Development
and Evaluation of Transdermal Drug Delivery System
using Natural Polysaccharides.
Megha B. Hiroji, Nagesh
C.*, Devdatt Jani, Chandrashekhara S.
Maratha Mandal’s College
of Pharmacy, Belgaum-590016, Karnataka.
ABSTRACT:
The purpose of
this research work was to develop and evaluate matrix-type transdermal
drug delivery system containing pioglitazone
hydrochloride as model drug, using different combinations and different ratios
of natural polysaccharides by solvent casting method. The compatibility study
of the drug and the polymers was studied by FT-IR spectroscopy. The results
suggested no incompatibility between the drug and the polymers. Eight transdermal patches were formulated by using different
combinations of natural polymers in different ratios of (sodium alginate and pectin, and sodium
alginate and xanthan gum), and using menthol 5%w/w as
permeation enhancer, glycerol 10%w/w as plasticizer and water as a solvent. The
prepared transdermal patches were evaluated for
thickness, weight uniformity, tensile strength, %
moisture absorption, % moisture loss, folding endurance, flatness, drug
uniformity and in vitro diffusion
study. The diffusion studies were performed by using diffusion cell. The
formulation, FP4 (sodium alginate and pectin) and FX8 (sodium alginate and xanthan gum) showed maximum
release of 89.65±0.38 and 94.53±0.78 % in 24 hrs. The drug release rate followed
diffusion mechanism (Higuchi) with first order release kinetics. The optimized
formulation (FP4 and FX8) were further study for in vitro drug release using rat skin. Stability studies were
performed for 3 months as per ICH guidelines, and results revealed that
formulations were stable.
Key words:.
KEYWORDS: Transdermal
patches, Sodium Alginate, Pectin, pioglitazone
hydrochloride, menthol
INTRODUCTION:
Controlled drug release can be achieved by transdermal
drug delivery systems (TDDS) which can deliver medicines via the skin portal to
systemic circulation at a predetermined rate over a prolonged period of time1-3.
TDDS has gained a lot of interest during the last decade as it offers many
advantages over the conventional dosage forms and oral controlled release
delivery systems notably avoidance of hepatic first pass metabolism, less
frequency of administration, reduction in gastrointestinal side effects and
improves patient compliance4
For transdermal products the goal of
dosage design is to maximize the flux through the skin into the systemic
circulation and simultaneously minimize the retention and metabolism of the
drug in the skin5, 6. Recently, biopolymers used in the fabrication
of transdermal films have received much attention due
to their excellent biocompatibility and bio degradation7.
Sodium alginate (SA) is a
natural polymer is very promising and has been widely exploited in
pharmaceutical industry, because of its tailor‐made to suit the demands of applications8,
9. Xanthan gum is a hydrophilic polymer, had
been limited for use in thickening, suspending, and emulsifying water based
systems. It is gaining appreciation for the fabrication of pharmaceuticals with
uniform drug release characteristics. Drug release property of matrices is
preceded by polymer hydration and the rate of drug release from polymer carrier
can be tailor‐made by
selecting a suitable polymer‐blends composition and drug concentration. Pectins,
including high and low ester and amidated, are used
in food all over the world. It is an edible plant polysaccharide, has been
shown to be useful for the construction of drug delivery systems for specific
drug delivery10
Pioglitazone
HCl is a thiazolidinedione antidiabetic agent that depends on the presence of insulin
for its mechanism of action. It decreases insulin resistance in the periphery
and in the liver resulting in increased insulin-dependent glucose disposal and
decreased hepatic glucose output. Pioglitazone HCl is a potent agonist for peroxisome
proliferator-activated receptor gamma (PPARγ). PPAR receptors are found in tissues important
for insulin action such as adipose tissue, skeletal muscle, and liver.
Activation of PPARγ nuclear receptors modulates
the transcription of a number of insulin responsive genes involved in the
control of glucose and lipid metabolism11.
MATERIALS AND METHODS:
Materials:
The gift sample of pioglitazone
hydrochloride was supplied by Zydus Cadila Healthcare Limited, Ahmedabad,
India. Xanthan gum (XG) was procured from Himedia Laboratories, Mumbai, India. Sodium alginate (SA)
was procured from Loba Chemie
Pvt Ltd, Mumbai, India. Pectin was procured from S.d. Fine-chem-limited, Mumbai,
India. Glycerol, methanol, menthol was procured from Loba
chemie Pvt, Ltd. Mumbai,
India. Potassium dihydrogen ortho
phosphate was procured from Rankem Chennai, India.
Sodium hydroxide was procured from Ozone international.
Preparation
of transdermal patches:
The matrix-type transdermal
patches containing pioglitazone hydrochloride were
prepared by solvent casting method using different ratios of natural polymers
(Table 1) like, sodium alginate and pectin, sodium alginate and xanthan gum, were fabricated for casting the patches. The polymers in different ratios were
dissolved in the water. Then the drug was added slowly to the polymeric
solution and stirred on the magnetic stirrer to obtain a uniform despersion. Glycerol was used as plasticizers and menthol
was used as the permeation enhancer. Then the solution was poured on a flate square shaped, glass molds
having surface area of 16cm2 and dried at the room temperature. The casted polymeric patches of
different formulations were peeled off and covered with aluminium
foil and stored in dessicator for further study. Drug
incorporated for each 2x2 cm2 patch was 15 mg10.
Investigation of physicochemical compatibility of
drug and polymer12:
FTIR spectra help
to identify drug and to detect the interaction of the drug with the polymer and
other excipents. IR spectroscopy of pure drug and
physical mixture of drug with polymers was carried out using shimadzu FTIR to check the compatibility between drug and
polymers. The FTIR spectra of drug with polymers were compared with the
standard IR spectrum of the pure drug.
Evaluation of
patches:
Thickness13
The thickness of patch was measured by screw gauge
micrometer with least count 0.01mm. The thickness uniformity was measured at
three different sites and average of three readings was taken with standard
deviation.
Weight uniformity14, 15
The patch of area 2x2 cm2 was to be cut in
different parts of the patch and weighed in digital balance. The average weight
and standard deviation values are to be calculated from the individual weights.
Table 1: Formulation table of transderaml patches
|
Formulation Code
|
Polymers
|
Drug (mg)
|
|
Sodium Alginate (mg)
|
Pectin (mg)
|
Xanthan
gum (mg)
|
|
FP1
|
300
|
50
|
-
|
60
|
|
FP2
|
250
|
100
|
-
|
60
|
|
FP3
|
200
|
150
|
-
|
60
|
|
FP4
|
150
|
200
|
-
|
60
|
|
FX5
|
325
|
-
|
25
|
60
|
|
FX6
|
300
|
-
|
50
|
60
|
|
FX7
|
325
|
-
|
75
|
60
|
|
FX8
|
300
|
-
|
100
|
60
|
Moisture uptake16, 17
The percent moisture absorption test was carried out
to check the physical stability and integrity of the films at high humid
conditions. In the present study the moisture absorption capacities of the
films were determined in the following manner.
The films were placed in the dessicator
containing saturated solution of aluminium chloride, keeping the humidity
inside the dessicator at 79.5 % R.H. After 3 days the
films were taken and weighed the percentage moisture absorption of the films
was found.
Moisture loss18
The prepared patches were to be weighed individually
and to be kept in a desiccator containing anhydrous
calcium chloride at room temperature. After 3 days the films were to be
reweighed and determine the percentage moisture content by below formula
Content uniformity test19
The patch of area 1x1 cm2 was cut and
dissolved in 100 ml phosphate buffer of pH 7.4. Then the solution was to be
filtered through a filter medium Then 1 ml was withdrawn from the above solution
and diluted to 10 ml solution of phosphate buffer of pH 7.4. The absorbance of
the solution was taken at 269 nm and concentration was calculated. By
correcting dilution factor, the drug content was calculated.
Tensile Strength 20
The tensile strength was determined by the apparatus
designed. The instrument was designed such that it had vertical wooden platform
with fixed scale and attachments for two clips that holds transdermal
patch under test. Out of the two clips one was fixed and other was movable.
Weights were hanged to one end of pulley and the other end of pulley was
attached with movable clip. The wooden platform was such fitted that it would
not dislocate while the test is running. Three strips of patch were cut having
4cm length and 1cm breadth. The thickness and breadth of strips were noted at
three sites and average value was taken for calculation. The elongation was
observed and the total weights taken were used for calculation. The tensile
strength was calculated by using following formula.
Where,
S = tensile strength
m = mass in grams
g = acceleration due to gravity
b = breadth of strip in centimeters
t = thickness of strip in centimetres
Folding endurance21
A specific area of strip was cut and repeatedly folded
at the same place till it broke. The number of times the film could be folded
without breaking gave the value of folding endurance.
Flatness20
Three longitudinal strips were to be cut from each
film at different portion like one from the center,
other one from the left side, and another one from the right side. The length
of each strip was measured and the variation in length because of
non-uniformity in flatness was measured by determining percent constriction,
with 0% constriction equivalent to 100% flatness.
Where,
= Initial length of
each strip.
= final length of
each strip.
Diffusion studies10, 22
Diffusion
cell:
The diffusion
studies were done to get an idea of permeation of drug through barrier from the
transdermal system. Diffusion cells generally
comprise two compartments, one containing the active Compartment (donor
compartment) and the other containing receptor solution (receptor compartment),
separated by barrier membrane (i.e. dialysis membrane or rat abdominal skin).
The cell consisted of sampling port and temperature maintaining jacket. The
outlet and inlet was connected with latex tube so the jacket had stagnant water
inside and heat was provided by hot plate. A magnetic bead was used to stir the
receptor solution using magnetic stirrer. The dialysis membrane and rat
abdominal skin was placed on receptor compartment and both compartments held
tight by clamps.
Preparation of skin:
A full thickness
of skin was excised from dorsal site of dead rat and skin was washed with
water. The fatty tissue layer was removed by using nails of fingers. The outer
portion with hair were applied with depilatory and allowed to dry. With the
help of wet cotton the hair were scrubbed and washed with normal saline
solution. The skin was kept in normal saline solution in refrigerator until
skin was used for diffusion study. Prior to use, the skin was allowed to
equilibrate with room temperature. Then skin was mounted between donor and
receptor compartment of cell. The skin was clamped in such a way that the dermal
side will be in contact with receptor medium.
Method:
Phosphate buffer
of pH 7.4 and methanol was used as receptor solution. The volume of diffusion
cell was 20 ml and stirred with magnetic bead. The temperature was maintained
at 37 ± 1°C with the help of hot plate. The formulated patches were cut into
size of 1cm2 and placed over the drug release membrane (dialysis
membrane and rat skin) The whole assembly was fixed on
a magnetic stirrer, and the solution in the receptor compartment was constantly
and continuously stirred using magnetic beads at 50 rpm; the temperature was
maintained at 37 ± 0.50C. The samples of 1 ml were withdrawn at time interval
of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 24 h, analyzed for drug content
spectrophotometrically at 269 nm. The receptor phase was replenished with an
equal volume of phosphate buffer at each time of sample withdrawal.
Release kinetics23-26
The results of in
vitro release profiles obtained for all the HBS formulations were fitted
into four models of data treatment as follows:
1 Cumulative
percent drug released versus time (zero-order kinetic model).
2 Log
cumulative percent drug remaining versus time. (First-order
kinetic model).
3. Cumulative
percent drug released versus square root of time (Higuchi’s model).
4. Log cumulative
percent drug released versus log time (Korsmeyer-Peppas
equation). Based on the slope and the R2 values obtained from the
above models the mechanism of drug release was decided.
Stability
evaluation27
Stability
studies were performed for 3 months for optimized formulation. All the
stability samples (packed in the backing membrane (Aluminum foil) were prepared
in triplicates and were kept for stability testing conditions, 250C/60%RH
in Stability Chamber, serving as test
condition as per ICH Guideline Q1A. Stability samples were evaluated for
physicochemical parameters, drug content and diffusion study at each sampling
point (1, 2 and 3 months).
RESULTS AND DISCUSSION:
Physicochemical
compatibility of drug and polymers:.
As a preformulation study for drug-polymer compatibility by FTIR
gave conformation about their purity and showed no interaction between drug and
selected polymers.
Evaluation of transdermal patches.:
The results of
the physicochemical characterization of the patches are shown in table 2. The
thickness of the patches ranged between 0.096±0.005 to 0.159±0.015 mm, which
indicates that they are uniform in thickness. The weights of the patches ranged
between 57.66±1.52 to 100.00±2.00 mg. The standard deviation values
indicate that all the formulations were having less variations and showed
uniform weight. The moisture
content of the prepared formulations was low, which could help the formulations
remain stable and reduce brittleness during long term storage. The moisture
uptake of the formulations was also low, which could protect the formulations
from microbial contamination and reduce bulkiness. Good uniformity of drug
content among the batches was observed with all formulations and ranged from
90.10±0.42 to 93.00±0.79%. The results indicate that the process employed to
prepare patches in this study was capable of producing patches with uniform
drug content and minimal patch variability. The flatness study showed that all
the formulations had the same strip length before and after their cuts,
indicating 100% flatness. Thus, no amount of constriction was observed; all
patches had a smooth, flat surface; and that smooth surface could be maintained
when the patch was applied to the skin. Folding endurance test results indicated
that the patches would not break and would maintain their integrity with
general skin folding when applied.
Diffusion study:
In vitro drug release studies of all the formulations of transdermal patches of pioglitazone
hydrochloride were carried out in phosphate buffer of 7.4 pH and ethanol. The
study was performed for 24 hrs, and cumulative drug release was calculated at
different time intervals. The in vitro
drug release profiles for the formulations (FP1-FP4) and (FX5-FX8) were
tabulated in Table 3 and 4. The plot of cumulative percentage drug release V/s
time (hr) for formulations (FP1-FP4) and (FX5-FX8) were plotted and depicted in
Figure 1 and Figure 2 respectively. Effects of various polymers and their
concentration on drug release were studied. It was observed that the type of
polymer influences the drug release pattern. The in vitro drug release was
observed that as the concentration of polymer is increased in formulations the
time of drug release was decreased.The best formulations (FP4 and FX8)
were subjected to in vitro drug release study using rat skin and the cumulative
percentage drug release was fonud to be 87.78±1.24 and 92.04±0.24 %. The plot of cumulative percentage drug
release V/s time (hr) for formulations FP4 and FX8 were plotted and depicted in
Figure 3.
Table 2: Physicochemical evaluation of tansdermal
patches.
|
Formulation
Code
|
Thickness
(mm)
|
Weight Uniformity
(mg)
|
% Moisture
Loss
|
% Moisture uptake
|
% Drug
Content
|
Folding
Endurance
|
Tensile strength Kg/mm2
|
|
FP1
|
0.096±0.005
|
58.66±3.51
|
2.87±1.10
|
2.85±1.02
|
93.00±0.79
|
306.66±9.71
|
2.19±0.05
|
|
FP2
|
0.133±0.015
|
64.33±3.05
|
2.56±0.80
|
2.58±1.76
|
90.75±0.70
|
300.00±14.52
|
2.27±0.12
|
|
FP3
|
0.143±0.005
|
59.33±1.52
|
2.82±1.02
|
3.37±0.08
|
90.10±0.42
|
302.00±8.18
|
2.36±0.03
|
|
FP4
|
0.156±0.015
|
57.66±1.52
|
2.33±1.07
|
3.44±1.69
|
90.47±0.91
|
310.00±5.56
|
2.47±0.03
|
|
FX5
|
0.110±0.010
|
84.66±3.05
|
1.57±0.69
|
2.76±0.70
|
88.24±0.72
|
307.00±10.81
|
2.05±0.01
|
|
FX6
|
0.116±0.005
|
89.66±3.05
|
1.13±1.12
|
2.22±1.11
|
90.92±0.66
|
304.00±12.12
|
2.14±0.02
|
|
FX7
|
0.116±0.005
|
100.00±2.00
|
1.00±0.20
|
2.00±0.04
|
92.25±0.66
|
301.00±12.16
|
2.20±0.02
|
|
FX8
|
0.123±0.005
|
98.33±3.21
|
1.36±0.60
|
2.03±1.04
|
91.64±0.62
|
302.66±8.62
|
2.35±0.03
|
All values are given in (mean ± SD) for n = 3.
Table 3: In vitro drug release profile of FP1,
FP2, FP3, and FP4
|
Time (Hours)
|
Cumulative percentage drug release
|
|
|
|
|
FP1
|
FP2
|
FP3
|
FP4
|
|
1
|
2.61±0.42
|
5.36±0.54
|
3.98±0.92
|
7.62±0.94
|
|
2
|
5.47±0.34
|
9.32±1.20
|
9.25±0.57
|
17.02±1.90
|
|
3
|
9.21±0.76
|
13.92±1.30
|
16.69±1.67
|
23.75±1.39
|
|
4
|
14.46±4.04
|
19.07±1.00
|
22.79±1.35
|
30.21±1.22
|
|
5
|
17.99±3.76
|
24.57±1.77
|
30.97±0.55
|
35.87±2.53
|
|
6
|
21.50±3.71
|
27.69±1.69
|
37.86±0.50
|
42.23±1.80
|
|
7
|
24.58±2.75
|
32.32±1.28
|
41.27±0.70
|
48.23±0.92
|
|
8
|
30.13±1.97
|
42.71±1.63
|
48.04±0.87
|
53.33±0.38
|
|
9
|
35.37±2.07
|
49.40±3.12
|
55.80±0.93
|
58.31±0.70
|
|
10
|
41.47±1.52
|
56.58±2.23
|
60.74±0.78
|
64.25±0.66
|
|
12
|
46.47±1.63
|
61.80±1.98
|
65.39±3.24
|
67.59±0.37
|
|
24
|
77.96±0.74
|
85.60±1.05
|
86.89±2.70
|
89.65±0.38
|
Table 4: In vitro drug release profile FX5, FX6,
FX7, and FX8
|
Time
(Hours)
|
Cumulative percentage drug release
|
|
FX5
|
FX6
|
FX7
|
FX8
|
|
1
|
3.21±0.55
|
4.381±0.43
|
7.28±0.72
|
8.041±0.61
|
|
2
|
7.71±0.70
|
9.20±0.72
|
11.74±0.62
|
14.95±0.92
|
|
3
|
11.08±0.64
|
13.76±0.28
|
17.13±0.91
|
20.00±0.87
|
|
4
|
16.03±0.47
|
18.15±0.35
|
24.94±1.33
|
26.60±0.62
|
|
5
|
18.61±0.72
|
23.03±0.64
|
28.82±0.68
|
35.42±0.80
|
|
6
|
22.83±0.33
|
28.79±0.82
|
35.70±0.70
|
43.12±1.00
|
|
7
|
27.95±0.51
|
33.94±1.16
|
42.24±0.74
|
47.81±0.29
|
|
8
|
33.96±0.59
|
39.12±1.71
|
47.20±0.76
|
54.90±0.79
|
|
9
|
39.51±0.28
|
43.82±0.61
|
55.58±1.22
|
61.99±1.12
|
|
10
|
45.33±0.47
|
49.24±0.59
|
61.56±0.59
|
66.55±0.87
|
|
12
|
54.43±0.50
|
59.97±0.52
|
68.12±1.00
|
73.08±0.78
|
|
24
|
87.22±0.94
|
90.61±0.4
|
92.16±0.52
|
94.53±0.78
|
Figure.1:
Drug release profile of FP1, FP2, FP3, and FP4
Figure.2: Drug
release profile of FX5,
FX6, FX7, and FX8
Figure.3: Drug
release profile of FP4
and FX8 using rat skin
Curve fitting analysis:
The data
obtained from in vitro drug release
studies were fitted to zero-order, first-order, higuchi
and Korsemeyer–Peppas equations. The drug release
data obtained were plotted as Time versus cumulative percent drug released as
zero order, Time versus log cumulative percent drug remaining as First order
release kinetics, Square root of time versus cumulative percent drug released
as Higuchi equation and Log time versus log cumulative percent drug released as
per Korsmeyer-Peppas equation. The best fit with the
highest determination R2 coefficients was shown by both peppas and first order models followed by Higuchi model
which indicate the drug release via diffusion mechanism. Zero-order rate equation, which describe the system where release
rate is independent of the concentration of the dissolved species. The Korsemeyer-peppas equation is used to analyze the release
of pharmaceutical polymeric dosage forms, when the release mechanism is not
well known or when more than one type of release phenomena could be involved.
The values of n with regression
coefficient of all the formulations are shown in Table 5. The value of n was
in the range of 0.568 to 0.787, indicating non- Fickian
diffusion. From the results it was confirmed that all the formulations are
following first order models followed by higuchi
model which indicate the drug release via diffusion mechanism. The slope
value from korsmeyer plots confirmed that the
formulations are following non-fickian diffusion. The
regression co-efficients for different drug release
kinetics models were shown in Table 5.
Stability studies:
The accelerated stability studies were carried out according to
ICH guidelines. Optimized formulations FP4 and FX8 were packed in aluminum foil
and this packed formulation was stored in ICH certified stability chambers
(Thermo labs, Mumbai) maintained at 250C ± 20C and 60 %
RH ± 5 % for 3 month. The films were evaluated before and after one month
interval for period of three months to access any change in appearance, the
drug content, and In vitro drug release.
The results of stability studies did not show any significant change in the
physical appearance, drug content and in-vitro
drug release studies of above two formulations as shown in the Table 6 and
Table 7.
Table 5: Kinetic modeling of drug release
|
Formulation code
|
Zero orderR2
|
First order R2
|
Higuchi’s equation
|
Korsemeyer-Peppas equation
|
|
Slope (n)
|
R2
|
|
FP1
|
0.979
|
0.987
|
0.913
|
0.98
|
0.989
|
|
FP2
|
0.919
|
0.988
|
0.925
|
0.95
|
0.979
|
|
FP3
|
0.879
|
0.992
|
0.943
|
0.99
|
0.958
|
|
FP4
|
0.868
|
0.997
|
0.969
|
0.79
|
0.968
|
|
FX5
|
0.978
|
0.981
|
0.910
|
0.98
|
0.991
|
|
FX6
|
0.966
|
0.972
|
0.933
|
0.99
|
0.992
|
|
FX7
|
0.909
|
0.991
|
0.948
|
0.88
|
0.980
|
|
FX8
|
0.987
|
0.994
|
0.955
|
0.83
|
0.974
|
Table 6.
Stability study data for FP4 formulation
|
Time (days)
|
Physicochemical parameters
|
% Drug content
|
% Cumulative drug release
|
|
0
|
No change
|
90.47
|
89.65
|
|
30
|
No change
|
90.84
|
89.92
|
|
60
|
No change
|
89.95
|
90.08
|
|
90
|
No change
|
90.92
|
90.45
|
Table 7.
Stability study data for FX8 formulation
|
Time (days)
|
Physicochemical parameters
|
% Drug content
|
% Cumulative drug release
|
|
0
|
No change
|
91.64
|
94.53
|
|
30
|
No change
|
91.49
|
93.98
|
|
60
|
No change
|
90.70
|
94.20
|
|
90
|
No change
|
91.08
|
94.84
|
CONCLUSION:
Formulations FP4 and FX8
containing was found to best among all the formulations because of its
consistent release rate for 24 hour. The formulation FP4 and FX8 has achieved
the object to extended release reduced frequency of administration, avoids the
first pass effect and thus may improve the patient compliance
ACKNOWLEDGEMENT:
The authors are highly thankful to the
chair person and management of Maratha Madal’s
College of Pharmacy for providing all the facilities to carry out the research
work and also extend thanks to Zydus Cadila Healthcare Limited, Ahmedabad
for providing the gift sample of pioglitazone
hydrochloride.
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