Formulation and Evaluation of Diclofenac Sodium Gels Using ...

Indian J.Pharm. Educ. Res. 44(4), Oct - Dec, 2010Formulation and Evaluation of Diclofenac Sodium Gels UsingSodium Carboxymethyl Hydroxypropyl Guar and HydroxypropylMethylcelluloseSwamy N.G.N.*, Mazhar Pasha and Zaheer AbbasDepartment of Pharmaceutics, Government College of Pharmacy, Bangalore – 560 027*Author for Correspondence: ngnswami@yahoo.co.inAbstractIn this investigation, Diclofenac sodium gels were formulated employing Sodium carboxymethyl hydroxypropyl guarand Hydroxypropyl methylcellulose as gelling agents. Hydroxypropyl methylcellulose (K4M) was employed at 5 %w/w strength whereas, Sodium carboxymethyl hydroxypropyl guar formed a gel at 2.5 % w/w strength, gels weresubjected for various evaluation tests such as pH measurement, assay, stability study, rheological evaluation, and invitrorelease studies across hairless albino rat skin. Gels formulated using Sodium carboxymethyl hydroxypropylguar displayed a pH value of 7.48, whereas Hydroxypropyl methylcellulose gels revealed a pH value of 7.26. Stabilitystudies revealed good physical stability and assay values did not show much variation from the initial drug content in0 0both the cases with formulations stored at 25 C, 60% RH and 40 C, 70% RH for six months. Hydroxypropylmethylcellulose at 5% w/w strength revealed shear-thinning property, whereas Sodium carboxymethyl hydroxypropylguar at 2.5 % w/w strength revealed both pseudoplastic and thixotropic property. The rheological data were fitted intoMartin and Co’-worker equation to obtain a linear relationship and from the linear curve fittings, the 'N'- values; thepossible flow indices for pseudoplasticity were arrived at. A 'N' value of 4.65 was obtained for Sodium carboxymethylhydroxypropyl guar gels in contrast to a 'N' value of 1.52 in case of Hydroxypropyl methylcellulose gels. Whensubjected to In-vitro release studies across hairless albino rat skin, Sodium carboxymethyl hydroxypropyl guar basedgels revealed a % cumulative drug release of 25.66 in contrast to a % cumulative drug release of 20.80 in case ofHydroxypropyl methylcellulose based gels at the end of 6 hours. From the above observations, Sodiumcarboxymethyl hydroxypropyl guar seems to be a promising pharmaceutical adjuvant in the formulation ofDiclofenac sodium gels.Keywords: Diclofenac sodium gels, Sodium carboxymethyl hydroxypropyl guar, Hydroxypropyl methylcellulose,Rheological evaluation, Pseudoplasticity indexINTRODUCTION1Gels consist of liquids gelled by means of suitablegelling agents. Gels comprise of homogenouspreparations intended to be applied to the skin or certainmucous membranes; Gels may contain auxiliarysubstances such as antimicrobial preservatives,2antioxidant and stabilizers. The active ingredients in gelbased formulations are better percutaneously absorbedthan cream or ointment bases. A gel based formulationcan hold/contain more percentage of ethyl alcohol thanointment and creams. A number of polymers are used toprovide the structural network for gel system. Thepolymers are used in the concentration range of 0.5 toIndian Journal of Pharmaceutical Education and ResearchReceived on 6/4/2010; Modified on 23/7/2010Accepted on 28/8/2010 © APTI All rights reserved15%. In the present study, two polymers have been usedas gelling agents namely Sodium carboxy methyl3hydroxy Propyl guar (NaCMHPG) and hydroxy Propyl4methyl cellulose (HPMC) .5Diclofenac Sodium , a non steroidal antiinflammatoryagent is frequently prescribed for the long term treatmentof rheumatoid arthritis, osteoarthritis and ankylosing6spondylitis. The drug undergoes substantial first passeffect and only 50% of drug is available systemically.Further, the drug is known to induce ulceration andbleeding of the intestinal wall. To avoid the adverseeffect, alternate routes of administration have been tried7, 8by investigators . Delivery of Diclofenac sodium via5skin offers the potential advantage of bypassing hepato310

Indian J.Pharm. Educ. Res. 44(4), Oct - Dec, 2010gastrointestinal first pass metabolism associated withoral administration. The drug is prescribed in a dose of75 to 150 mg daily in divided doses by oral route. Thedosing frequency can be reduced if patients are instructedto use topical products along with the conventionaltablets.Materials and method:Materials: Diclofenac sodium was obtained as a giftsample from Bangalore Pharmaceutical and ResearchLaboratories. NaCMHPG used in the formulation wasprepared in our laboratory The polymer revealed a DS of9 10value of 1.5 and sodium content of 10.44%w/w. HPMCwas obtained from Zydus cadila pharmaceuticals limitedBangalore; Propylene glycol, sodium methyl parabenand sodium Propyl paraben were obtained from Nicechemicals.MethodA quantity of HPMC (gel-I)/NaCMHPG (gel-II) asspecified in table-1 were dispersed separately in about 40ml of deionised water. In case of HPMC dispersion, it was11warmed to form a gel . Diclofenac sodium was dispersedin 40 ml of deionised water. To the drug solution,propylene glycol and preservatives (sodium salts ofmethyl paraben and Propyl paraben) were added andstirred until the solutioning was effected. The drug,humectant and preservatives solution was added to thepolymer solution in small increments with constantstirring using a propeller mixer. Stirring speed wasadjusted to minimize the air entrapment in the gel anddeionised water was added to adjust the gel weight to 100grams. The agitation was continued until a uniform gelresulted. The prepared gels were filled in emptyaluminium collapsible tubes and sealed by crimping theends and preserved in a cool and dry place until furtheruse.EVALUATION OF DICLOFENAC SODIUM GELSThe Diclofenac sodium gels were subjected for extensiverheological evaluation, drug content estimation, pHmeasurement, stability study and drug release studyacross hairless albino rat skin.Rheological studies: Brookfield synchrolectric12 13viscometer , analog model was used for the studies.First, the spindle was dipped into the gel till the notch onthe spindle touched the gel surface.100 g each of gel I andgel II was used in the study. The spindle no.7 was selectedbased on the viscosity of the gel for both theformulations. This spindle was rotated at 0.5 rpm, anddial reading was recorded until 2 consecutive similarreadings were obtained. Similarly dial readings wererecorded at 1.0, 2.5, 5.0, 10.0, 20.0, and 50.0 and up to100 rpm. As soon the sample was sheared at the highestrate, another set of dial readings were recorded byreducing the spindle rotation in the decreasing order tothe pool the data on the down curve. Rheograms wereconstructed by plotting the dial readings on the X-axisand rpm values along the Y-axis. Rheological data werepooled for (i) polymer dispersion in preservative solution(ii) dispersion of polymer and drug in preservativesolution (iii) dispersion of polymer and humectant inpreservative solution (iv) all together.Drug content estimation: An accurately weighed 1 gmquantity of the gel was transferred into a 250ml stopperedvolumetric flask and shaken vigorously with 2x25 mlquantity of methanol to extract the drug. The contentswere filtered into a 50 ml volumetric flask and volumewas made up to the mark with methanol. From the abovesolution, 0.5 ml was pipetted in to a 25 ml volumetricflask and volume was made up to 25 ml with methanol.Finally, the UV absorbance of the resulting solution wasmeasured at 280 nm against the blank solution ofmethanol.14Diclofenac Sodium obeys Lambert's beers law in theconcentration range of 2 to 16 µg/ml. A calibration curvewas constructed which revealed a slope value of 0.0421and intercept value of 0.0025. These values were used infinding the drug content in the formulation afterextracting the drug in suitable dilutions and recording theabsorbance at 280 nm.15,16pH measurement: The pH measurement was carriedout by using a calibrated digital type pH meter by dippingthe glass electrode and the reference electrodecompletely into the gel system so as to cover theelectrodes.17In-vitro release studies: The hairless albino rat skinobtained from the discards of the animal sacrifice at thepharmacology department in the college was used. The18skin was soaked in 0.32 N ammonium hydroxidesolution for 30 to 35 minutes to remove subcutaneous fatand hair. The skin was rinsed well with saline followed bydistilled water.311

Indian J.Pharm. Educ. Res. 44(4), Oct - Dec, 201019Franz diffusion cell was used for permeability study: 1 gof the gel was uniformly spread over the rat skinmembrane and tied over the donor compartment. Theskin was placed with stratum corneum facing the donorcompartment and the dermis facing the receptorcompartment containg 100ml distilled water. At hourlyintervals, 5ml of sample was withdrawn from the receptorand replaced with fresh 5ml distilled water.The 5 mlwithdrawn sample was made up to 25 ml with distilledand the absorbance was recorded at 280nm. The receptormedium was magnetically stirred for uniformdistribution and was maintained at a temperature of 37°C± 0.2°C .Stability studyStability studies for Diclofenac sodium gels were carried20out as per ICH guidelines .0 0The gel samples were stored at 25 C, 60% RH and 40 C,70% RH, in stability chambers for a period of 6 months,samples were drawn at regular interval for stabilityanalysis. At the end of 6 months assay was carried out tofind out if there is any interaction between the drug andother ingredients of the formulation upon storage.RESULTS AND DISCUSSION1%w/w Diclofenac Sodium gels were formulated usingtwo different polymers namely NaCMHPG and HPMC at2.5% w/w and 5% w/w respectively. A 5% w/wdispersion of HPMC containing 10% w/w humectant and0.2% w/w of preservatives in water revealed a viscosityof 1, 44,000 cps units when sheared at 5 rpm usingspindle-7 in Brookfield synchrolectric viscometer RVTmake, analog model in contrast to a value of 1,52,000 cpsunits for a 2.5% w/w NaCMHPG dispersion of similarcomposition when sheared under similar conditions.From the rheological investigations, it is observed thatwhile HPMC gels have revealed only shear thinningproperty, NaCMHPG gels have revealed both thixotropicas well as pseudoplastic behavior. The rheologicalbehavior for the gel samples is depicted in fig 1. Further,based on Martin and Co’-worker equation, the21rheological data are transposed to a linear plot byconstruction of a log- log graph to obtain the value for'N'. Such plots were constructed to know the influence ofdrug, humectant and the preservative on variations in 'N'value in the system. The NaCMHPG gels by virtue if itshigher intrinsic viscosity and improved interaction coefficienthave revealed a higher value of 'N' compared toHPMC gels. The log-log plot for NaCMHPG and HPMCgels is shown in fig 2 .The N values for HPMC based gels(gel-1) varied between 1.49 to 1.52, whereas, forNaCMHPG based gels (gel-2), the value of variedbetween 4.52 - 4.65. This is indicative of the fact that, thecontributions by the components towards the N valuesare insignificant.Gels prepared using NaCMHPG had a pH value 7.48whereas HPMC based gels revealed a pH of 7.46. Thegels which have pH value in the range of 5.5 to 7.5 aremost ideal, as they near the pH of the skin and do notcause irritation.In-vitro release study for the drug across hairless albinorat skin with NaCMHPG based gels revealed a % CDR of25.66, while HPMC based gels revealed a % CDR of2220.80 at the end of 6 hrs .The drug release pattern isdepicted in fig 3. The release of drug from both the23formulations followed zero-order kinetics . Stabilitystudies for gels revealed good physical stability, color andconsistency for both the formulations. The drug contentremained the same as was seen in the gel formulationsbefore being subjected for the stability study.CONCLUSIONA 1% w/w gel of Diclofenac sodium in a 5% w/wdispersion of HPMC gel base revealed shear thinningqualities only, whereas in a gel base of 2.5% w/wNaCMHPG, both pseudoplastic as well as thixotropicproperties were observed. The NaCMHPG basedDiclofenac Sodium gels with a higher 'N' value areexpected to have better ease of application. Further, betterspreadability is expected in case of NaCMHPG basedgels. Since NaCMHPG in half the strength has displayedbetter performance in respect to the drug release , incontrast to HPMC based gels, it can be concluded thatNaCMHPG is a better gelling agent in the formulation ofDiclofenac Sodium gels.ACKNOWLEDGEMENTThe authors wish to thank(I) Messrs Juggat Pharma Pvt. Ltd, Kumbalagodu,Bangalore for sponsoring gift sample of propylene oxide(II) Bangalore Pharmaceutical Research Laboratories forsponsoring gift sample of Diclofenac Sodium.(III)The Principal, Govt. College of Pharmacy forpermitting to avail the research facilities in the college.312

Indian J.Pharm. Educ. Res. 44(4), Oct - Dec, 2010Table-1: Composition of gelsIngredients Gel-I Gel-IIDiclofenac sodium 1.0 gm 1.0 gmHPMC 5.0 gm -NaCMHPG - 2.5 gmPropylene glycol 10 gm 10 gmMethyl paraben 0.18 gm 0.18 gmPropyl paraben 0.02 gm 0.02 gmPurified water QS 100 gm 100 gmFig 1: Rheogram of HPMC gels (5% w/w) andNaCMHPG gels (2.5% w/w) containing Drug (1% w/w),Humectant (10% w/w) and preservative (0.2% w/w) .Fig 2: Log Rheogram of HPMC gels (5% w/w) andNaCMHPG gels (2.5% w/w) containing Drug (1% w/w),Humectant (10% w/w) and preservative (0.2% w/w) )Comparative Release Rate Profile for Diclofenac Sodium fromGel I and Gel II Prepared using NaCMHPG and HPMC% drug retained in the gelFig 3: Comparative in-vitro release studies of Diclofenacgels formulated using NaCMHPG and HPMC313

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