.73 10 0.10. 01
100
Eudragit S- 951 Transparent 190.3 15 0.20. 09
100
10%
HPMC 1143 Transparent 250.01 98 0.3350.04
Ethyl 1135 Transparent 260.43 99 0.3610.02
cellulose
Eudragit L- 1942 Transparent 390.29 10 0.10.03
100
Eudragit S- 1925 Transparent 350.38 14 0.20.02
100
20%
cellulose
Eudragit L- 2942 Transparent 550.03 8 0.10.02
100
100
30%
cellulose
Eudragit L- 4015 Transparent 74 2 0.1 0.02
100
100
40%
cellulose
Eudragit L- 4855 Transparent 970.43 Unable to fold 0. 0.01
100
100
50%
cellulose

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EVALUATION PARAMETERS OF TRANSDERMAL PATCHES
TABLE NO:5 Physical evaluation of drug loaded formulations
Formulation Weight Appearance Thickness Folding Tensile %

code (mg) (mm) endurance strength elongation
2
(Kg/cm )
E10 680 3 Transparent 840.4 73 0.3640.03 260.07
E20 10346 Transparent 910.8 73 0.3470.41 250.08

E30 1652 3 Transparent 920.3 67 0.3240.05 180.05
E40 1989 5 Transparent 1020.3 38 0.2870.41 120.02
E50 9964 Transparent 930.4 65 0.3320.05 260.04
E60 2065 6 Transparent 1030.1 28 0.2650.03 130.09
H10 690 4 Transparent 860.3 69 0.3620.08 240.09
H20 11245 Transparent 950.5 67 0.3460.03 240.08
H30 1451 2 Transparent 990.4 56 0.3130.02 170.06
H40 1985 9 Transparent 1120.4 32 0.2770.03 120.09
H50 10231 Transparent 960.5 55 0.3180.02 250.07
H60 2195 8 Transparent 1110.2 25 0.2560.03 120.09
Table no: 6 Permeation studies of the best formulations through rat

abdominal skin
%CPR (Cumulative
percentage drug release)
Si No Time
H20 E20
1 1/2 0.303 0.368
2 1 0.346 0.519
3 2 0.443 0.368
4 3 0.454 0.617
5 4 0.606 0.801
6 5 0.768 0.887
7 10 1.071 1.125
8 15 1.114 1.309
9 27 1.190 1.342

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TABLE NO.7 Permeation study of H20 with different permeation enhancers
Si Time %CPR(Cumulative percentage drug release)
No H20 H20 with 2ml H20 with 2ml H20 with 2ml H20 with 2ml
eucalyptus oil oleic acid tween 80 DMSO
1 1/2 0.303 0.476 0.519 0.432 0.692
2 1 0.346 0.606 0.638 0.584 0.887
3 2 0.443 0.909 0.952 0.887 1.071
4 3 0.454 1.136 1.147 1.234 1.331
5 4 0.606 1.331 1.298 1.450 1.602
6 5 0.768 1.418 1.428 1.645 2.089
7 10 1.071 1.710 1.731 2.045 2.652
8 15 1.114 2.045 2.078 2.273 2.749
9 27 1.190 2.435 2.554 2.630 3.171
FIGURE NO.3 Permeation study of H20 with different permeation enhancers

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TABLE NO.8 Permeation study of E20 with different permeation enhancers
Si Time %CPR(Cumulative percentage drug release)
No E20 E20 with 2ml E20 with 2ml E20 with 2ml E20 with 2ml
eucalyptus oil oleic acid tween 80 DMSO
1 1/2 0.368 0.368 5.520 0.443 0.627
2 1 0.519 0.519 6.711 0.606 0.887
3 2 0.368 0.801 9.742 0.909 1.017
4 3 0.617 1.104 1.298 1.277 1.212
5 4 0.801 1.190 1.504 1.515 1.537
6 5 0.887 1.331 1.721 1.764 2.035
7 10 1.125 1.656 2.110 2.110 2.338
8 15 1.309 2.002 2.392 2.327 2.684
9 27 1.342 2.435 2.771 2.781 2.944
FIGURE NO.4 Permeation study of E20 with different permeation enhancers

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TABLE NO. 9 Permeation study of E20 and H20 formulations with different
concentrations of DMSO through rat abdominal skin using distilled water as receptor
medium
Si Time
No %CPR(Cumulative percentage drug release)
H20 with H20 with H20 with E20 with E20 with 3ml E20 with
1ml DMSO 3ml DMSO 4ml DMSO 1ml DMSO DMSO 4ml DMSO
1 0.627 0.573 0.368 0.562 0.790 0.562
2 1 0.811 0.811 0.552 0.736 0.974 0.844
3 2 0.985 1.093 0.898 0.985 1.309 0.865
4 3 1.212 1.428 1.190 1.309 1.537 1.071
5 4 1.428 1.872 1.504 1.537 1.970 1.331
6 5 1.786 2.089 1.775 1.818 2.175 1.656
7 10 2.154 2.359 2.110 2.154 2.944 2.143
8 15 2.359 2.857 2.532 2.413 3.236 2.608
9 27 2.836 3.258 2.857 2.836 3.734 3.128
FIGURE NO.5 Permeation study of E20 and H20 formulation with different concentration of DMSO
through rat abdominal skin using distilled water as receptor medium

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Table No:10 Water vapor transmission study for formulation H20 and E20
Amount of water vapor transmission
Sl .No. Time (hours) rate
(gm/cm2/h)
E20 H20
1 1 0.01512 0.01612
2 2 0.026548 0.03124
3 4 0.032154 0.03978
4 8 0.044125 0.04983
5 12 0.055421 0.05876
6 18 0.068745 0.07654
7 24 0.084512 0.08875
8 36 0.098457 0.15634
9 48 0.167981 0.19754
10 72 0.2987630 0.36487
FIGURE NO. 11 Flux and Permeability coefficient of H20 and E20
Si No H20 formulation E20 formulation
Flux Permeability Flux Permeability
( in mg) Coefficient( in mg) ( in mg) Coefficient ( in mg)
1 5.310-2 0.410-2 3.8 0.29
2 6.610-2 0.26 5.7 0.21
3 8.910-2 0.172 5.8 0.11
4 10.410-2 0. 12 7.2 0.09
5 13.410-2 0.128 9 0.089
6 14.810-2 0.113 11.2 0.086
7 2010-2 0.072 14.5 0.055
8 2210-2 0.056 17.7 0.045
9 25.410-2 0.035 21.3 0.030

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TABLE NO. 12 Determination of release kinetics and mechanism of drug release of E20
and H20 formulation
Formul Zero order First order Higuchi Korsemeyer- Best fit
ation Peppas Model
Slope R2 Slope R2 Slope R2 Slope R2
E20 0.070 0.967 -0.001 0.975 0.070 0.967 0.070 0.967 First
order
H20 0.061 0.987 -0.001 0.991 0.070 0.967 0.070 0.967 First
order
Figure No: 6 Infra-red spectra of pure drug

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Figure No: 7 Infra- red spectra of formulation E20

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Figure No: 8 DSC Spectra for pure Drug

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Figure No: 9 DSC Spectra for pure Polymer

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Figure No:10 DSC Spectra for Drug and Polymer

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CONCLUSION 7. Yei. W. Chien. Transdermal Drug Delivery

System. In: Novel Drug Delivery
Systems. IInd Edition, Marcel Dekker, Inc.,
Simvastatin is currently available as New York, 1992; 311; 315; 338-342.
conventional tablets in strength of 8. Alfred Martin, Drug product and Design of
10mg/20mg. It has to be administered two to Physical Pharmacy, IVth edition: 539.
three times a day. Simvastatin and its 9. Donald.L.Wise,Hand book of
metabolites have a half life of around 2 Pharmaceutical Controlled Release
Technology: 143-151.
hours and their oral bioavailability is less 10. Palo.Colombo.,Patrizia. Santi., Ruggero
than 5% of the dose administered. In order Bettin., Christopher. S. Bazel. And
to overcome the above problems associated Nicholas. A. Peppas.: Drug Release from
with simvastatin, Transdermal drug delivery Swelling-Controlled System: 183-205.
system of Simvastatin was developed.
Out of the polymers investigated, HPMC
and Ethyl Cellulose in a concentration of 4%
with DMSO as permeation enhancer in a
concentration 30% of polymer weight gave
the most satisfactory results.
In view of the results obtained we could
conclude that a transdermal patch of the
drug of area of 3.5cm2 would achieve the
minimum effective concentration required
for drug action in one hour time. Thus it is
possible to make a transdermal drug delivery
system of Simvastatin which could
overcome the problems associated with
conventional dosage forms primarly
overcoming the first pass metabolism and
thus decreasing its dosage and the dose
related side effects.
REFERENCES
1. http://www.heartacademy.org/newsletter/9/1
.pdf
2. Assessed from Zocor clinical Pharmacology
3. Goodman, Gilmans, Joel. G, Hardman. Lee
and E. Limbird., The Pharmacological
Basis of Therapeutics 2001; 10:988-994.
4. M. Berlin. Jr. MD. Chairperson, D.Gail
May, Mc. Carrer. MD.A review article of
American Academy of Pediatrics,
Committee on drugs, 1995 to 1997.
5. Mghan F. Wilkosz, Robin H. Bonger.
Transdermal Drug Delivery. Part I: Current
status.U.S.Pharmacist vol. No. 28;04:38-42.
6. Leon Lachman and Herbert. A Libarman,
Partion coeficient In, Theory and practice
of industrial pharmacy, 3rd edition; 188-189.

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JOURNAL OF DRUG DELIVERY RESEARCH

Kusumdevi V*, Asha AN, Agadi SS, Mathew D

Dept. Of Pharmaceutics, Al-Ameen College of Pharmacy, Near Lalbagh

INTRODUCTION: triglycerides).In the management of

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to the corresponding -hydroxyacid form. Eudragit S-100, Ethyl cellulose were

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a circular section about 3 cm diameters. 5. FORMULATION OF

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found negligible. The study was carried

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Dose calculation 3ml and 4ml) were subjected to

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amorphous form. The DSC spectra for

4. Log Mt / M versus log time (

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Table No: 1 Simvastatin transdermal patch of different concentrations of Ethyl cellulose

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Table No: 2 Permeation study of a saturated solution of Simvastatin through cellophane

membrane using different receptor media

SI NO Time( hrs) %CPR

Water Alcohol Phosphate

1 0.2808 0.1872 0.2247

2 1 0.6367 0.4681 0.4494

3 2 1.3483 1.0486 1.1610

4 3 1.8539 1.6666 1.5916

5 4 2.2471 2.5093 2.0599

6 5 3.1460 2.9775 2.3970

7 10 3.6516 3.7078 3.0711

8 15 4.7003 3.9325 3.5393

9 27 6.4606 4.8314 3.9325

different receptor media

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Table No:3 Permeation study of a saturated solution of Simvastatin through rat

abdominal skin using different receptor media

SI NO Time( hrs) %CPR

Water Alcohol Phosphate

different receptor media

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Table No: 4 Physical evaluation of polymer films containing different concentrations of

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EVALUATION PARAMETERS OF TRANSDERMAL PATCHES

TABLE NO:5 Physical evaluation of drug loaded formulations

Formulation Weight Appearance Thickness Folding Tensile %

E20 10346 Transparent 910.8 73 0.3470.41 250.08

Table no: 6 Permeation studies of the best formulations through rat

1 1/2 0.303 0.368

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TABLE NO.7 Permeation study of H20 with different permeation enhancers

Si Time %CPR(Cumulative percentage drug release)

eucalyptus oil oleic acid tween 80 DMSO

1 1/2 0.303 0.476 0.519 0.432 0.692

2 1 0.346 0.606 0.638 0.584 0.887

3 2 0.443 0.909 0.952 0.887 1.071

4 3 0.454 1.136 1.147 1.234 1.331

5 4 0.606 1.331 1.298 1.450 1.602

6 5 0.768 1.418 1.428 1.645 2.089