development and evaluation of nsaid topical gel …

www.wjpr.net Vol 5, Issue 11, 2016.

962

Ahmed. World Journal of Pharmaceutical Research

DEVELOPMENT AND EVALUATION OF NSAID TOPICAL GEL

USING DIFFERENT PERMEATION ENHANCERS

Md. Mazher Ahmed*

Department of Pharmaceutics, Luqman College of Pharmacy, Gulbarga, India.

ABSTRACT

Nimesulide is a COX-2 specific, non-steroidal mitigating drug

(NSAID) with analgesic and antipyretic properties. Topical gel

formulations of nimesulide were produced by utilizing gel framing

specialist like Carbopol 934P. Tween 80, Eucalyptus oil, Almond oil

and Eudragit were utilized as entrance enhancers. Glycerin was utilized

as a humectant. The gel definitions were characterized by IR study

recommended that the plan arranged is a physical blend. The readied

gel definitions were assessed for drug content, pH and rheological

parameters like viscosity, spreadability and extrudability. The percent

release of nimesulide from plain gel was moderate when contrasted

with other medication stacked gel definitions. The plan (F11) demonstrated most extreme

percent discharge (99.56%). The Gael plans were assessed for in vitro penetration study

about the detailing, containing 2% Eudragit demonstrated most astounding saturation

contrasted with different definitions. Stability studies of selected gel formulations were

performed to assure that the formulation retains its activity. The formulations were found to

be stable. Hence, from the overall study it can be concluded that nimesulide gels along with

different penetration enhancers can be prepared to improve the permeation through the skin

surface.

KEYWORDS: Nimesulide; Eudragit; Eucalyptus oil; Almond oil; Tween 80, Penetration

enhancers.

INTRODUCTION

Drug delivery based on gelling system is gaining popularity day by day. According to a

review article oleogels, hydrogels proniosomal gels, emulgels, bigels, aerogels are in constant

research for its application as transdermal drug delivery system.[1]

Apart from that other

World Journal of Pharmaceutical Research SJIF Impact Factor 6.805

Volume 5, Issue 11, 962-973. Research Article ISSN 2277– 7105

*Corresponding Author

Md. Mazher Ahmed

Department of

Pharmaceutics, Luqman

College of Pharmacy,

Gulbarga, India.

Article Received on

28 August. 2016,

Revised on 18 Sept. 2016,

Accepted on 08 Oct. 2016

DOI: 10.20959/wjpr201611-7234


963


forms of gelling system like in situ.[2]

gels are exploited by different researchers to evaluate

its advantage over conventional delivery.

Drug delivery to the skin is an effective and targeted therapy for local dermatological

disorders. This route of drug administration is gaining popularity due to its avoidance of first

pass metabolism.[3]

Many antimicrobial agents like ofloxacin and antibacterial agents like Fucidin had been

developed into the topical drug delivery system over the last decade.[3,4]

Transdermal drug delivery system gains pace over the last decade. Several drugs have been

successfully delivered by this route for both local and systemic action. However, the

transdermal drug transport is limited by the permeation characteristics of the stratum corneum

and is frequently insufficient for medical use; so many attempts of improving topical

absorption of various drugs have been performed. Enhancement of drug delivery through the

skin may come up with the following possible outcomes:

1. Improvement in the release characteristic of drug from the transdermal pharmaceutical

preparation bases.

2. Enhancement or retention in the flux of drug through the skin

3. Increase in topical or localized skin delivery or tissue targeting of drugs.

Continuous intravenous infusion (i.v. Infusions) at a programmed rate is regarded as a

superior mode of drug delivery not just to bypass the hepatic first-pass elimination, but also

to maintain a constant, prolonged and therapeutically effective drug level in the body. A

closely monitored intravenous infusion can come up with the advantage of both the direct

entry of drug into the systemic circulation as well as to control the circulating drug levels.

However, such a mode of drug delivery entails certain risks and therefore it needs

hospitalization of the patient and close medical supervision of the medication. Recently there

has been an increasing awareness that the benefit of intravenous drug infusion is close to the

transdermal drug administration through intact skin.[5]

Nimesulide is a relatively COX-2 selective, non-steroidal anti-inflammatory drug (NSAID)

with analgesic and antipyretic properties. The therapeutic effects of nimesulide are through

the targeting of key mediators of the inflammatory process such as COX-2 mediated

prostaglandins, free radicals, proteolytic enzymes and histamines. Nimesulide is approved for


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the treatment of acute pain, symptomatic treatment of osteoarthritis and primary

Dysmenorrhoea in adolescents and adults above 12 years old.[6]

Although the use of nimesulide is banned for oral administration, due to its potential for

inducing hepatotoxicity and thrombocytopenia, the use of nimesulide as topical delivery

system is still prominent in the treatment of many inflammatory conditions including

rheumatoid arthritis.

Hence, in the present work an attempt will be made to prepare the topical gel of Nimesulide

and to study the effect of various permeation enhancers on in vitro permeation of Nimesulide.

MATERIALS AND METHODS

Nimesulide was as a gift sample from Dr. Reddys lab, Hyderabad and Carbopol 934 from

Lobachem Pvt Ltd, Mumbai. Tween 80, Almond oil and Eudragit was obtained from SD

Fine Chem. Ltd. Mumbai.

Formulation of Nimesulide gel

The prepared different gel formulations contains 1% w/w of Nimesulide using carbopol 934p

as gel base according to the formula mentioned in table 1 and 2.

Table – 1: Formulation details of Nimesulide gel with different permeation enhancers

Ingredient (%w/w) F1 F2 F3 F4 F5 F6 F7 F8

Drug 1 1 1 1 1 1 1 1

Carbopol 1 1 1 1 1 1 1 1

Tween 80 - 2 - - - 1 1 1

Almond oil - - 2 - - 1 - -

Eucalyptus oil - - - 2 - - 1 -

Eudragit - - - - 2 - - 1

Methanol 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Triethanol amine Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S

Glycerine 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4

Water 43.82 43.82 43.82 43.82 43.82 43.82 43.82 43.82

Table – 2: Formulation details of Nimesulide gels with different permeation enhancers

Ingredient (%w/w) F9 F10 F11 F12 F13 F14 F15

Drug 1 1 1 1 1 1 1

Carbopol 1 1 1 1 1 1 1

Tween 80 - - - 0.5 0.5 0.5 -

Almond oil 1 1 - 0.5 - 0.5 0.5

Eucalyptus oil - 1 1 - 0.5 0.5 0.5

Eudragit 1 - 1 0.5 0.5 - 0.5


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Methanol 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Triethanol amine Q.S Q.S Q.S Q.S Q.S Q.S Q.S

Glycerine 2.4 2.4 2.4 2.4 2.4 2.4 2.4

Water 43.82 43.82 43.82 43.82 43.82 43.82 43.82

PROCEDURE

The gels were prepared by soaking 1% carbopol in 25ml of water for 24h and then neutralize

with sufficient amount of triethanolamine, mixed well with glass rod and kept for 15 minutes.

The drug was dissolved in sufficient quantity of methanol. Accurately weighed quantity of

Tween 80 was dissolved in sufficient quantity of distilled water and then added to the

neutralized carbopol with continuous stirring. Finally the drug solution was added to the

neutralized carbopol solution with continuous stirring for about an half an hour to get a

sparkling clear gel. Finally make up the volume up to 50ml with distilled water with

continuous stirring. The stirring was stopped periodically to expel the entrapped air during

the process of stirring.[4]

Same procedure is followed for other remaining formulations

containing different permeation enhancers like almond oil.

Evaluation of Nimesulide gels

1) Appearance

The readied gel details were reviewed outwardly for clarity, shading, homogeneity, nearness

of particles and filaments.

2) Determination of pH

1 gm of the gel formulation was dispersed in 10 ml of distilled water and the pH was

determined by digital pen pH meter.[7]

3) Drug content

Drug substance was resolved precisely measured amount of 10mg gel and exchanged to 100

ml volumetric flask containing 7.4 pH phosphate buffers and permitted to sonicated and

filtered, from which 1 ml of aliquot was pipette out and weakened to 10 ml. The substance of

nimesulide was dictated by utilizing Shimadzu UV-noticeable spectrophotometer at 299.5 nm

against clear. The test was completed in triplicate.[8]


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3) Rheological properties

a) Viscosity

The viscosity was determined using Brookfield LVDV-III ultra programmable rheometer.

The spindle No (CP-52) was used for the measurement. An optimum speed (2 rpm) was used

to measure the viscosity of the preparation.

b) Spreadability

Spreadability of the definitions was controlled by a mechanical assembly recommended by

Mutimer et al, which was reasonably altered in the research facility and utilized for the study.

It comprises of a wooden square which was given by a pulley toward one side. A rectangular

ground glass plate was settled on the piece. An overabundance of gels (around 2 gm) under

study was set on the lower plate. The gel was then sandwiched between lower glass plate and

another upper glass plate having the same measurements, gave the snare.

A 1 Kg weight was set on the highest point of the two plates for 5 minutes to remove air and

to give a uniform film of the gel between the plates. Overabundance of gel was scrapped off

from the edges. The upper plate was then subjected to a draw of 50 gm. With the assistance

of a string connected to the snare and the time (in sec) required by the upper plate to cover a

separation of 10 cm was noted. A shorter the time interim shows better spreadability.[4]

The spreadability was ascertained utilizing the equation: S = m.l/t.

Where S = spreadability

m = weight tide to upper side

l = length moved on the glass slide

t = time taken in seconds.

c) Extrudability

In the present study, the strategy embraced for assessing gel definition for extrudability was

based upon the amount in rate of gel expelled from tube on use of certain heap. Progressively

the amount expelled better was extrudability. The definition under study was filled in a clean,

lacquered aluminum collapsible one-ounce tube with a nasal tip of 5 mm opening. It was then

put in the middle of two glass slides and was braced. Extrudability was controlled by

measuring the measure of gels expelled through the tip when a consistent heap of 1 Kg was


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put on the slides and gels expelled was gathered and weighed. The percentage of gel extruded

was calculated and grades were allotted (+++ good, ++ fair and, + poor).[9]

4) In vitro Diffusion Study

In vitro release of Nimesulide from gel was done by using modified apparatus.

Through Cellophane Membrane[10]

The contraption comprises of barrel shaped glass tube with 14 mm inward breadth and 62

mm tallness which was opened at both end. The gels plan equal to 10 mg of nimesulide was

spread consistently on the surface of cellophane film (already absorbed refined water for

overnight) and was altered to the one end of the tube such that arrangement involves internal

circuit of the tube. The entire gathering was settled containing gel was touched (1-2 mm

profound) the surface of dispersion medium i.e., 100 ml of 7.4 pH phosphate cushion and

kept up temperature 37±2˚C. The cellophane layers go about as boundary between the gel

and 7.4 pH phosphate support. The medium were mixed utilizing attractive stirrer at 50±5

rpm. An amount of 5 ml test was pulled back from receptor liquid at the time interim of 1, 2,

3, 4, 6 and 8 hours and supplanted at every time with 7.4 pH phosphate cradle.[10]

The arrival

of medication was assessed by utilizing Shimadzu UV – noticeable spectrophotometer at

299.5 nm. The study was carried out in triplicate.

In vitro permeation studies.[11]

The pretreated stomach skin of pale skinned rats was utilized as a part of the Franz dispersion

cell. Hairs from the stomach district were precisely expelled with fine forceps. A full

thickness of skin was taken and after that trimmed to remove the greasy material. At last, the

epidermal skin was taken and inspected infinitesimally to guarantee the trustworthiness of the

SC. The readied rodent skin was put painstakingly between the contributor and receptor

compartment in the Franz dispersion cell so that the SC surface confronted the giver side. The

dynamic dissemination region was 3.14 cm2. The receptor compartment was then loaded with

12 ml phosphate support arrangement (pH, 7.4) and 1 g of the gel was put on the skin surface

in the giver compartment. The receptor medium was thermostatically controlled at 37 ± 0.2˚C

by an encompassing water coat associated with a thermostatic shower and a peristaltic pump

and attractively mixed at the speed of 500 r/min during the analysis. After utilization of the

test detailing on the benefactor side, 400 μl aliquots were gathered from the receptor side at

assigned time interims, for a 8 h period and supplanted by the same volume of new cradle to

keep up a consistent volume.[11]

The measure of nimesulide in the collector stage was


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examined by UV Spectroscopy at 299.5nm.The experiments were carried out in triplicate.

The linearity established was 0.5–20 μg/ml with y = 0.0484 x + 0.0767 with R2 = 0.9996.

Stability studies[12]

The steadiness of chose detailing was examined according to ICH guidelines. The gel plan

was pressed in holder and kept at temperature 30±2º and relative stickiness 65±5% for 3

months. Solidness Studies were completed for the medication substance, thickness, and pH of

the details.

RESULTS AND DISCUSSION

In the present study topical gels were prepared and evaluated for the effect of permeation

enhancers on topical gel of nimesulide. To enhance the penetration through rat skin

penetration enhancers like tween 80, Almond oil, Eucalyptus oil and eudragit were

incorporated in the gel formulation.

The gel formulations were characterized by FTIR study suggested that the formulations

prepared is a physical mixture; no chemical reaction took place between drug and polymer as

depicted in figure 1 and figure 2.

Fig 1: IR spectra of pure drug Nimesulide

Fig 2: IR spectra of Nimesulide + Carbopol 934 + Tween 80 + Eudragit + Almond oil +

Eucalyptus oil


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The formulated gel plans were assessed for medication substance, pH and rheological

parameters like consistency, spreadability and extrudability and results are arranged in table

3. The medication substance was found in the scope of 91.83 to 99.66% for all gel definitions

recommended uniform dissemination of Nimesulide in gels. The pH of all gel detailing was

more than 6.

Table 3: Evaluation of Nimesulide gel formulations:

Formulation code pH Drug content% Viscosity (cps) Extrudability Spreadibility gm cm/sec

F1 6.2±0.13 99.66±0.50 6829.32 +++ 21.21

F2 6.6±0.09 96.6±0.43 7600.12 +++ 12.45

F3 7.3±0.13 94.75±0.45 6158.18 +++ 15.55

F4 6.75±0.17 99.48±0.70 3246.31 ++ 28.13

F5 6.0±0.14 98.90±0.27 4646.31 +++ 20.21

F6 7.02±0.20 98.39±0.35 5767.48 +++ 16.30

F7 7.1±0.12 95.80±0.43 6012.36 +++ 14.28

F8 6.34±0.12 98.40±0.13 4983.21 ++ 19.23

F9 6.6±0.13 96.13±0.42 4524.57 +++ 17.23

F10 7.42±0.16 99.63±0.15 5087.29 +++ 14.51

F11 6.86±0.13 95.06±0.15 6820.12 +++ 20.88

F12 7.05±0.14 97.66±0.18 5832.13 +++ 17.23

F13 6.33±0.19 97.13±0.45 6888.64 +++ 20.11

F14 6.89±0.07 91.83±0.39 4712.64 +++ 22.12

F15 6.99±0.10 96.90±0.55 5820.32 +++ 18.97

(mean±SD, n=3).

Consistency is an imperative parameter for describing the gel as it influences the

spreadability, extrudability and arrival of medication. Every one of the plans indicated great

consistency between 3246.31 to 7600.12.

The gels were assessed for in vitro dissemination study utilizing cellophane film as a part of

phosphate cradle pH 7.4. The plan (F11) containing 1% nimesulide alongside 1% Eucalyptus

and 1% Eudragit demonstrated most elevated in vitro percent dispersion of nimesulide

contrasted with detailing (F1) containing alone nimesulide and different definitions

containing diverse infiltration enhancers. The results are depicted in figure 3.

The penetration data of nimesulide contained penetration enhancers through rat skin is

documented in table 4. Table 5 and table 6 demonstrate that the formulation was stable over a

period of three months.


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Fig 3: Comparative in vitro diffusion of Nimesulide from gel containing pure drug with

gels containing Nimesulide along with different penetration enhancers

(F1,F5,F9,F11,F14).

Table 4: The penetration data of nimesulide delivered from gels containing penetration

enhancers through rat skin (mean ± SD, n = 3).

S.no Enhancer Steady state flux Permeability Coefficient Lag time Enhancement

1 Control 4.59 ± 0.36 0.45 ± 0.03 0.50 ± 0.23 1.00

2 2% Eudragit 11.60 ± 1.25 1.16 ± 0.12 2.02 ± 0.35 2.53

3 2% Almond oil 6.91 ± 0.18 0.69 ± 0.02 0.33 ± 0.13 1.51

4 2% Eucalyptus oil 16.28 ± 2.57 1.62 ± 0.25 1.20 ± 0.49 3.55

5 2% Tween 80 33.06 ± 0.81 3.33 ± 0.08 1.60 ± 0.57 7.20

6 1% Eudragit 6.1±1.12 0.91±0.8 1.02±0.30 1.39

7 1% Almond oil 3.8±0.9 0.45±0.02 0.22±0.11 .098

8 1% Eucalyptus oil 9.23±1.9 1.20±0.18 0.99±0.32 1.78

9 1% Tween 80 16.8±0.49 1.76± 1.00±0.32 3.40

Table 5: Stability studies of selected nimesulide gel formulations. (F5, F9)

Time interval (months) F5 F9

pH Drug

content%

Viscosity

(cps) pH

Drug

content%

Viscosity

(cps)

0 6.0 98.9 4646.30 6.6 96.13 4524.57

1 6.0 98.7 4646.29 6.5 96.11 4524.55

2 5.98 98.7 4646.25 6.5 96.11 4524.53

3 5.98 98.6 4646.25 6.3 96.10 4524.50

Table 6: Stability studies of selected nimesulide gel formulations. (F11, F14)

F11 F14

Time interval

(months) pH

Drug

content%

Viscosity

(cps) pH

Drug

content%

Viscosity

(cps)

0 6.86 95.06 6820.12 6.89 99.83 4712.64

1 6.85 95.02 6820.09 6.86 99.80 4712.60

2 6.84 94.99 6820.05 6.85 99.79 4712.59

3 6.85 94.99 6820.00 6.88 99.80 4712.59


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CONCLUSION

Topical gel plan containing 1% nimesulide alongside various infiltration enhancers in various

concentrations was set up by utilizing carbopol 934p as gel base/brave. All out fifteen

definitions were readied.

The gels were described by FTIR study, presumed that no changeless polymer-polymer

cooperation and with polymer-drug communication has occurred. All the readied gels were in

worthy scope of drug substance, pH, and rheological parameters. The in vitro percent

dissemination study was done utilizing cellophane layer. The plan (F11) containing 1%

neomycin alongside 1% Eucalyptus oil and 1% Eudragit indicated most astounding in vitro

percent dispersion of nimesulide when contrasted with definition (F1) containing alone

nimesulide and different details containing distinctive entrance enhancers. The gel details

were assessed for in vitro saturation ponder the plan containing 2% Eudragit demonstrated

highest pervasion. Dependability investigations of chose gel details were performed to

guarantee that the plan holds its action. The formulations were observed to be steady.

Subsequently, from the overall study it can be inferred that nimesulide gels alongside various

entrance enhancers can be set up to enhance the penetration through skin surface. Topical gel

enumerating containing 1% nimesulide close by different invasion enhancers in different

concentrations were set up by using carbopol 934p as gel base/chivalrous. Total fifteen

arrangements were prepared.

The gels were depicted by FTIR study, contemplated that no ceaseless polymer-polymer

affiliation and with polymer-drug cooperation has happened. All the prepared gels were in

commendable extent of prescription substance, pH, and rheological parameters. The in vitro

percent spread study was done using cellophane film. The definition (F11) containing 1%

neomycin close by 1% Eucalyptus oil and 1% Eudragit showed most lifted in vitro percent

scattering of nimesulide when stood out from arrangement (F1) containing alone nimesulide

and diverse subtle elements containing unmistakable passageway enhancers. The gel

arrangements were evaluated for in vitro infiltration consider the itemizing containing 2%

Eudragit showed highest immersion. Security examinations of picked gel points of interest

were performed to ensure that the definition holds its development. The formulations were

seen to be relentless.


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Hence, from the overall study it can be induced that nimesulide gels nearby different

penetration enhancers can be set up to improve the pervasion through skin surface.

ACKNOWLEDGEMENT

The authors are thankful to the Management, Luqman College of pharmacy, Gulbarga,

Karnataka for providing all the necessary facilities to carry out this research work.

Conflict of Interest: None

REFRENCES

1. Khurram Rehman and Mohd Hanif Zulfakar (2014) Recent advances in gel technologies

for topical and transdermal drug delivery, Drug Development and Industrial Pharmacy,

40: 4, 433-440, DOI: 10.3109/03639045. 2013; 828: 219.

2. Jahangir MA, Kazmi I, Muheem A, Ahmad K. Development and evaluation of a novel

oro-sustained stomach specific floating in situ gelling system of Azithromycin dihydrate.

Int.J. PharmTech Res. 2014; 6(6): 1774-1782.

3. Ahmed MM, Jahangir MA, Saleem MA, Kazmi I, Bhavani PD, Muheem A. formulation

and evaluation of fucidin topical gel containing wound healing modifiers. Am. J. Pharm

Tech Res. 2015; 5(5).

4. Kota S, Jahangir MA, Ahmed MM, Kazmi I, Bhavani PD, Muheem A, Saleem MA.

Development and evaluation of oflfoxacin topical gel containing wound healing modifiers

fro natural sources. Der Pharmacia Lettre. 2015; 7(10): 226-233.

5. Chien YW. Novel Drug Delivery systems. 2nd

edition. New York: Marcel Dekker Inc;

1992. http://www.drugbank.ca/drugs/DB04743.

6. Derle DV, Sagar BSH, Kotwal RS, Ingole RD, Chauhan SS. A comparative in vitro

evaluation of Transdermal permeation of valdecoxib and its complex with HP β-

cyclodextrin from microemulsion based gel. Indian Drugs. 2006 Aug; 43(8): 625-629.

7. Panigrahi L, Ghosal SK, Snigdha pattnaik, Mahasana L and Barik BB. Effect of

permeation enhancer on the release and permeation kinetics of Lincomycin hydrocloride

gel formulation through mouse skin. Ind J Pharm Sci. 2006; 68(2): 205-211.

8. Gupta GD and Goud RS. Release rate of tenoxicam from acrypol gels. The Indian

Pharmacist. 2005; 69-75.

9. Janathanaprapap R, Stangi G. Effect of penetration enhancer on in vitro permeability of

meloxicam gels. Indian Journal of Pharmaceutical Science. 2007; 343: 26-33.

http://www.drugbank.ca/drugs/DB04743


973


10. Nikhil K, Dilip D, Jeetendra N, Kushal G. Effect of penetration enhancer on the release

and permeation kinetics of meloxicam gel formulation through rat skin. Asian J Pharm

Sci. 2008; 3(5): 193-199.

11. Tao K et al., In vivo and in vitro antibacterial activity of neomycin against plant

pathogenic bacteria. Scientific Research and Essays. 2011; 6(34): 6829-6834.

development and evaluation of nsaid topical gel …

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