Development and Characterization of Transdermal Patch for Controlled Release of Fluocinolone Acetonide

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]

mailto:[email protected]


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 patient’s

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


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

(5×3=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


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

(0.45μm) 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



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


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 88.09±2.26 % and batch F9 shows

61.41±1.1 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



Fig 1b : FTIR of Formulation

Table: 2a Physicochemical Characteristics of Patch

Batch Code Physical appearance

Thickness (µm) (n=3)

Weight Uniformity (mg) (n=3)

Folding Endurance (n=3)

F1 ++ 310±10 586±0.98 197±3.14 F2 +++ 350±7.56 694±1.96 165±2.12 F3 ++ 380±5.77 856±1.74 126±1.8 F4 +++ 320±5.90 604±0.85 230±5.65 F5 +++ 360±7.88 722±1.45 174±2.77 F6 + 390±5.77 925±2.06 143±3.1 F7 ++ 320±10 635±1.61 210±6.21 F8 ++ 360±5.77 780±1.56 190±4.26 F9 + 400±10 986±2.12 139±7.83

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 0.320±0.19 14.21±0.57 4.14±0.68 96.24±1.23 F2 0.280±0.32 15.09±0.34 10.1±1.15 98.46±1.05 F3 0.230±0.20 15.98±0.45 21.2±1.88 98.05±0.97 F4 0.305±0.15 18.24±0.32 5.2±0.87 99.14±0.78 F5 0.255±0.22 19.34±0.25 12.1±1.2 97.35±1.18 F6 0.190±0.12 20.22±0.13 22.3±2.32 100.24±1.86 F7 0.287±0.14 24.21±0.34 6.8±0.68 96.97±0.88 F8 0.243±0.29 25.11±0.56 15.2±0.95 98.23±1.13 F9 0.195±0.13 25.87±14 23.1±1.45 95.78±1.54


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 7.19±0.71 7.90±0.85 7.19±0.96 7.19±1.08 8.62±0.91 2 9.67±0.98 10.42±1.02 10.39±0.85 11.11±0.77 11.17±1.26 3 14.08±1.73 14.83±0.98 15.55±1.04 15.58±0.63 14.86±1.63 4 18.59±1.56 20.06±1.02 19.37±1.36 17.93±1.71 20.06±1.54 5 22.37±1.46 23.88±0.89 23.84±1.85 21.62±1.63 23.88±0.53 6 27.57±2.48 29.07±1.32 29.07±2.12 26.82±0.56 29.07±1.88 7 32.11±2.4 34.33±0.86 32.89±1.68 31.36±1.12 33.61±2.01 8 35.90±0.86 38.15±1.42 37.37±1.63 34.43±1.75 37.40±1.66 9 40.37±1.02 42.63±1.23 41.87±1.96 36.71±1.68 41.87±1.44 10 44.88±2.62 47.13±0.96 44.95±2.16 41.12±1.45 45.66±2.03 11 49.39±0.84 51.64±1.56 48.67±1.85 44.19±1.85 49.42±1.85 12 52.46±1.53 57.59±1.98 53.86±2.45 47.20±1.75 52.46±2.45 18 68.40±1.65 75.09±2.16 69.18±2.46 64.58±2.37 69.12±2.48 24 81.33±1.54 88.09±2.26 79.21±1.75 78.29±2.06 79.93±2.56

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 8.62±1.36 7.19±1.32 7.90±2.01 7.90±2.01 2 10.45±1.45 9.67±0.54 11.86±2.10 9.70±0.42 3 14.11±0.98 15.52±0.87 14.89±0.32 14.08±0.35 4 19.30±1.65 20.81±1.2 18.62±1.02 17.87±1.02 5 23.13±2.45 23.91±1.6 22.37±1.86 23.06±0.86 6 27.60±1.63 27.63±2.2 26.85±0.86 26.16±0.36 7 30.67±1.12 31.39±1.45 29.92±0.68 29.17±0.56 8 34.39±1.23 35.15±0.96 33.64±2.45 33.61±1.01 9 37.43±1.23 38.18±1.25 36.68±0.96 37.40±0.86

10 41.16±2.42 43.34±2.21 40.41±1.01 41.16±0.65 11 44.91±1.23 47.89±0.86 44.16±0.77 45.63±1.22 12 48.67±1.68 50.24±1.52 47.20±2.3 47.98±1.3 18 61.77±2.01 56.80±1.3 58.83±3.12 56.70±0.56 24 70.26±1.95 64.28±2.4 67.25±2.44 61.41±1.1



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


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


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


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



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.

Development and Characterization of Transdermal Patch for Controlled Release of Fluocinolone Acetonide

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