formulaton and evaluation of film forming gel of

www.wjpps.com Vol 7, Issue 6, 2018.

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Saravanan et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATON AND EVALUATION OF FILM FORMING GEL OF

DICLOFENAC DIETHYLAMINE

J. Saravanan*, K. Elango, S. Daisy Chellakumari and K. Arulkumar

Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai- 03.

ABSTRACT

Objective: The present aim of the study was to formulate and evaluate

film forming gel of diclofenac diethylamine for sustained release of the

drug. Methods: The gel was formulated using hydroxyl propyl methyl

cellulose and polyvinyl pyrrolidine as gelling agents and various

Eudragit polymers as film forming agent. The physical and chemical

compatibility of the ingredients were studied using FT-IR spectroscopy

and the results reveal the compatibility of the ingredients with each

other. The formulated gel was subjected to rheological studies,

characterization of the film and invitro drug release studies. Results:

The formulation F1 shown considerably better characteristics than

other formulations and subjected to invivo anti inflammatory studies. The results of the

invitro and invivo studies were compared with that ofthe marketed gel. Conclusion: The

optimized formulation shows a sustained release of the drug, better characteristics of the film

and the same efficacy as that of the marketed formulation.

KEYWORDS: Film forming gel, Hydroxy propyl methyl cellulose, Eudragit, Diclfenac

diethylamine.

INTRODUCTION

Skin is the most readily accessible organ of the body with a surface area of about 2 m2

receiving about one third of the total blood circulating throughout the body. The goal of drug

administration through skin is for topical treatment of skin diseases or for transdermal

absorption of drugs in the systemic circulation. The topical route offers a large and varied

surface in addition to the ease of application via self administration and provides an

alternative to oral delivery of drugs as well as hypodermic injection.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 7, Issue 6, 1106-1117 Research Article ISSN 2278 – 4357

*Corresponding Author

J. Saravanan

Department of

Pharmaceutics, College of

Pharmacy, Madras Medical

College, Chennai- 03.

Article Received on

03 April 2018,

Revised on 24 April 2018,

Accepted on 14 May 2018,

DOI: 10.20959/wjpps20186-11757


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The current dosage forms i.e. patches, ointments, creams, etc. are associated with various

limitations. Patches have various disadvantages, most commonly skin irritation, occlusive

nature, pain while peeling and poor aesthetic appeal. Semisolid dosage forms like ointment

and creams overcome some of these disadvantage and have others. They don’t have persistent

contact with the skin and easily wiped off by the cloth from the skin. Hence repeated

application is necessary.[1]

Film forming system is a novel approach which can be used as an alternative to conventional

topical and transdermal formulations. Film forming preparations are defined as non-solid

dosage forms that produce a substantial film in situ after application on the skin or any other

body surface. Such compositions can either be liquids or semisolids with a film forming

polymer as basic material for the matrix. The formed film is sufficiently substantial to

provide a sustained drug release to the skin.[2]

Diclofenac is an aryl acetic acid derivative used as NSAID for the treatment of pain

associated various disease conditions such as arthritis, traumatic pain, etc. It is administered

oral, parenteral and topical routes.[3]

MATERIALS AND METHODS

Preparation of Film forming gel[4][5]

Table 1: Formulation table for Film forming gel of Diclofenac diethylamine.

Ingredients* F1 F2 F3 F4 F5 F6 F7 F8 F9

DDE 1.13 1.13 1.13 1.13 1.13 1.13 1.13 1.13 1.13

HPMC K100M 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5

Povidone --- --- --- 0.5 0.5 0.5 0.5 0.5 0.5

Eudragit E 100 0.5 1.5 2.5 --- --- --- --- --- ---

Eudragit S 100 --- --- --- 0.5 1.5 2.5 --- --- ---

Eudragit RS100 --- --- --- --- --- --- 0.5 1.5 2.5

Menthol 1 1 1 1 1 1 1 1 1

PG 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

Triethylcitrate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

Water 40 40 40 40 40 40 40 40 40

Ethanol q.s to

100

q.s to

100

q.s to

100

q.s to

100

q.s to

100

q.s to

100

q.s to

100

q.s to

100

q.s to

100

* Quantities in % w/w

The gel was prepared using high speed homogenizer rotated at 1500 rpm. HPMC K100M and

PVP K30 were dispersed in water taken in a beaker. The dispersion was kept undisturbed for

one hour. Diclofenac diethylamine was dissolved in about 3 ml of ethanol and mixed


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thoroughly with the HPMC dispersion until a uniform dispersion is formed. Then Eudragit

polymer was dissolved in sufficient quantity of ethanol previously mixed with triethyl citrate

and the solution was mixed with the dispersion of HPMC and DDE until a uniform dispersion

was obtained. Menthol was dissolved in propylene glycol and added to the dispersion and it

was thoroughly mixed for about two hours to obtain a smooth uniform dispersion. The

formulated gel was packed in a collapsible tube.

Drug content of the gel[6]

A quantity of the gel equivalent to 100 mg of diclofenac diethylamine was dissolved in 100

ml of Phosphate buffer 6.8. The volumetric flask containing gel was shaken for 2 hours to

ensure complete solubility of the drug. It was filtered, diluted suitably and estimated

spectrophotometrically at 276.0nm using phosphate buffer pH 6.8 as blank.

Evaluation of the Gel

The pH and viscosity of the formulations were evaluated.

Spreadability of the formulation[6]

100 mg of the sample was kept at the center of a glass slide. The slide was covered with

another slide and the slides were pressed between fingers until no more expansion of the

circle formed by the gel between the slides is observed. The diameter of the circle formed by

the gel is measured in centimeters.

Drying time[4]

For the assessment of drying time the formulation was applied to the inner sides of the

forearm of a volunteer. After 2 minutes glass slide was placed on the film without applying

pressure. If no remains of liquid were visible on the glass slide after removal, the film was

considered dry. If remains of liquid were visible on the glass slide the experiment was

repeated until the film was found to be completely dry.

Properties of the film

Integrity of the formulation on the skin[4]

The formulation was applied to the forearm of a volunteer as described for the assessment for

the drying time. The dry film was then worn overnight by the test subject. After 24 hours the

test area was examined visually for completeness of the film, appearance of cracks or flaking.


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Film formation[1]

The films are formed in a Petri dish. Film-formation is evaluated and rated as complete and

uniform, incomplete or non-uniform, with or without precipitation of the film-forming

polymer. The cosmetic aspects of the film are given in terms of transparency or opaque,

sticky or dry, peelable or non-peelable.

Film flexibility[1]

Film flexibility is evaluated on the basis of cracking and skin fixation and this is determined

by stretching the skin in 2–3 directions. The film is rated flexible if there is no cracking or

skin fixation and non-flexible if there is cracking and skin fixation.

In vitro diffusion study[6]

The diffusion study of the formulation was performed using open ended tubes of diameter 24

mm, one end of which is tied with cellophane membrane previously soaked in the medium.

100 ml of phosphate buffer pH 6.8 maintained at a temperature of 37o±2

oC was used as the

diffusion medium which was stirred at 100 rpm in a magnetic stirrer with heat control system.

Formulation equivalent to 100 mg of diclofenac diethylamine was inserted into the tube and

the tube was placed in the medium so that the closed end of the tube just touches the surface

of the diffusion medium. The samples were withdrawn at intervals of one hour for 12 hours

and were analyzed spectroscopically. The cumulative percentage release of the drug was

calculated. The results are plotted against time.

Formulation of the film[4]

The film was formed by spreading about 1 gram of the gel in an area of about 4 cm2 on a

petridish. The gel was allowed to dry in open air at room temperature until the glass slide

touched on the film shows no traces of liquids on it. The film was removed carefully and

subjected to further evaluations.

Characterization of the formed film

Percentage elongation of the film[4]

The percentage elongation of the film was measured using the laboratory assembled

equipment. The film of length 2 cm and breadth 1 cm was taken and clamped between two

holders such that one end is tied to a stable support and the other end is joined to a movable

support. A stainless steel pan of 4 grams was tied to the movable support. Weight was added


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to the pan and the maximum length to which the film can be stretched before it was torn was

measured in millimeters. The test was conducted in triplets and the results are tabulated.

Water vapor permeability test[4]

Water vapor permeability (WVP) was determined according to a method modified from

British Pharmacopoeia. Films were produced with the evaporation of solvent and a circular

film of diameter 2 cms was cut out with a scalpel. 3 ml of water was filled in a glass vial and

the vial was covered with the formed film and tied. Initial weight of the vial covered with the

film was noted and kept in a desiccator for 24 hours. The decrease in the weight of the vial

was noted. The % water vapor permeability was calculated using the formula.

WVP= Difference in weight of vial/( Surface area of film x time) (gm cm-2

24 hrs-1

)

In vivo anti inflammatory activity[7][8][9]

Approval for the conduct of anti inflammatory activity in wistar albino rats was obtained

from Institutional Animal Ethics Committee.

Male or female Wistar albino rats with a body weight between 100 and 150 g were used. The

animals were starved overnight.

The animals were grouped into four groups of 6 six animals each and the grouping was

represented in the Table 2.

Table 2: Grouping of animals for in vivo anti inflammatory activity.

S.No Group No. of Animals Treatment

1 Group I 6 0.2 ml of 1% carrageenan solution

2 Group II 6 0.2 ml of 1% carrageenan solution +

Blank Formulation

3 Group III 6 0.2 ml of 1% carrageenan solution

+ Marketed Formulation

4 Group IV 6 0.2 ml of 1% carrageenan solution

+ Optimized Formulation

Initially the hair from the left hind leg of the animals was removed by using depilatory cream.

The formulations were applied to the depilated area of the animals of respective groups.

Thirty minutes later, the rats were challenged by a subcutaneous injection of 0.05ml of 1%

solution of carrageenan into the plantar side of the left hind paw. The paw is marked with ink

at the level of the lateral malleolus and immersed in mercury up to this mark.


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The paw volume was measured plethysmographically immediately after injection, and for six

consecutive hours.

RESULTS

Drug content of the formulations

Table 3: Drug content of the Formulations.

Formulation % Drug content

F1 95.38

F2 95.24

F3 97.16

F4 102.16

F5 101.74

F6 99.29

F7 98.50

F8 97.84

F9 100.61

Figure 1: Drug content of the Formulations.

Post formulation studies

The pH, viscosity, spreadability and drying time of the formulations are given in Table 4.

Table 4: Post Formulation studies.

Formulation pH Viscosity

(cps)

Spreadability*

(in cms)

Drying time*

( Minutes)

F1 6.82 85638 5.87 ± 0.08 6.33 ± 0.17

F2 6.70 96347 5.50 ± 0.05 7.33 ± 0.17

F3 6.91 109638 6.23 ± 0.03 9.00 ± 0.28

F4 5.89 94037 4.93 ± 0.08 6.17 ± 0.17

F5 6.01 103243 5.10 ± 0.05 7.33 ± 0.17

F6 5.93 119679 4.83 ± 0.03 8.17 ± 0.17

F7 6.25 98354 5.90 ± 0.05 7.67 ± 0.17

F8 6.25 117348 5.80 ± 0.11 8.67 ± 0.44

F9 6.35 129675 6.30 ± 0.05 10.17 ± 0.17

*Mean ± SEM (n=3)


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Properties of the film

Table 5: Properties of the Film.

Formulation Integrity Film formation Observation

F1 Complete C, P, T Flexible

F2 Complete C, NP, T Flexible

F3 Complete C, NP, O Flexible

F4 Partially missing C, P, T Not Flexible

F5 Partially missing C, P, T Not Flexible

F6 Partially missing C, NP, T Not Flexible

F7 Partially missing NC, P, T Not Flexible

F8 Partially missing C, P, O Not Flexible

F9 Partially missing C, P, O Not Flexible

C- Complete NC- Non Complete

T- Transparent O- Opaque

P- Peelable NP- Non Peelable

In vitro diffusion study of the formulations

The in vitro diffusion results of the formulations are given in the Table 6

Table 6: in vitro diffusion study of the formulations.

Time

(Hrs)

Cumulative % Drug Release

F1 F2 F3 F4 F5 F6 F7 F8 F9

1 17.58 9.11 4.27 32.9 25.64 20 30.48 23.62 16.77

2 34.28 12.83 7.94 57.82 39.92 31.89 60.62 41.60 32.66

3 43.92 15.77 10.84 70.09 53.71 47.12 80.58 56.53 43.07

4 54.00 18.35 12.96 77.63 75.61 58.48 96.70 67.98 54.38

5 63.61 20.55 14.70 91.65 85.62 68.32 --- 84.03 64.19

6 69.67 22.35 15.65 97.43 93.72 78.27 --- 85.94 76.91

7 79.39 24.16 17.02 --- 98.67 83.46 --- 92.40 83.33

8 81.97 25.6 19.19 --- --- 89.21 --- 98.14 98.29

10 94.85 28.24 20.99 --- --- 94.40 --- --- ---

12 98.58 31.79 22.80 --- --- 97.71 --- --- ---

Figure 2: In vitro diffusion study of formulations.


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The diffusion study of the various formulated gel through the cellophane membrane shows

various degree of sustaining the release of the drug from the formulation.

The formulations F4, F5, F7, F8 and F9 released the drug too quickly revealing their inability to

sustain the release to a desired level whereas the formulation F2 and F3 did not released the

drug to a considerable extent which could result in a sub therapeutic effect of the drug.

The formulations F1 and F6 has sustained the release of the drug to a considerable extent and

could produce an effect to a desired extent of time

Film characterization

The folding endurance of the film is given in Table 9.19.

Table 7: Characteristics of the film.

Formulation Folding

endurance*

% elongation

of the film*

Water vapor

permeability*

(g cm-2

24 hrs-1

)

F1 182.33 ± 1.76 46.67 ± 4.40 0.052 ± 0.00

F2 165.67 ± 2.33 60.00 ± 2.88 0.050 ± 0.00

F3 152.67 ± 2.02 70.00 ± 2.88 0.046 ± 0.00

F4 150 ± 1.52 28.33 ± 4.40 0.044 ± 0.00

F5 135 ± 2.08 33.33 ± 1.66 0.044 ± 0.00

F6 122.33 ± 2.18 41.67 ± 3.33 0.041 ± 0.00

F7 166.67 ± 6.33 23.33 ± 1.66 0.050 ± 0.00

F8 149.33 ± 1.45 40.00 ± 2.88 0.047 ± 0.00

F9 137.67 ± 4.40 51.67 ± 3.33 0.045 ± 0.00

*Mean ± SEM (n=3)

Comparison of in vitro release of optimized formulation and marketed formulation

Table 8: Comparison of in vitro release of Optimized and Marketed formulation.

Time (Hrs) F1 Marketed formulation

0 0 --

0.25 -- 15.56

0.5 -- 37.49

0.75 -- 50.76

1 17.58 61.63

1.5 -- 72.44

2 34.28 80.81

2.5 -- 88.05

3 43.92 94.94

3.5 -- 99.07

4 54.00 --

5 63.61 --


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6 69.67 --

7 79.39 --

8 81.97 --

10 94.85 --

12 98.58 --

Figure 3 Comparison of in vitro release of Optimized formulation and Marketed

formulation.

Table 9: Percentage Change in Paw Volume.

Time (Hrs) % Change in Paw volume*

Group I Group II Group III Group IV

0 0 0 0 0

1 4.34±0.35 5.07±0.28 4.83±0.29 4.57±0.24

2 3.62±0.31 5.07±0.28 2.89±0.39 1.92±0.31

3 2.88±0.36 4.58±0.42 0.95±0.48 0.48±0.30

4 2.65±0.24 3.61±0.29 0.24±0.24 0

5 2.4±0.30 3.61±0.29 0 0

6 1.67±0.23 3.61±0.29 0 0

*Mean ± SEM (n= 6)

Figure 4: Percentage Change in Paw Volume.


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Table 10: p value.

Group p value

Control 0.4005

Blank 0.0392*

F1 0.9805

* P < 0.05

DISCUSSION

The drug excipient interaction was investigated with FT-IR Spectroscopy. The study

indicated that there was no interaction between the drug and the excipients used in the

formulation.

The gel was formulated using various concentrations of Eudragit E (0.5 %, 1.5 %and 2.5 %),

Eudragit S 100 (0.5 %, 1.5 %and 2.5 %) and Eudragit RS 100 (0.5 %, 1.5 %and 2.5 %) using

high speed homogenizer.

The formulated gel was evaluated for pH, viscosity, spreadability, film formation, and

flexibility. The drug content of the formulated gel was within acceptable limit.

The film was formed from the formulated gel and the optimized formulation had a folding

endurance of 182.33±1.73 folds, percentage elongation of 46.67±4.40 and water vapour

permeability of .052 g cm-2

24 hrs-1

.

The in vitro drug diffusion study of the formulated film forming gels was performed using

the open ended tubes through cellophane membrane.

The formulation was optimized based on the in vitro diffusion study and the properties of the

formulated gel such as film formation, flexibility and water vapour permeability.

The Formulation F1 (with 0.5% of Eudragit E100) was found to sustain the release up to 12

hours and has acceptable film properties such as film formation, integrity of the film,

flexibility and water vapour permeability of the film formed.

Thus the formulation F1 may be considered as optimized formulation and was subjected to

further evaluation.


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The in vitro drug release of the formulation F1 was compared with that of the marketed gel.

The release of the optimized formulation was sustained.

The in vivo anti-inflammatory activity of the optimized formulation F1 was performed in

wistar albino rats of either sex by carrageenan induced paw edema method and the anti-

inflammatory activity of the formulation was evaluated plethysmographically for six

consecutive hours. Results were compared with the result of marketed gel. The significance

of the study was measured using Dunnet Multiple comparison test.

The results show that the there was no significant difference in the anti-inflammatory activity

of the formulation and the marketed gel. The activities of both the formulations are similar.

The activity of the blank formulation has a significant difference with marketed formulation

which shows that the blank formulation has no activity. It does not interfere with the activity

of the formulation.

CONCLUSION

The present work involves the design, development, in vitro and in vivo evaluation of Film

forming gel of Diclofenac Diethylamine for the treatment of local pain. The gel was

formulated with 1.5% of Hydroxy propyl methyl cellulose K100M as gelling agent and

various polymethacrylate polymers such as Eudragit E100, Eudragit S100 and Eudragit RS

100 as film forming agents.

The gel formulated using 1.5 % of hydroxyl propyl methyl cellulose and 0.5% of Eudragit E

100 had shown comparatively good results in many studies and it sustained the release of the

drug to a desired level and found to be better formulation among others.

ACKNOWLEDGEMENT

I am grateful to College of Pharmacy, Madras Medical College, Chennai, for providing

facilities for conducting my research work. I am also thankful to Kaushikh Therapeutics Pvt.

Ltd., Tirstar formulation and Saimirra Laboratories, Chennai for providing the materials for

conducting the research.


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