IJPRD, 2014; Vol 5(12): February-2014 ( ) International Standard Serial Number

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1 IJPRD, 2014; Vol 5(12): February-2014 ( ) International Standard Serial Number FORMULATION AND EVALUATION OF MEFENAMIC ACID EMULGEL Teena Oswal* 1, Sonali Naik 1 *1 MET Institute of Pharmacy, MET Complex, Bandra Reclamation, Bandra (west), Mumbai , India. ABSTRACT Emulgels have emerged as a promising drug delivery system for the delivery of hydrophobic drugs and with their use even a hydrophobic drug can enjoy the unique properties of gels. Mefenamic acid 2-[(2,3-dimethylphenyl)amino]benzoic acid is a non-steroidal anti-inflammatory agent. Oral administration of this drug is associated with severe gastrointestinal side effects likeulceration and gastro intestinal bleeding. The solution of this problem lies in the fact that, topically applied NSAIDs are safer than oral NSAIDs. The objective of the study was to prepare an emulgel of Mefenamic Acid using different gelling agents. The emulsion was prepared and it was incorporated in different gelling agents (Carbopol 940, Carbopol 934, Lutrol 127 and Lutrol 87). Evaluation of the Mefenamic Acid emulgel was carried out for Physical appearance, ph, Spreadability, Extrudability, Rheological studies, Drug content and in vitro release. Drug content was found to be uniform in all the formulations. The results demonstrate that the release of the drug is dependent on viscosity of the polymer used. The ph range of Carbopol and Lutrol emulgels were found to be suitable for topical application. The accelerated stability studies were performed according to ICH guidelines for 3 months and the results were found to be stable in varying temperature. Correspondence to Author Teena Oswal 1 MET Institute of Pharmacy, MET Complex, Bandra Reclamation, Bandra (west), Mumbai , India. oswalteena9@gmail.com Key words: Emulgel, hydrophobic drugs, Mefenamic acid, topically applied. INRODUCTION Topical drug delivery systems allow localized administration of the drug anywhere in the body through ophthalmic, vaginal, skin and rectal routes. Drugs may be administered for localized or systemic effect. [1] Gels are created by entrapment of large amounts of aqueous or hydroalcoholic liquid in a network of colloidal solid particles, which may consist of inorganic substances, such as aluminium salts or organic polymers of natural or synthetic origin. They have a higher aqueous component that permits greater dissolution of drugs, and also permit easy migration of the drug through a vehicle that is essentially a liquid, 91

2 compared with the ointment or cream base. In spite of many advantages of gels a major limitation is in the delivery of hydrophobic drugs. So to overcome this limitation emulgels are prepared and with their use even a hydrophobic drug can enjoy the unique properties of gels. [3] In recent years, emulgel formulations have been developed for a number of drugs intended for topical or systemic action. [1] When gels and emulsions are used in combined form the dosage forms are referred as Emulgels. [2] It is prepared by mixing an oil-in-water type or water-in-oil type emulsion with a gelling agent. Direct (oil-in-water) system is used to entrap lipophilic drugs where as hydrophilic drugs are encapsulated in the reverse (water-in-oil) system. Emulgels allow dual control of dug release from the formulation, i.e. emulsion and gel. Incorporation of the emulsion into a gel enhances its stability. [1] Emulsions possess a certain degree of elegance and are easily washed off whenever desired. They also have a high ability to penetrate the skin. Emulgels have several favourable properties such as being thixotropic, greaseless, easily spreadable, easily removable, emollient, nonstaining, water-soluble, and longer shelf life, [3] bio-friendly and pleasing appearance. So Emulgels can be used as better topical drug delivery systems over present systems. Mefenamic acid 2-[(2,3-dimethylphenyl)amino]benzoic acid is a non-steroidal anti-inflammatory agent with analgesic, anti-inflammatory, and antipyretic properties. [4] The primary mechanism of action of NSAIDs is reversible inhibition of the Cyclooxygenase (COX) enzyme responsible for synthesis of prostaglandins, which are mediators of the inflammatory process. Nonsteroidal antiinflammatory drugs (NSAIDs) are among the most commonly prescribed drugs worldwide for patients [5] with rheumatic disease. However like other NSAIDs, oral administration of this drug is also associated with severe gastrointestinal side effects like- ulceration and gastro intestinal bleeding liver and kidney trouble. The solution of this problem lies in the fact that, topically applied NSAIDs are safer than oral NSAIDs. Furthermore, the transdermal route of administration has a high patient compliance, which derives from it being non-invasive and the long interval between applications. [6] Topical administration of NSAIDs offers the advantage of local, enhanced drug delivery to affected tissues with a reduced incidence of systemic adverse effects, such as peptic ulcer disease and GI haemorrhage. [5] MATERIALS & METHODS Materials: Mefenamic acid was received as a gift sample from Flamingo pharmaceuticals Ltd. (Navi-Mumbai, India). Lutrol 127 and Lutrol 87 were procured as gift sample from BASF (Navi-Mumbai, India). Carbopol 940, Carbopol 934, Propylene glycol, Tween 80, Methyl paraben, Propyl paraben, Dimethyl sulfoxide, Ethanol, Triethanolamine were obtained from S.D Fine Chemicals Ltd. (Mumbai, India). Span 80 was supplied by CDH Ltd. (Mumbai, India). Wintergreen oil was purchased from Siddhi aromatics (Mumbai, India). Methods: Preparation of emulgel Gelling agents (Carbopol940, Carbopol934, Lutrol127 and Lutrol 87) were dispersed in purified water. ph was adjusted using TEA. The oil phase of the emulsion was prepared by dissolving Span 80 in light liquid paraffin while the aqueous phase was prepared by dissolving Tween 80 in purified water. Methyl and Propyl paraben was dissolved in propylene glycol whereas drug (Mefenamic Acid) was dissolved in ethanol and DMSO and both solutions were mixed with the aqueous phase. Both the oily and aqueous phases were separately heated to 70 to 80 C; then the oily phase were added to the aqueous phase with continuous stirring until it got cooled to room temperature. Obtained emulsion was mixed with gel in 1:1 ratio with gentle stirring. [7] Various formulations prepared are given in Table no 1. 92

3 Table 1: Composition of emulgel formulations F1 F2 F3 F4 F5 F6 F7 F8 Mefenamic 1% 1% 1% 1% 1% 1% 1% 1% acid Carbopol % 1% Carbopol % 1% Lutrol % 15% - - Lutrol % 18% Light liquid 7.5% 7.5% 7.5% 7.5% 7.5% 7.5% 7.5% 7.5% paraffin Tween % 1.3% 1.3% 1.3% 1.3% 1.3% 1.3% 1.3% Span80 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% Propylene 5% 5% 5% 5% 5% 5% 5% 5% glycol Ethanol 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% DMSO 5% 5% 5% 5% 5% 5% 5% 5% Methyl 0.001% 0.001% 0.001% 0.001% 0.001% 0.001% 0.001% 0.001% paraben Propyl paraben 0.003% 0.003% 0.003% 0.003% 0.003% 0.003% 0.003% 0.003% Wintergreen 2% 2% 2% 2% 2% 2% 2% 2% oil Water Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Fourier Transform Infrared (FT-IR) Studies FTIR spectra of pure Mefenamic Acid and Gelling agents as shown Figure 1-5 were taken to assure the compatibility between the two. Infrared spectrum was taken (Shimadzu FT-IR system, Japan) by scanning the samples in KBr discs. Figure 1: Infrared Spectra of Mefenamic Acid 93

4 Figure 2: Infrared Spectra of Mefenamic Acid + Carbopol 934 Figure 3: Infrared Spectra of Mefenamic Acid + Carbopol

5 Figure 4: Infrared Spectra of Mefenamic Acid + Lutrol 87 Figure 5: Infrared Spectra of Mefenamic Acid + Lutrol 127 Evaluation Emulgels were evaluated for their physical appearance, ph, viscosity, Spreadability, drug content, in vitro diffusion studies, Extrudability. All studies were carried out in triplicate and average values were reported. Physical Appearance The prepared Emulgel formulations were inspected visually for their colour, homogeneity, consistency, grittiness and phase separation. [8] ph determination The ph of the prepared gellified emulsions was determined by using a digital ph meter. 1g of the gellified emulsion was stirred in distilled water, until a uniform dispersion was formed. It was kept aside for 2 hours. The volume was then made up to 100 ml, i.e. 1% solution of prepared formulation. Then, ph measurement was performed. [9] Spreadability Spreading coefficient was determined by apparatus suggested by Mutimer.It consists of wooden block, which is attached to a pulley at one end. Spreading coefficient was measured on the basis of Slip and Drag characteristics of Emulgel. A ground glass slide was fixed on the wooden block. An excess of Emulgel (about 2 gm) under study was placed on 95

6 this ground slide. Emulgel preparation was then sandwiched between this slide and second glass slide having same dimension as that of the fixed ground slide. The second glass slide is provided with the hook. Weight of one g was placed on the top of the two slides for 5 min to expel air and to provide a uniform film of Emulgel between the two slides. Measured quantity of weight was placed in the pan attached to the pulley with the help of hook. The time (in sec) required by the top slide to separate from ground slide was noted. A shorter interval indicates better Spreading coefficient. It is calculated by using the formula: S = M. L / T Where M = weight tied to upper slide L = length of glass slides T = time taken to separate the slides. [8] Extrudability The Extrudability test was carried out using hardness tester. A 15 gm of gel was filled in aluminum tube. The plunger was adjusted to hold the tube properly. The presence of 1kg/cm 2 was applied for 30 sec. the quantity of gel extruded was weighed. The procedure was repeated at 3 equidistance places of the tube. [10] Rheological studies Viscosity measurements were done on Brookfield viscometer by selecting suitable spindle number and rpm. 50 gm of preparation was kept in 50 ml beaker which was set till spindle groove was dipped and rpm was set and dial reading was measured after 3 minutes. From the reading obtained, viscosity was calculated by using factor. The procedure was repeated three times and observations are recorded as mean. [11] Drug Content Determination Drug concentration in Gellified Emulsion was measured by spectrophotometer. Gellified Emulsion was measured by dissolving known quantity of Gellified Emulsion in solvent (methanol) by Sonication. Absorbance was measured after suitable dilution in UV/VIS spectrophotometer. [12] In vitro release studies The in vitro drug release studies were carried out using a modified Franz diffusion (FD) cell. The formulation was applied on membrane which was placed between donor and receptor compartment of the FD cell. Phosphate buffer ph 7.4 was used as a dissolution media. The temperature of the cell was maintained at 37 C. This whole assembly was kept on a magnetic stirrer and the solution was stirred continuously using a magnetic bead. Sample (1 ml) was withdrawn at suitable time intervals and replaced with equal amounts of fresh dissolution media. Samples were analyzed spectrophotometrically at 285 nm and the cumulative % drug release was calculated. [7] Stability studies Stability studies were carried out at 40 ± 2 C/75 ±5%RH for the all the formulations for 3 months. The emulgels were stored at 40 C/75% RH in collapsible tubes for 3 months. The samples were withdrawn on 0 day and after period of 1 month, 2 months and 3 months. The samples were analyzed for physical appearance, ph and drug content [6].Stability data for all the formulations is discussed in Table no. 9. Table 2: Physicochemical characteristics of Mefenamic Acid Emulgel formulations Sr Formulation Colour Phase Grittiness Homogeneity no code separation 1 F1 White None No Homogenous 2 F2 White None No Homogenous 3 F3 White None No Homogenous 4 F4 White None No Homogenous 5 F5 White None No Homogenous 6 F6 White None No Homogenous 7 F7 White None No Homogenous 8 F8 White None No Homogenous 96

7 Table 3: ph of formulations F1- F8 Sr no Formulation code ph value 1 F1 6.53± F2 6.44± F3 6.58± F4 6.57± F5 6.30± F6 6.46± F7 6.45± F8 6.09±0.06 Table 4: Spreadability coefficient of formulations F1- F8 Sr no Formulation code M (gm) L(cm) T(sec) S=M*L/T 1 F ± F ±1.1 3 F ±1 4 F ± F ± F ± F ± F ±1.15 Table 5: Extrudability of formulations F1- F8 Sr no Formulation code Wt extruded from the tube 1 F1 0.9±0.1 2 F2 0.83± F3 0.53± F4 0.91± F5 1.16± F6 0.91± F7 0.82± F8 0.62±0.1 Table 6: Viscosities of formulations F1-F8 Sr no Formulation code Dial reading Factor Viscosity in centipoise 1 F ,000±0.5 2 F ,666.67± F ,333.33± F ,333.33± F ,000±0.5 6 F ,000±1 7 F ,08,666.7± F ,18,666.7±

8 Table 7: Drug content of formulations F1-F8 Sr no Formulation code Drug content(g) 1 F1 1.01± F2 0.99± F3 1.01± F4 1.01± F5 1.01± F6 1.01± F7 1.00± F8 1.01±0.001 Table 8: % Cumulative drug release of formulations F1-F8 % drug release Time (mins) F1 F2 F3 F4 F5 F6 F7 F Table 9: Stability study data of formulations F1-F8. Sr.no Formulation code Month Appearance ph Drug content 1 F1 0day White day White day White day White F2 0day White day White day White day White F3 0day White day White day White day White

9 4 F4 0day White day White day White day White F5 0day White day White day White day White F6 0day White day White day White day White F7 0day White day White day White day White F8 0day White day White day White RESULTS AND DISCUSSIONS Emulgel formulations were white viscous creamy preparation with a smooth homogeneous texture and glossy appearance as shown in Table no. 2. The ph value of all developed formulation of Carbopol emulgel (F1-F4) were in range of and Lutrol emulgel (F5-F8) were in range of which lies in the normal ph range of the skin as shown in Table no. 3. The value of Spreadability indicates that the gel is easily spreadable by small by small amount of shear. Spreadability of Carbopol emulgels (F1-F4) was in range of 26-32g.cm/sec and Spreadability of Lutrol emulgels (F5-F8) was in range of 7-19 g.cm/sec. indicating spredability of Carbopol 940 emulgel good as compared to Carbopol 934, Lutrol 127 and Lutrol 87 as shown in Table no. 4. The extrusion of the gel from tube is important during its application. Gels with high consistency may not extrude from tube whereas, low viscous gel may flow quickly and hence suitable consistency is required in order to extrude the gel from the tube. Extrudability of Carbopol emulgel 90day White formulation was found to be good as shown in Table no. 5. The Emulgel was rotated at 10 rpm for 10 min with spindle 07. The viscosity of the formulations increases as concentration of polymer increases as shown in Table no. 6. The drug content of the formulated Emulgel was estimated spectrophotometrically at λmax 352. The results were in the limits as shown in Table no. 7. The release profile was shown to get extended upto 6 hrs and steady release patterns were observed throughout the formulations. Carbopol 940% and Lutrol % showed best in- vitro release % and 63.11% respectively as shown in Table no. 8. CONCLUSION: Mefenamic acid was successfully incorporated into the gellified emulsion bases consisting of different gelling agents. From the present investigation that proper selection of polymers and drug is a pre requisite for designing and developing a topical 99

10 drug delivery system. The IR studies suggest that polymer selected i.e. Carbopol 940, Carbopol 934, Lutrol 87 and Lutrol 127 was found to be compatible with Mefenamic Acid. The varying concentrations of four polymers were found to affect the gel parameters like drug release, spreadability and its viscosity. Based on results of evaluation parameters and stability studies Carbopol 940 1% emulgel declared as an optimized batch. ACKNOWLEDGEMENTS: The authors are thankful to Flamingo pharmaceuticals Ltd. for gift sample of Mefenamic Acid. REFERENCES 1. Prajapati M, Patel M, Patel K, Patel N, Emulgels: A Novel Approach To Topical Drug Delivery, International Journal of Universal Pharmacy and Bio Sciences, vol 2(1), 2013, Khullar R, Saini S, Seth N, Rana AC, Emulgels: A Surrogate Approach For Topically Used Hydrophobic Drugs, International Journal of Pharmacy and Biological Sciences, Vol1(3), 2011, Jain A, SP Gautam, Gupta, Jain S, Development and characterization of Ketoconazole emulgel for topical drug delivery, Der Pharmacia Sinica, vol 1(3), 2010, /DB00784[Accessed 18 th July 2013]. 5. Heyneman C, Liday C, Wall G, Oral versus Topical Nsaids in Rheumatic Diseases A Comparison, Drugs, vol 60(3), 2000, Sheikh A, Ali S, Siddiqui A, Zahir Z, Ahmad A, Formulation development and characterization of aceclofenac gel containing linseed oil and ginger oleoresin, International Journal of PharmTech Research, vol 3(3), 2011, Khullar R, Kumar D, Seth N, Saini S, Formulation and evaluation of mefenamic acid emulgel for topical delivery, Saudi Pharmaceutical Journal, vol 20, 2012, Joshi B, Singh G, Rana AC, Saini S, Development and Characterization of Clarithromycin Emulgel for topical delivery. International Journal of Drug Development & Research, vol 4(3), 2012, Thakur N, Pratibha B, Mahant S, Rao R, Formulation and Characterization of Benzoyl Peroxide Gellified Emulsions, Scientia Pharmaceutica, vol 80, 2012, Gallagher S, Trottet L, Heard C, Ketofrofen release from permeation across and rheology of simple gel formulation that stimulate increasing dryness, International journal of pharmaceutics, vol 268, 2003, Thakur V, Prashar B, Arora S, Formulation and in vitro Evaluation of Gel for Topical Delivery of Antifungal Agent Fluconazole Using Different Penetration Enhancers, Drug Invention Today, vol 4(8), 2012, [12]. Joshi B, Singh G, Rana A.C., Saini S, Single V, Emulgel: A Comprehensive Review On The Recent Advances In Topical Drug Delivery, International journal of pharmacy, vol 2(11), 2011, ***** 100