Page1271 Indo American Journal of Pharmaceutical Research, 2015 ISSN NO: 2231-6876 FORMULATION, DESIGN, DEVELOPMENT AND EVALUATION OF EMULGEL FOR TOPICAL DELIVERY OF MELOXICAM IN THE TREATMENT OF RHEUMATOID ARTHRITIS Wesley Z. D Souza 1, Mrs. Rajashree Gude 2. 1 Quality Assurance ( Student), Goa College of Pharmacy / Goa University, India. 2 Associate Professor Pharmaceutics Department, Goa College of Pharmacy / Goa University, India. ARTICLE INFO Article history Received 28/08/2014 Available online 02/03/2015 Keywords Meloxicam, Emulgel, Spreadibility, Extrudability, Rheumatoid Arthritis. ABSTRACT Objective: Meloxicam is a nonsteroidal anti-inflammatory drug used to relieve the symptoms of arthritis, primary dysmenorrhea, and as an analgesic. The aim of the present study was to enhance the permeation of the drug Meloxicam through the skin by formulating an Emulgel using suitable permeation enhancers. Method: Tween 20 and Span 20 were used as emulsifiers ( 2 and 4 %), Hydroxypropyl Methyl Cellulose (HPMC K4) and Carbopol 934 were used as gelling agents. The Emulgels were prepared using various combinations of oil, emulsifiers and gelling agents. Menthol ( 5 %), Clove Oil (8%), Isopropyl Myristate (5%), Dimethyl sulfoxide (5%)and Oleic Acid (1%) were used as permeation enhances. Results: Prepared Emulgels were evaluated in terms of their appearance, ph,, Extrudability, Drug Content, and In- Vitro Drug Release ( 8 Hours). The drug release profile exhibited zero order kinetics. The optimized formula was found to be formulation F9b containing highest concentration of Emulsifiers (4%) and Menthol as Permeation Enhancer. The amount of drug release from the optimal formula F9b was found to be 87.79 % after 8 Hours.Conclusion: The overall drug release from all the formulations were observed to follow zero order kinetics and the data obtained fitted well with Higuchi s equation following non- Fickian mechanism. It was thus proved from this research work that Emulgel containing Meloxicam was a promising delivery system for the treatment of Rheumatoid Arthritis. Corresponding author Wesley Z. D Souza Zeff Villa, Bamon Vaddo, Siolim, Bardez,Goa India. + 919923764537 dsouza.wesley@yahoo.in Please cite this article in press as Wesley Z. D Souza et al. Formulation, Design, Development and Evaluation of Emulgel For Topical Delivery of Meloxicam in The Treatment of Rheumatoid Arthritis. Indo American Journal of Pharm Research.2015:5(03). Copy right 2015 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Page1272 INTRODUCTION Emulgels have emerged as one of the most interesting topical delivery system as it has dual release control system i.e. gel and emulsion. The major objective behind this formulation is delivery of hydrophobic drugs to systemic circulation via skin. A unique feature of topical drug delivery is the direct accessibility of the skin as a target organ for the diagnosis and treatment. When gel and emulsion are used in combined form the dosage form are referred as Emulgel. Emulgel are having major advantages on novel vesicular systems as well as on conventional systems in various aspects. [1] Most of the hydrophobic drugs cannot be incorporated directly into the gel base because solubility act as a barrier and problem arises during the release of the drug. Emulgel helps in the incorporation of hydrophobic drugs into the oil phase and then oily globules are dispersed in aqueous phase resulting in o/w emulsion. And this emulsion can be mixed into gel base [3]. This may be proving better stability and release of drug than simply incorporating drugs into gel base. Other novel approaches like niosomes and liposomes are of nano size and due to vesicular structures may result in leakage and result in lesser entrapment efficiency. But gels due to vast network have comparatively better loading capacity [2]. The present study aims at preparing an Emulgel formulation of Meloxicam using emulsifiers and various gelling agents along with the use of permeation enhancers. Tween20 and San20 were used as emulsifiers ( 2 and 4 %) and gelling agents ( HPMC K4 and Carbopol 934). The oily phase used comprised of liquid paraffin (5 and 7.5% )and Cetyl Alcohol (5 %). Permeation enhancers used included DMSO (5%), Menthol (5%), Clove Oil (8%), Isopropyl Myristate(5%), and Oleic Acid (1%) which were used so as to enhance the drug release profile of the drug. MATERIALS AND METHODS Materials Meloxicam was procured from Unichem Pvt. Ltd. Pilerne Goa, Carbopol 934 was obtained from Loba chemicals Mumbai. HPMCK4M was obtained as gift sample from Colorcon Asia Pvt. Ltd. Goa. Isopropyl Myristate was provided by Ranbaxy Pharmaceuticals Goa. A gift sample of Clove Oil was provided by Genuine Chemical Corporation Mumbai. All other chemicals were used of analytical grade and without any further chemical modification Preparation of Emulgel Different formulations were prepared using various gelling agent and penetration enhancer. The method only differed in the process of making gel in different formulations. The preparation of emulsion was same in all the formulations. The gel bases were prepared by dispersing Carbopol 934 in distilled water separately with constant stirring at a moderate speed using mechanical shaker. Formulations F1, F2, F3, F4, F5, F4a, F4b, F4c, F4d and F4e were prepared using Carbopol 934 as gelling agent whereas formulations F6, F7, F8, F9, F10, F9a, F9b, F9c, F9d and F9e were prepared by dispersing HPMC in heated distilled water (80 C), and the dispersion was cooled and left overnight. The ph of all the formulations was adjusted to 6-6.5 using tri ethanol amine (TEA). The oil phase of the emulsion was prepared by dissolving Span 20 in light liquid paraffin / Cetyl Alcohol while the aqueous phase was prepared by dissolving Tween 20 and ethanol in purified water. Methylparaben was dissolved in propylene glycol and mixed with aqueous phase. Meloxicam, being hydrophobic was dissolved in oil phase. Permeation enhancers were dissolved in the oily phase. Both the oily and aqueous phases were separately heated to 70 to 80 C, then the oily phase was added to the aqueous phase with continuous stirring until it got cooled to room temperature. The obtained emulsion was mixed with the gel in 1:1 ratio along with the addition of a few drops of glutaraldehyde followed by gentle stirring to obtain the Emulgel. [4, 5, 6] Composition of Formulations ( % w/w) Ethanol:- 2.5g, Methylparaben :- 0.03g, Purified water qs :- 100 %, Glutaraldehyde qs. Table 1 : Shows the composition of Emulgel Formulations. Formulation code Meloxicam (g) Carbopol 934 (g) HPMC (g) Liquid paraffin (g) Cetyl Alcohol (g) Span 20 (g) Tween 20 (g) F1 1 1-5 - 1.16 0.84 5 F2 1 1-7.5-1.16 0.84 5 F3 1 1-5 - 2.32 1.68 5 F4 1 1-7.5-2.32 1.68 5 F5 1 1 - - 5 0.42 1.58 5 F6 1-3.5 5-1.16 0.84 5 F7 1-3.5 7.5-1.16 0.84 5 F8 1-3.5 5-2.32 1.16 5 F9 1-3.5 7.5-2.32 1.16 5 F10 1-3.5-5 0.42 1.58 5 Formulation 4 was then modified by adding Permeation Enhancers to enhance the release of Meloxicam from Emulgel. Propylene Glycol (g)
Page1273 Table 2 : Shows the composition of Emulgels with permeation enhancers in Carbopol gel base. Formulation code F4a F4b F4c F4d F4e Meloxicam 1 1 1 1 1 Carbopol 934 1 1 1 1 1 Liquid paraffin 7.5 7.5 7.5 7.5 7.5 Span 20 2.32 2.32 2.32 2.32 2.32 Tween 20 1.68 1.68 1.68 1.68 1.68 Propylene Glycol 5 5 5 5 5 PERMEATION ENHANCERS DMSO (a) 5 - - - - Menthol (b) - 5 - - - Isopropyl Myristate (c) - - 5 - - Clove Oil (d) - - - 8 - Oleic Acid (e) - - - - 1 Formulation 9 was further modified by adding permeation enhancers to further increase the release rate of the drug. Table 3 : Shows the composition of Emulgels with permeation enhancers in HPMC gel base. Formulation code F9a F9b F9c F9d F9e Meloxicam 1 1 1 1 1 HPMC 3.5 3.5 3.5 3.5 3.5 Liquid paraffin 7.5 7.5 7.5 7.5 7.5 Span 20 2.32 2.32 2.32 2.32 2.32 Tween 20 1.68 1.68 1.68 1.68 1.68 Propylene Glycol 5 5 5 5 5 PERMEATION ENHANCER DMSO (a) 5 - - - - Menthol (b) - 5 - - - Isopropyl Myristate (c) - - 5 - - Clove Oil (d) - - - 8 - Oleic Acid (e) - - - - 1 Evaluation of Emulgel Appearance The prepared Emulgel formulations were visually inspected for colour, appearance and homogeneity. [7] ph ph is one of the most important parameters involved in the evaluation of Emulgels. The ph values has an effect on the balance of the ionized and unionized form of the drug, and ionized and unionized forms of the drug would show different penetration behavior. The ph of all the formulations was evaluated using a ph meter and the ph was measured at room temperature [8]. of the Emulgel was determined 48 hours after preparation of the Emulgel by using the wooden block and the glass slide apparatus. 1 g of the prepared Emulgel was placed between two 10 10 cm glass plates(125g each ). A weight of 25g was placed it in a pan and the time required for the upper glass plate to completely separate from the fixed glass plate was recorded. The spreadability was then calculated from the equation as under :- T Where S = L = length of the glass plate used M = weight tied to the upper slide T = time taken to separate slide completely from each other. was measured in terms of g.cm/sec. [9] S = m L
Page1274 Extrudability [10, 11] The method adopted for evaluating gel formulation for extrudability was based upon the quantity in percentage of gel extruded from lacquered aluminum collapsible tube on application of weight in grams required to extrude at least 0.5 cm ribbon of gel in 10 seconds. More quantity extruded better was extrudability. The measurement of extrudability of each formulation was in triplicate and the average values were presented. The extrudability was than calculated by using the following formula: Extrudability = Applied weight to extrude gel from tube (in gm) / Area (in cm2) Swelling Index Emulgel of known weight (1 gram) was wrapped with Aluminium Foil ( pricked with a pin to make holes ) and placed in phosphate buffer ph 7.4 for 6 hours. After 6 hours, the gels were scrapped and the wet weight of the swollen gel was determined by first blotting the gels with filter paper to remove absorbed water on surface and then it was immediately weighed on an electronic balance. The weight of the swollen gels was determined using an electronic balance [12]. The swelling index of was calculated using the following formula, Where, Sw = percentage of swelling of Emulgel Wt = the weight (g) of the gels at time t Wo = initial weight (g) of the Emulgel. Sw = [(Wt Wo) / Wo] 100 Drug Content Uniformity [13] The content uniformity of Meloxicam from the various Emulgel formulations was determined by weighing 1 g of the Emulgel formulation and extracting the drug from it using a suitable medium and finally determining the amount of Meloxicam present. 1 g of the Emulgel was transferred to a 100 ml volumetric flask and to this about 70 ml of phosphate buffer ph 7.4 was added. This mixture was then shaken for about 15 mins so as to completely extract the drug from the Emulgel. The volume was finally made up to 100 ml using Phosphate Buffer ph 7.4. The solution was filtered and then the dilution was made taking 1 ml of the filtrate and diluting to 25 ml ( dilution Factor 25). The absorbance of this solution was measured at 363 nm. Phosphate Buffer ph 7.4 was used as blank. The drug content was calculated from the following formula: Content uniformity = conc in mcg/ml 100 Dilution Factor 1000 The percentage content uniformity is calculated by : % Content Uniformity = Practical Yield 100 Theoretical yield In-Vitro Release Studies of Prepared Meloxicam Emulgel Formulations [14] Cellophane membrane previously soaked in the respective dissolution medium overnight was used as the permeation membrane. 200 ml of Phosphate buffer ph 7.4 was placed in a beaker ( receptor compartment). An accurately weighed quantity ( 1 g )of the formulated Emulgel was then uniformly spread on the cellophane membrane (donor compartment) and this membrane was tied to the diffusion tube ( a hollow tube open on both sides ). One side of the cellophane membrane was kept in contact with the medium ( Phosphate Buffer ph 7.4. The medium was constantly agitated using a magnetic stirrer and the temperature was maintained at a constant of 37 ± 1 C throughout the operation. Samples of 10 ml volume were then withdrawn from the receptor compartment at intervals of 1 hour over a period of 8 hours and the amount withdrawn was replaced with fresh volume of the medium. The samples withdrawn were then anaysed for the amount of Meloxicam released by UV spectrophotometric method by measuring the absorbance of the samples at 363 nm against Phosphate Buffer p H 7.4 taken as blank. Stability Studies [15, 16, 17] Stability of the drug has been defined as the ability of a particular formulation in a specific container to remain within its physical, chemical, therapeutic and toxicological specification. Stability studies were performed on the optimal Formulation F9 b which was subjected to 3 different storage conditions : 5 C ± 2, 45 C and room temperature at 75 % RH for a period of 2 months. The samples were evaluated physically for their appearance (color and odour) and also checked for the drug release, drug content and ph.
Page1275 RESULTS Appearance The prepared Emulgels were yellow in color free from grittiness and had good consistency. Table 4 : shows the appearance characteristics of the Emulgels. Formulation Color Grittiness Consistency Formulation Color Grittiness Consistency F1 Yellow - ++ F4a Yellow - ++ F2 Yellow - ++ F4b Yellow - ++ F3 Yellow - +++ F4c Yellow - +++ F4 Yellow - +++ F4d Yellow - ++ F5 Yellow - +++ F4e Yellow - ++ F6 Yellow - ++ F9a Yellow - +++ F7 Yellow - +++ F9b Yellow - +++ F8 Yellow - +++ F9c Yellow - +++ F9 Yellow - +++ F9d Yellow - ++ F10 Yellow - +++ F9e Yellow - +++ PH The ph of all the formulations was found to range between 6.31±0.04 to 6.68±0.04 which is within the tolerable ph range for the skin. Table 5 : Table indicating ph values of prepared Emulgel Formulations. Formulation p H Formulation p H Formulation p H Formulation p H F1 6.46 ± 0.03 F6 6.68 ± 0.04 F4a 6.62±0.04 F9a 6.36 ± 0.03 F2 6.33 ± 0.013 F7 6.52 ± 0.08 F4b 6.61±0.023 F9b 6.42± 0.05 F3 6.40 ± 0.08 F8 6.32 ± 0.05 F4c 6.31±0.04 F9c 6.44 ± 0.02 F4 6.52 ± 0.03 F9 6.50 ± 0.03 F4d 6.38±0.02 F9d 6.42 ± 0.02 F5 6.38 ± 0.023 F10 6.54 ±0.02 F4e 6.56±0.034 F9e 6.42 ±0.03 Studies Emulgels prepared from carbopol used as a gelling agent exhibited spreadability values ranging from 11.11 to 16.12 g.cm/s and HPMC Emulgel exhibited values ranging from 16.66 to 31.25 g.cm/s. Since the spreadability values obtained were higher in case of HPMC Emulgels it indicates that they have better spreadability as compared to Carbopol Emulgels. Formulat-ion Value Table 6 : Table indicating Studies Values. Formulation Value Formulation Value Formulation Value F1 12.5±1.24 F6 20.83±2.8 F4a 16.12±3.7 F9a 31.25±5.3 F2 13.51±3.4 F7 22.72±3.7 F4b 14.49±1.9 F9b 26.31±2.3 F3 11.36±2.4 F8 19.23±2.4 F4c 15.62±2.8 F9c 25.2±1.5 F4 12.5±1.6 F9 22.72±2.1 F4d 16.66±2.2 F9d 29.41±4.1 F5 11.11±2.7 F10 16.66±1.5 F4e 14.70±4.2 F9e 27.77±3.2 Extrudability Test The extrudability was determined as per the method mentioned using a weight of 20 gms most of the gels exhibited excellent extrudability characteristics. ( + fair, ++ Average, +++ Excellent ). Table 7 : Table indicating Extrudability results. Formulation Extrudability Formulation Extrudability Formulation Extrudability Formulation Extrudability F1 + F6 ++ F4a ++ F9a +++ F2 ++ F7 ++ F4b ++ F9b +++ F3 + F8 ++ F4c ++ F9c +++ F4 + F9 ++ F4d ++ F9d +++ F5 + F10 ++ F4e ++ F9e +++
Page1276 Swelling Index Table 8 : Table exhibiting Swelling Index values of the prepared Emulgels. Formulation Swelling Formulation Swelling Formulation Swelling Formulation Swelling Index Index Index Index F1 32.56% F6 40.5% F4a 37.29% F9a 44.82% F2 27.58% F7 42.29% F4b 31.5% F9b 48.23% F3 33.7% F8 46.34% F4c 34.33% F9c 45.9% F4 36.2% F9 44.82% F4d 31.90% F9d 40.12% F5 28.3% F10 38.3% F4e 33.23% F9e 42.7% Drug Content Uniformity in Emulgel The drug content ranged from 9.818 to 10.2 mg of Meloxicam in the Prepared Emulgel Formulations. Table 9 : Table indicating Drug Content Uniformity in prepared Emulgel Formulations. Formulation code Content Formulation code Content Formulation code Content Formulation code Content F1 9.818 F6 10.05 F4a 10.09 F9a 9.94 F2 9.96 F7 10.14 F4b 10.16 F9b 10.2 F3 10.01 F8 10.01 F4c 10.13 F9c 9.87 F4 10.04 F9 9.836 F4d 10.16 F9d 9.94 F5 10.2 F10 9.85 F4e 9.95 F9e 10.04 In vitro Cumulative Drug Release Cumulative Drug Release of all formulations has been shown in table 10 and 11. Table 10: Table indicating % Cumulative Drug Release of formulations F1 to F10. Time in Hrs F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 1 11.48 14.24 15.43 14.93 15.05 17.80 18.21 18.63 18.55 18.01 2 18.92 24.73 25.38 24.27 27.60 27.93 26.6 25.13 26.54 22.96 3 26.03 31.93 33.10 32.23 34.72 33.32 33.13 32.07 32.94 29.64 4 35.25 42.32 43.17 41.91 48.34 42.11 40.81 39.66 42.36 36.28 5 41.11 46.17 46.87 46.84 51.40 47.83 46.58 46.20 47.80 44.26 6 48.14 53.76 54.85 54.47 55.72 57.16 55.40 54.96 57.85 47.73 7 53.40 57.86 58.42 58.54 56.71 64.11 60.53 63.24 65.51 56.18 8 58.37 61.86 64.17 62.76 59.07 68.21 66.23 68.40 70.09 65.41 Table 11: Table indicating % Cumulative Drug Release of formulations F4a, F4b, F4c, F4d, F4e F9a, F9b, F9c, F9d and F9e. Time in Hrs F4a F4b F4c F4d F4e F9a F9b F9c F9d F9e 1 22.47 21.33 16.83 18.68 19.8 21.1 24.21 20.96 24.62 28.97 2 29.31 29.01 28.28 28.31 28.68 30.69 33.72 29.5 29.99 38.75 3 39.29 36.5 37.54 32.67 34.32 37.14 45.61 36.4 40.42 48.89 4 48.03 46.23 39.95 39.90 40.99 45.77 53.92 45.14 50.11 60.66 5 55.44 53.73 48.03 50.85 47.07 54.40 59.10 57.64 57.87 68.27 6 60.55 62.81 56.17 58.26 54.21 67.85 71.12 62.43 66.32 75.60 7 64.74 69.91 61.67 62.91 62.30 72.37 81.21 70.88 73.23 76.96 8 70.97 78.32 68.67 67.57 71.63 83.77 87.79 73.36 78.61 78.88
Page1277 % Cumulative Drug Release % Cumulative Drug Release 80 70 60 50 40 30 20 10 0 0 5 10 Time in Hours F1 F2 F3 F4 F5 F6 F7 F8 F9 Fig 1: It shows % Cumulative Drug Release of formulations F1 to F10. 100 90 80 70 60 50 40 30 20 10 0 0 5 10 Time in Hours F4a F4b F4c F4d F4e F9a F9b F9c F9d Fig 2: It shows % Cumulative Drug Release of formulations F4a, F4b, F4c, F4d, F4e F9a, F9b, F9c, F9d and F9e. Stability Studies Stability studies were carried out for a period of 2 months on the optimal formula wherein samples were evaluated after 15, 30, 45 and 60 days. After the stability storage period it was observed that there were minute changes in the ph, drug content and release profile of the drug from the Emulgel.
Page1278 Table 12: Table indicating Stability Studies data. Formulation Time in Days Cumulative Drug ph Drug Content (mg) Release after 8 hours. RT:- 85.06 % 6.32 9.96 F9b 15 5 ⁰C :- 84.47 % 6.21 10.03 45⁰ C:- 84.14 % 6.18 9.94 RT:- 84.21 % 6.15 9.82 F9b 30 5 ⁰C :- 82.18 % 6.24 9.76 45⁰ C:-83.6 % 6.38 10.23 RT:- 81.9 % 6.21 9.75 F9b 45 5 ⁰C :- 80.2 5 6.14 10.01 45⁰ C:- 79.2 % 6.37 10.4 RT:- 78.3 % 6.2 10.2 F9b 60 5 ⁰C :- 76.4 % 6.15 10.32 45⁰ C:- 74.9 % 6.28 9.98 Regression studies data for optimal formulation. Table 13: Table indicating Regression analysis data. Formulation Zero Order First Order Higuchi Plot Erosion Plot F9b 0.994 0.943 0.982 0.987 CONCLUSION The study revolved around the formulation of Emulgel containing Meloxicam for topical delivery of the drug. Emulgel are formulated with an aim to enhance the permeation of poorly water soluble drugs within the body. A set of 20 different Emulgel formulation batches were devised (with and without the use of permeation enhancers). These Emulgel formulations were then evaluated for their appearance, ph, Viscosity,, Extrudability, Drug Content, Swelling Index and In-Vitro Drug Release profile. Cumulative % release data revealed that formulation F9b was the optimum formulation which exhibited 87.79% drug release after 8 hrs. The formulated Emulgel formulations best fitted Zero order kinetics and Higuch s model with non- Fickian Diffusion. The Erosion plot obtained also hinted that the drug release was by erosion. Stability studies were performed on the optimsed formulation for a period of 2 months wherein there were no significant variations observed. It was concluded on the basis of results of evaluation that formulation containing the highest concentration of emulsifiers (4%), Menthol as permeation enhancer and HPMC K4 as the gelling agent was the optimized formulation having % cumulative drug release as 87.79% after 8 hrs. Thus Emulgels exhibit a promising future for topical delivery of Drugs. Authors Statements Competing Interests The authors declare no conflict of interest. REFERENCES 1) Prajapati M, Kumar N, Dr. Patel MR, Dr. Patel Emulgel : A Novel Approach to Topical Drug Delivery. International Journal of Universal Pharmacy and Biological Sciences 2013; 2(1) : 134-148. 2) Dhawal M. Emulgel : A Novel Approach to Topical Drug Delivery. International Journal of Pharma and Biological Sciences 2013; 4(1) : 847 856. 3) Singla V, Saini S, Joshi B and Rana A.C. Emulgel: A Novel Platform for Topical Drug Delivery. International Journal of Pharmacy and Biological Sciences 2012; 3 (1) : 485 498 4) Singla V, Saini S, Rana A.C., Singh G Development and Evaluation of Topical Emulgel of Lornoxicam using Different Polymer bases. International Pharmaceutica Scientia 2012; 2(3) : 36-44 5) Mohamad MI Optimization of Chlorphenasine Emulgel Formulation. AAPS 2004; 6 (3) : 1 6 6) Jain A, Devada P, Vyas N, Chauhan J Developemnt of Antifungal Emulsion based gel for Topical Fungal Infection. IJPRD 2011; 2 (12) : 18 22 7) Khullar R, Kumar D, Seth N, Saini S Formulation and Evaluation of Mefanamic cid Emulgel for Topical Delivery. Saudi Pharmaceuticals Journal 2012; 20 (1) : 63 67 8) Colin JP, McKean, Huggins B W ph Determination and measurement. Ministry of Environmental Province of British Coloumbia 1989; 26 27 9) Karade PG, Shah Rohit R, Chougale DD, Bhise SB Formulation and Evaluation of Celecoxib Gel. Journal of Drug Delivery and Therapeutics 2012; 2 (1) : 132 135
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