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The purpose of this research was to design matrix type of transdermal patch of Fluocinolone acetonide. Polyvinyl pyrrolidone K-30 (PVP K-30) and polyvinyl alcohol (PVA) was used in fixed ratio of 2:5 throughout the study and was concluded from preliminary study. Single layer matrix was chosen for providing 24 hrs. of continuous release. Solvent casting method was used for preparation of patches. 3 level 2 factor full factorial designs was applied for optimization of batch for optimising amount of poly ethylene oxide ( Polyox WSR 1105) and Propylene Glycol (PG). The effects of polymer type, polymer ratio, permeation enhancer, plasticiser on drug release were evaluated by in-vitro release using treated cellophane paper by using Franz diffusion cell. In addition various other characterizations like appearance, folding endurance, tensile strength, % moisture content, % drug content, thickness, flatness was done. ANOVA for Response Surface Quadratic Model for % cumulative drug release and % moisture content responses applied and found significant for optimization. From the contour plot and over lay plot range of various amounts of PG and Polyox found to provide desired responses. Validity of equation was checked by checkpoint batch was true for present work.
Citation preview
ISSN No:2321-8630, V 1, I 1, 2014 Journal Club for Pharmaceutical Sciences (JCPS)
Manuscript No: JCPS/RES/2014/8, Received On: 01/08/2014, Revised On: 05/08/2014, Accepted On: 08/08/2014
RESEARCH ARTICLE
Copyright reserved by Journals Club & Co. 21
Development and Characterization of Transdermal Patch for Controlled Release of
Fluocinolone Acetonide
Joshi DM, Patel S, Moin MK, Patel AK, Patel VM Pharmaceutics Department, A.P.M.C. College of Pharmaceutical Education and Research,
Motipura, Himatnagar 383001, Gujarat ABSTRACT
The purpose of this research was to design matrix type of transdermal patch of Fluocinolone
acetonide. Polyvinyl pyrrolidone K-30 (PVP K-30) and polyvinyl alcohol (PVA) was used in fixed
ratio of 2:5 throughout the study and was concluded from preliminary study. Single layer matrix was
chosen for providing 24 hrs of continuous release. Solvent casting method was used for preparation
of patches. 3 level 2 factor full factorial designs was applied for optimization of batch for optimising
amount of poly ethylene oxide ( Polyox WSR 1105) and Propylene Glycol (PG). The effects of
polymer type, polymer ratio, permeation enhancer, plasticiser on drug release were evaluated by in-
vitro release using treated cellophane paper by using Franz diffusion cell. In addition various other
characterizations like appearance, folding endurance, tensile strength, % moisture content, % drug
content, thickness, flatness was done. ANOVA for Response Surface Quadratic Model for %
cumulative drug release and % moisture content responses applied and found significant for
optimization. From the contour plot and over lay plot range of various amounts of PG and Polyox
found to provide desired responses. Validity of equation was checked by checkpoint batch was true
for present work.
KEYWORDS
Transdermal drug delivery system (TDDS), Fluocinolone acetonide, solvent casting method, anti-inflammatory.
INTRODUCTION
Conventional systems of medication which
require multi dose therapy have numerous
problems and complications. The design of
conventional dosage form, whether a tablet, an
injection, to deliver the right amount of
medicine at the right target site becomes
complicated, so controlled release drug
delivery system, a novel drug delivery
approach evolves, which facilitates the drug
release into systemic circulation at a pre-
*Address for Correspondence: Mihir D Joshi Pharmaceutics Department, A.P.M.C. College of Pharmaceutical Education and Research, Motipura, Himatnagar 383001, Gujarat, India. E-Mail Id: [email protected]
Copyright reserved by Journals Club & Co. 22
determined rate. Controlled drug release can
be achieved by transdermal drug delivery
systems (TDDS) which can deliver medicines
via the skin portal to systemic circulation and
also provide local effect at a predetermined
rate over a prolonged period of time.1
Controlled drug delivery (CDD) has become
important in the pharmaceutical industry in
recent years. The pharmacological response,
both the desired therapeutic effect and the
undesired adverse effect, of a drug is
dependent on the concentration of the drug at
the site of action, which in turn depends upon
the dosage form and the extent of absorption
of the drug at the site of action.
The potential of using the intact skin as the
port of drug administration to the human body
has been recognized for several decades, but
skin is a very difficult barrier to the ingress of
materials allowing only small quantities of a
drug to penetrate over a period of time. There
are main pathways by which drugs can cross
the skin and reach the systemic circulation are
trans cellular pathway, intercellular route,
follicular route.2
TDDS also known as patches are dosage
forms designed to deliver a therapeutically
effective amount of drug across a patients
skin. Several TDDS containing drugs such as
clonidine, estradiol, fentanyl, nicotine,
nitroglycerin, oxybutynin and scopolamine are
available in the United States and other
countries.3
FA is highly potent corticosteroid drug, can be
used for eczema disease treatment and to
suppress the symptoms of disease, e.g. -
pruritus, itching, dryness of skin etc. FA has
very low half-life so it is desirable to increase
frequency of dosing for optimum drug plasma
concentration. The controlled release
formulation shall be prepared as FA is highly
potent so devoid of overdosing. By preparing
patch formulation occlusion provides moisture
to skin which is further advantageous for skin
dryness symptom and may help to provide
aesthetic feel for being in society.
The aims of the present study were to prepare
matrix type transdermal patches of FA using
povidone, polyvinyl alcohol and Polyox WSR
1105 polymers and study the in-vitro diffusion
behaviour of prepared matrix type transdermal
patch formulations. The purpose was to
provide the delivery of the drug at a controlled
rate.
MATERIALS & METHODS
Fluocinolone acetonide (Tripda
Pharmaceuticals, Ahmedabad) and Polyox
WSR 1105 (Colorcon, Verna, Goa) were
obtained as gift sample. Povidone and
polyvinyl alcohol (MCC laboratory chemicals,
Ahmedabad), propylene glycol (S.D.Fine
Chemicals, Mumbai), Ethanol (Ureca
consumers, Ahmedabad) were obtained
commercially. All the chemicals were used as
received without any further treatment and
purification.
From the preliminary trials for selection of
polymer and plasticiser the ratio for the PVP
K-30 and PVA was taken as constant in 2:5
Development and Characterization of Transdermal Patch for Controlled Release of Fluocinolone Acetonide
Copyright reserved by Journals Club & Co. 23
and various amounts of Polyox WSR 1105 and
PG was selected as independent factors for 3
level 2 factor full factorial designs. As the
dependent factor % cumulative drug release
(at 24 hrs) and % moisture content were taken.
Method of preparation of Patch
Transdermal patches containing FA and
various amounts of propylene glycol and
Polyox WSR 1105 were prepared by solvent
casting method. The detail composition of
various pathes is furnished in table. Accurately
weighted drug were dissolved in ethanol, than
selected ratio of polymer were weighted. PVP
K-30 was dissolved in Ethanol. PVA was then
stirred with magnetic stirrer in cold water. The
temperature was gradually increased to
solubilised, then after cooling Polyox was
added to PVA solution with continuous
stirring. PG was added to above solution. The
alcoholic solution was added to aqueous
solution stirred for 30 min. The mixture
solution was then set aside for 20 min to
release air entrapment. Then on the one side
silicone coated release liner the solution was
poured. After 60 min at room temperature the
backing membrane was put on patch matrix
and given rolling press for PSAs (pressure
sensitive adhesives) to stick with backing
membrane.
The dried patches were cut in to required size
(53=15 cm2). The patches were packed in
aluminium foil and store in desiccator till
study. All the formulas shown in table 1 were
used for 80 cm2 patch preparation.
Physicochemical Compatibility of Drug and
Excipients 4
The FTIR of pure drug and physical mixture
of formulation ingredients of optimized patch
were measured using Fourier Transform
Infrared Spectrophotometer. The amount of
each ingredient in the physical mixture was
same as that in the optimized batch. The pure
drug and formulation mixture were than
separately mixed with IR grade KBr and liquid
holder respectively. This mixture was then
scanned over a wave number range 4000 to
400 cm-1
Physical Appearance 5
All the transdermal patches were visually
inspected for colour, clarity, flexibility and
smoothness. It is qualitative test which is
mentioned by + and as the number of +
increases the appearance was considered as
better.
Thickness 6
Patch thickness was determined using
Micrometre screwguage and recorded. Results
were reported as the mean of five
measurements in that 4 corners and the centre
of each patch.
Weight Uniformity 6
Three randomly selected patches of each
formulation patch were weighed individually
and their average weights were calculated.
Folding Endurance 7
It was determined by repeatedly folding a
small strip of films at the same place till it
broke. The number of times, the films could be
Copyright reserved by Journals Club & Co. 24
folded at the same place without breaking
gave the value of folding endurance.
Tensile Strength 8
The tensile strength should be determined by
using a modified pulley system. Weight was
gradually increased so as to increase the
pulling force till the patch broke. The force
required to break the film was consider as a
tensile strength and it was calculated as
kg/cm2.
Percentage Elongation Break Test 1
The percentage elongation break is to be
determined by noting the length just before the
break point, the percentage elongation can be
determined from the below mentioned
formula.
Elongation percentage = (L1-L2) / L2
100
Where, L1is the final length of each
strip and
L2 is the initial length of each strip.
Percentage Moisture Content 1
The prepared films are to be weighed
individually and to be kept in a desiccator
containing fused calcium chloride at room
temperature for 24 hrs. After 24 hrs, the films
are to be reweighed and determine the
percentage moisture content from the below
mentioned formula.
Percentage moisture Content = [(Initial
weight- Final weight) / Final weight]
100
Drug Content Analysis 6
For drug content determination, the total
content of transdermal patch was placed in a
100 ml volumetric flask and dissolved in
phosphate buffer pH7.4. The solution was
filtered through a Whatman filter membrane
(0.45m) prior to spectrophotometric drug
analysis at 240 nm (Shimadzu, model UV-
1700 PC, Kyoto, Japan).
In Vitro Diffusion Studies (Drug release
profile) 9
In vitro permeation studies were performed by
using a modified Franz diffusion cell across a
cellulose membrane using phosphate buffer
pH 7.4 as the in vitro study fluid in the
receptor compartment. The polymeric film
was placed on the cellulose membrane. The
holder contains the cellulose membrane. The
formulation was then placed on the receiver
compartment of the modified diffusion cell
containing phosphate buffer pH 7.4. The donor
and receiver compartments were kept in
immediate contact by wrapping para film at
the junction. The temperature of the diffusion
cell was maintained at 32 0.5-C by a
circulating water jacket. The whole assembly
was kept on a magnetic stirrer, and solution in
the receiver compartment was constantly and
continuously stirred throughout the
experiment using magnetic beads. The
samples were withdrawn (1 mL each time) at
different time intervals (up to 24 Hrs.) and an
equal amount of phosphate buffer pH 7.4 was
replaced each time. The intensities of samples
Development and Characterization of Transdermal Patch for Controlled Release of Fluocinolone Acetonide
Copyright reserved by Journals Club & Co. 25
were measured spectro photometrically. The
amount of drug permeated per square
centimetre at each time interval was calculated
and plotted against time.
Table: 1 Formulation batches of transdermal patches of Fluocinolone acetonide
Formulation FA(mg) PVA(gm) PVPK30 Polyox PG Ethanol Water
F1 2.0 0.5 0.2 0.10 0.3 3 10
F2 2.0 0.5 0.2 0.25 0.3 3 10
F3 2.0 0.5 0.2 0.40 0.3 3 10
F4 2.0 0.5 0.2 0.10 0.6 3 10
F5 2.0 0.5 0.2 0.25 0.6 3 10
F6 2.0 0.5 0.2 0.40 0.6 3 10
F7 2.0 0.5 0.2 0.10 0.9 3 10
F8 2.0 0.5 0.2 0.25 0.9 3 10
F9 2.0 0.5 0.2 0.40 0.9 3 10
and chemical interaction between drug and
excipients used. Infrared spectra of FA drug
and formulation. From the figure , it was
observed that there were no change in these
main peak in IR spectra of formulation, which
shows there were no physical interactions
because of some bond formation between the
drug and polymers.4
Patches were visually inspected for colour,
clarity, flexibility and smoothness and batch
F2, F4, F5 were found best in all inspection
for visual inspection. Results shows as the
amount of Polyox increases the appearance
gone bad for features. It may be due to higher
swelling property and more the cross linkage
more the moisture content. As the amount of
Polyox increases the color gone opaque and
clarity reduces.4, 10, 11
All the patches were examined for thickness ,
weight uniformity and folding endurance as
repeated each for 3 times so as standard
deviation (n=3). The results show as the
amount of Polyox and PG increases the
thickness and weights were increased. Lesser
the standard deviation provide the assuredly of
reproducibility of procedure and product
quality. Thickness was varied from 310-400
micron.5, 11
The batches had folding endurance >150 can
be accepted for the formulation. Here the
amount of Polyox increases the folding
endurance decreases might be due to loosen
the matrix inter linkage because of swelling
property. But as the amount of PG increase the
folding endurance gone higher in number due
to flexibility plasticizer property.5, 12, 13
Tensile strengths were found from result
0.190-0.320 kg/cm2. As the hydrophilic
polymer increases the % moisture content
increases. Here the % moisture content 10-
13% was found optimum for adhesion and
Copyright reserved by Journals Club & Co. 26
other properties. Adhesion was simply
evaluated by thumb tack test which is
qualitative. 6,14,15
Drug content was found within limits (96-
104%) 16, 17, 18 for all formulations. And tests
were done by using Shimadzu 1700
Spectrophotometer.
By applying ANOVA for Response Surface
Quadratic Model by Design Expert (Version
8) for % cumulative drug release (at 24 hrs.) p-
value was found 0.0109 which was significant
at 0.05> t-test. And ANOVA for Response
Surface Quadratic Model for % moisture
content p-value was found 0.0017 significant.
Contour plot provide graphical representation
of desired values of response from the factor
values.
By over laying the responses the over lay plot
provide the optimal area of factor can be used
for desired response.
From the overlay plot one check point batch
was prepared and validity of equation was
checked for both response and found
minimum relative error 2.42 for % cumulative
release (at 24 hrs.) and 0.84 for % moisture
content.
From the results of % cumulative drug release
(at 24 hrs.) the Batch F2 show maximum
release 88.092.26 % and batch F9 shows
61.411.1 lowest release of drug for in-vitro
release study. % Cumulative drug release (at
24 hrs.) decreases as the amount of Polyox
increase as the thickness of the formulation
decreases the amount of drug available for
release was decreases due to more the
torturous path and the release was found slow.
Fig 1a:FTIR of pure drug FA
Development and Characterization of Transdermal Patch for Controlled Release of Fluocinolone Acetonide
Copyright reserved by Journals Club & Co. 27
Fig 1b : FTIR of Formulation
Table: 2a Physicochemical Characteristics of Patch
Batch Code Physical appearance
Thickness (m) (n=3)
Weight Uniformity (mg) (n=3)
Folding Endurance (n=3)
F1 ++ 31010 5860.98 1973.14 F2 +++ 3507.56 6941.96 1652.12 F3 ++ 3805.77 8561.74 1261.8 F4 +++ 3205.90 6040.85 2305.65 F5 +++ 3607.88 7221.45 1742.77 F6 + 3905.77 9252.06 1433.1 F7 ++ 32010 6351.61 2106.21 F8 ++ 3605.77 7801.56 1904.26 F9 + 40010 9862.12 1397.83
Table: 2b Physicochemical Characteristics of Patch
Batch Code Tensile
strength (kg/cm2) (n=3)
% Elongation at break (n=3)
% Moisture content (n=3)
% Drug content (n=3)
F1 0.3200.19 14.210.57 4.140.68 96.241.23 F2 0.2800.32 15.090.34 10.11.15 98.461.05 F3 0.2300.20 15.980.45 21.21.88 98.050.97 F4 0.3050.15 18.240.32 5.20.87 99.140.78 F5 0.2550.22 19.340.25 12.11.2 97.351.18 F6 0.1900.12 20.220.13 22.32.32 100.241.86 F7 0.2870.14 24.210.34 6.80.68 96.970.88 F8 0.2430.29 25.110.56 15.20.95 98.231.13 F9 0.1950.13 25.8714 23.11.45 95.781.54
Copyright reserved by Journals Club & Co. 28
Table: 2c Release Profile of Factorial Batch F1 to F5
Time (Hrs)
% Cumulative Drug Release
F1 F2 F3 F4 F5
0 0 0 0 0 0
1 7.190.71 7.900.85 7.190.96 7.191.08 8.620.91 2 9.670.98 10.421.02 10.390.85 11.110.77 11.171.26 3 14.081.73 14.830.98 15.551.04 15.580.63 14.861.63 4 18.591.56 20.061.02 19.371.36 17.931.71 20.061.54 5 22.371.46 23.880.89 23.841.85 21.621.63 23.880.53 6 27.572.48 29.071.32 29.072.12 26.820.56 29.071.88 7 32.112.4 34.330.86 32.891.68 31.361.12 33.612.01 8 35.900.86 38.151.42 37.371.63 34.431.75 37.401.66 9 40.371.02 42.631.23 41.871.96 36.711.68 41.871.44 10 44.882.62 47.130.96 44.952.16 41.121.45 45.662.03 11 49.390.84 51.641.56 48.671.85 44.191.85 49.421.85 12 52.461.53 57.591.98 53.862.45 47.201.75 52.462.45 18 68.401.65 75.092.16 69.182.46 64.582.37 69.122.48 24 81.331.54 88.092.26 79.211.75 78.292.06 79.932.56
Table: 2d Release Profile of Factorial Batch F6 to F9 Time (Hrs)
% Cumulative Drug Release F6 F7 F8 F9
0 0 0 0 0 1 8.621.36 7.191.32 7.902.01 7.902.01 2 10.451.45 9.670.54 11.862.10 9.700.42 3 14.110.98 15.520.87 14.890.32 14.080.35 4 19.301.65 20.811.2 18.621.02 17.871.02 5 23.132.45 23.911.6 22.371.86 23.060.86 6 27.601.63 27.632.2 26.850.86 26.160.36 7 30.671.12 31.391.45 29.920.68 29.170.56 8 34.391.23 35.150.96 33.642.45 33.611.01 9 37.431.23 38.181.25 36.680.96 37.400.86
10 41.162.42 43.342.21 40.411.01 41.160.65 11 44.911.23 47.890.86 44.160.77 45.631.22 12 48.671.68 50.241.52 47.202.3 47.981.3 18 61.772.01 56.801.3 58.833.12 56.700.56 24 70.261.95 64.282.4 67.252.44 61.411.1
Development and Characterization of Transdermal Patch for Controlled Release of Fluocinolone Acetonide
Copyright reserved by Journals Club & Co. 29
Fig 1c : Cumulative % Drug Release v/s Time (F1-F9)
Fig 1d : Contour Plot Showing the Effect of X1 and X2 on % Cumulative Drug Release
Design-Expert SoftwareFactor Coding: Actual% drug release
Design Points88.16
62.3
X1 = A: Amount of PolyoxX2 = B: amount of PG
0.10 0.17 0.25 0.33 0.40
0.30
0.40
0.50
0.60
0.70
0.80
0.90% drug release
A: Amount of Polyox
B: a
mou
nt o
f PG
6570
75
80
85
Copyright reserved by Journals Club & Co. 30
Fig 1e : Contour Plot Showing the Effect of X1 and X2 on % Moisture Content
Design-Expert SoftwareFactor Coding: Actualmoisture content
Design Points23.1
4.14
X1 = A: Amount of PolyoxX2 = B: amount of PG
0.10 0.17 0.25 0.33 0.40
0.30
0.40
0.50
0.60
0.70
0.80
0.90moisture content
A: Amount of Polyox
B: a
mou
nt o
f PG
5
10 15 20
Fig If : Overlay Plot Shows Optimal Area of Factor Can be Used for Desired Response
CONCLUSION
From the various amount of Polyox and PG,
batch F2 was found optimum for use further.
The patch of F2 batch (Polyox 0.25 gm and
PG 0.30 gm) also found good in appearance,
smoothness, folding endurance and adhesion.
% Cumulative release (at 24 hrs.) of F2 batch
was found highest among all the batches
which are reasonably desirable for formulation
and can be used for controlled release
formulation.
Design-Expert SoftwareFactor Coding: ActualOverlay Plot
% drug releasemoisture content
Design Points
X1 = A: Amount of PolyoxX2 = B: amount of PG
0.10 0.17 0.25 0.33 0.40
0.30
0.40
0.50
0.60
0.70
0.80
0.90Overlay Plot
A: Amount of Polyox
B: a
mou
nt o
f PG
% drug release: 80.000moisture content: 8.000 moisture content: 12.000
% drug release: 86.970moisture conten 8.316X1 0.20X2 0.30
Development and Characterization of Transdermal Patch for Controlled Release of Fluocinolone Acetonide
Copyright reserved by Journals Club & Co. 31
ACKNOWLEDGEMENT
Authors wishes to acknowledge Tripda
Pharmaceuticals, Ahmedabad for providing
gift sample of drug, Fluocinolone acetonide.
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HOW TO CITE THIS ARTICLE Joshi, D. M., Patel, S., Moin, M. K., Anandkumar, K. P., Patel, V. M. (2014). Development and
Characterization of Transdermal Patch for Controlled Release of Fluocinolone Acetonide. Journal
Club for Pharmaceutical Sciences, 1(I), 21-32.