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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
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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.
www.wjpr.net Vol 5, Issue 11, 2016.
973
Ahmed. World Journal of Pharmaceutical Research
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.