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DEVELOPMENT OF MELOXICAM SODIUM TRANSDERMAL GEL Dr. Shashikant D. Barhate1*, Mrugendra B. Potdar1, Prashant Nerker1 Department of Pharmaceutics, Smt.Sharadchandrika Suresh Patil College of Pharmacy, Chopda- 425107, Maharastra, India. Email: mrugen.potdar@gmail.com
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Dr. Shashikant Barhate

ABSTRACT High molecular weight water soluble homopolymer of carbapol 934P resins are reported to possess very high viscosity in low concentration, transparency and film forming properties useful for gels. The meloxicam sodium gels were prepared by varying the concentration of penetration enhancers ethanol, PEG 400, menthol and azone. Selection of optimized batch was done on the basis of results of rheological studies and in-vitro drug permeation. Formulation F19 with highest amount of menthol shows highest permeability of meloxicam sodium (89.96%) at the end of 12 hrs this indicates that menthol showed significant permeation enhancement effect. The permeation rate (flux) for F19 was 260.11 g/cm2/h. Obtained R2 values for zero-order model suggests that the drug follows zero-order release kinetics. The rheological characterization of formulated systems showed that the systems exhibit non-Newtonian behavior and The optimized formulation C1 showed higher % cumulative permeation of meloxicam sodium (> 95.00%) and permeation rates (flux). Key Words: Meloxicam Sodium, Carbapol 934P, Box-Behaken design. INTRODUCTION Meloxicam sodium is a non-steroidal antiinflammatory drug with analgesic and antipyretic action. It inhibits cyclo-oxygenase with reduction in tissue production of prostaglandins such as PGE2. The aim of present study is to formulate and evaluate transdermal drug delivery of meloxicam sodium with improved bioavailability. Transdermal drug delivery systems are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and targeting the delivery of drug to a tissue. The advantages of transdermal drug delivery systems is that they maintain constant drug concentration in plasma over a prolong period of time. MATERIALS AND METHODS Material Meloxicam was received as gift from Cipla Pvt., Ltd, Kurkumbh, Maharashtra. Carbopal 934P was received from Colorcon Asia Ltd, Goa.

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Triethanolamine, Propylene glycol, Dimethyl sulfoxide, Glycerin, Menthol were received from S.D. Fine Chemicals Ltd., Mumbai. All the other solvents and chemicals used were of analytical grade. Preparation of transdermal meloxicam sodium gel The transdermal meloxicam sodium gel was prepared by dual neutralization method. Carbopol 934P resin (1%) was dispersed in water. Sodium hydroxide 1% was added in the above dispersion for the purpose of thickening. The pH was kept in the range of 5.5 to 7.0 for maximum efficiency. Then in this dispersion triethanolamine and penetration enhancers was added and mixed thoroughly. Into this glycerin was added in a slow and steady stream with constant mixing. Finally meloxicam sodium previously dissolved in propylene glycol was added and mixed thoroughly. Formulation of Box-Behnken factorial batches of meloxicam sodium gel The influence of a combination of different mechanisms of penetration enhancers on the permeation of meloxicam sodium from transdermal gels was studied by adopting BoxBehnken design. In this design content of ethanol (X1), PEG 400 (X2), menthol (X3) and azone (X4) are independent variables and used as multi-enhancers. The % cumulative drug permeated at 3h (Y1), % cumulative drug permeated at 6h (Y2), % cumulative drug permeated at 9h (Y3) and % cumulative drug permeated at 12h (Y4) are the response variables. Evaluation of transdermal meloxicam sodium gel Measurement of pH The pH of various gel formulations was determined by using digital pH meter. One gram of gel was dissolved in 100 ml distilled water

and stored for two hours. The measurement of pH of each formulation was done in triplicate and average values are calculated. Spreadability One of the criteria for a gel to meet the ideal quantities is that it should possess good spreadability. It is the term expressed to denote the extent of area to which gel readily spreads on application to skin or affected part. The therapeutic efficacy of a formulation also depends upon its spreading value. Spreadability is expressed in terms of time in seconds taken by two slides to slip off from gel and placed in between the slides under the direction of certain load. Lesser the time taken for separation of two slides, better the spreadability. It is calculated by using the formulaS=MxL/T Where, M is the weight tied to upper slide, L is the length of glass slides and T is the time taken to separate the slides. Drug content 1 g of the prepared meloxicam sodium transdermal gel was mixed with 100 ml of propylene glycol/ phosphate buffer pH 7.4. The solution was filtered through 0. 45 m membrane filter and analyzed at 363 nm and the drug content was caculated. In-vitro skin permeation and release kinetics The extent and rate of skin permeation of meloxicam sodium from gels were determined using a Franz-diffusion cell. The freshly excised hairless rat abdominal skin was mounted on the receptor compartment with the stratum corneum side facing upwards into the donor compartment and the dermal side facing downwards into the receptor compartment. The donor cell was filled with 1 g of 1% meloxicam gel and occluded by liquid paraffin. The receptor compartment was filled with propylene glycol/ phosphate buffer pH 7.4. The temperature of the receptor compartment was maintained at 370.5 0C by circulating hot water through the jacket of 2

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Franz-diffusion cell. The samples were removed at predetermined intervals and analyzed at 363 nm on UV/VIS spectrophotometer. The data obtained from in-vitro permeation study of factorial formulations of transdermal meloxicam sodium gel was fitted to various kinetic models to determine the kinetics of drug release. Rheological studies Rheological studies were carried out on Brookfield LVDV-III ultra viscometer using small sample adopter and SCW-16 spindle. The choice of accessories was based upon the requirement of small sample of meloxicam sodium gel. The data at 0.3, 0.6 and 0.9 RPM was accumulated with respect to % torque, viscosity, shear stress and shear rate at 25 0C for characterization of the prepared systems. Data analysis and optimization The formulation variables of all model formulations were treated by Design-Expert software. Statistical analysis including stepwise linear regression and response surface analysis were conduced. The significant terms (p<0.005) were chosen for final equations. The best fitting mathematical model was selected based on the comparisons of several statistical parameters including multiple correlation coefficient (R2), and adjusted multiple correlation coefficient (adjusted R2) and PRESS proved by DesignExpert software. A numerical optimization methodology based on the response surface methodology was utilized for optimization. RESULT AND DISCUSSION The formulated Box-Behnken design formulation of meloxicam sodium gel showed pH between 5.62 and 7.00 (average 6.2 pH), spreadability between 17.08 and 28.83 (average spreadability 25.95 gm.cm/sec) and drug content between 97.26 and 99.99 % (average drug content 98.46 %). Thus all the parameters of factorial design formulations of meloxicam sodium gel were found to be

practically within limits.The in-vitro permeation studies of factorial formulations of meloxicam sodium gel were performed on freshly excised rat abdominal skin. The results of these studies showed wide variations in permeation profiles of factorial formulations, this could be due to different enhancer combination with different enhancement effects on drug permeation. The formulation F19 showed highest permeation of meloxicam sodium (89.96 %) at the end of 12 h, whereas formulation F10 showed lowest permeation (66.87 %) at the end of 12 h. The formulation F10 contains ehanol (20%), PEG 400 (20 %), menthol (2 %) and azone (2 %) as penetration enhancers. The formulation F19 contains ehanol (20%), PEG 400 (15 %), menthol (6 %) and azone (1 %) as penetration enhancers. This indicated that menthol at higher levels have significant effect on permeation of meloxicam sodium through rat skin. This assumption was proved by the higher permeation rate (flux) values of formulation F19 and F10. The Formulation F19 and F10 showed a flux value of 246.10 and 160.15 g/cm2/h. The obtained R2 values for zero-order model reflect that the drug from gels follows zero-order release kinetics. The generated data of shear stress (the force per unit area required to move a material), shear rate (the velocity gradient in a flowing matrial) and viscosity of factorial formulations of transdermal meloxicam sodium gel fitted in power law model. On the basis of coefficient of fit, power law is the best and appropriate model to represent the viscosity of factorial formulations of meloxicam sodium gel. The fluidity can be dictated by flow index and rigidity by consistency; hence flow index can be taken as an indicator of fluidity and consistency as a rigidity of the system. The results of rheological studies indicated that the factorial formulations were non-Newtonian systems because as shear rate changes the formulations showed change in the viscosity. In order to obtain composition for an optimal formulation with fewer experimental trials and quantify the 3

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ISSN 0974 9446

effect of these enhancers, a numerical optimization technique was used. Based on the results of evaluation studies of factorial formulations desired constraints were set and the grid search was performed over the experimental domain to extract the optimum formulation. The generated formulations C1 and C2 were prepared. The in-vitro permeation study showed identical permeation profile for C1 and C2. In comparison with the best factorial formulation F19, the optimal formulations showed higher percentage cumulative permeation of meloxicam sodium (> 95.00%). The permeation rate (flux) for C1 and C2 was 260.11 and 161.00 g/cm2/h, respectively. CONCLUSION The transdermal meloxicam sodium gel was prepared by utilizing Box-Behnken factorial design by using carbopol 934P and penetration enhancer mixture containing ethanol, PEG 400, menthol and azone. The results of in-vitro skin permeation studies showed highest permeation of meloxicam sodium from factorial formulation F19. The release of meloxicam sodium follows zero-order release kinetics. The rheological characterization of formulated systems showed that the systems exhibit non-Newtonian behavior and The optimized formulation C1 showed higher % cumulative permeation of meloxicam sodium (> 95.00%) and permeation rates (flux). ACKNOWLEDGEMENTS The authors are thankful to Dr. M. M. Patel, Principal Institute of Pharmacy, Kalol, Gujarat

for their guidance and Cipla Pvt.Ltd., Kurkumbh for providing gift sample of meloxicam sodium. REFERENCES: 1. Hamed E, Sakar A. Application of multiple response optimization technique to extended release formulations design. 2001; J. Control Release. 73:329-338 2. Mayer,R.H. Response surface methodology: In process and product optimization using designed experiments. 1995, Wileys, NY. 3. Chang, J.S.In vitro evaluation of meloxicam permeation using response surface methodology. J. Food Drug Anal. 2006; 14:236241. 4. Morimoto, Y, Sugibayashi. A new enhancercoenhancer system to increase skin permeation of morphine hydrochloride in vitro. Int. J. Pharm. 1993; 91:9-14. 5. Gupta, S.K. Comparision of analgesic and anti- inflammatory activity of meloxicam gel with diclofenac and piroxicam gels in animal models: pharmacokinetic parameters after topical application. Skin Pharmacol. Appl. Skin Physiol. 2002; 15:105-111. 6. Panigrahi. L. S.K. Effect of permeation enhancers on the release and permeation kinetics of lincomycin hydrochlorie gel formulations through mouse skin. Ind. J. Pharm. Sci. 2006;68(2): 205-211.

TABLES AND FIGURES:

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Table 1: Composition of Box-Behnken design formulations of meloxicam sodium gel Formulation Meloxicam sodium (%) Ehanol (%) PEG 400 (%) Menthol (%) Azone (%)

F1 1.5 20.00 15.00 4.00 2.00 F2 1.5 20.00 15.00 2.00 3.00 F3 1.5 30.00 20.00 4.00 2.00 F4 1.5 20.00 20.00 4.00 3.00 F5 1.5 20.00 10.00 2.00 2.00 F6 1.5 20.00 15.00 6.00 3.00 F7 1.5 20.00 15.00 4.00 2.00 F8 1.5 20.00 20.00 6.00 2.00 F9 1.5 20.00 15.00 4.00 2.00 F10 1.5 20.00 20.00 2.00 2.00 F11 1.5 20.00 15.00 4.00 2.00 F12 1.5 20.00 10.00 6.00 2.00 F13 1.5 30.00 10.00 4.00 2.00 F14 1.5 20.00 10.00 4.00 3.00 F15 1.5 30.00 15.00 2.00 2.00 F16 1.5 10.00 15.00 4.00 3.00 F17 1.5 20.00 15.00 2.00 1.00 F18 1.5 10.00 20.00 4.00 2.00 F19 1.5 20.00 15.00 6.00 1.00 F20 1.5 30.00 15.00 4.00 3.00 F21 1.5 10.00 15.00 4.00 1.00 F22 1.5 20.00 15.00 4.00 2.00 F23 1.5 10.00 10.00 4.00 2.00 F24 1.5 10.00 15.00 2.00 2.00 F25 1.5 30.00 15.00 6.00 2.00 F26 1.5 20.00 20.00 4.00 1.00 F27 1.5 20.00 15.00 4.00 2.00 F28 1.5 10.00 15.00 6.00 2.00 F29 1.5 30.00 15.00 4.00 1.00 F30 1.5 20.00 10.00 4.00 1.00 *Above formulations contain carbopol (1% w/w), propylene glycol (40% w/w), triethanolamine (2.5% w/w), glycerin (10% w/w) and water (up to 100

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Tables 2: pH, spredability and drug content of meloxicam sodium gel Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16 F17 F18 F19 F20 F21 F22 F23 F24 F25 F26 F27 F28 F29 F30 pH 5.63 7.00 5.56 5.42 6.40 6.75 6.60 6.49 6.62 5.52 6.53 5.48 6.34 5.98 6.45 6.67 6.83 6.90 6.45 6.35 5.57 5.65 6.47 5.62 7.09 6.53 6.94 6.34 6.60 6.22 Spreadability (gm.cm/sec) 22.76 22.85 21.43 24.91 24.55 18.45 25.68 26.58 22.11 19.64 25.13 23.65 24.53 22.13 25.53 28.95 24.23 25.34 25.70 17.65 19.56 24.23 28.83 28.34 17.08 22.45 23.46 24.98 21.89 22.80 Drug content % 97.86 98.56 98.88 99.90 98.83 98.89 99.25 100 99.20 98.25 99.63 95.58 98.92 98.85 98.35 98.48 99.56 100 98.89 98.89 97.58 96.95 97.26 98.26 99.36 99.28 100 98.40 98.75 97.22

Table 3: Permeation rate (flux) of factorial formulations Formulation Flux Formulation (g/cm2/h) F1 216.75 F16 F2 197.40 F17 F3 226.35 F18 F4 230.25 F19 F5 193.50 F20 F6 217.50 F21

Flux (g/cm2/h) 227.01 177.60 240.00 246.10 185.85 220.95

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F7 F8 F9 F10 F11 F12 F13 F14 F15

231.45 232.80 198.45 160.15 248.75 231.45 177.75 196.35 208.35

F22 F23 F24 F25 F26 F27 F28 F29 F30

190.65 191.10 215.55 209.25 208.35 222.15 233.33 231.29 233.70

Table 4: Composition of optimal formulation Formulation Meloxicam Ehanol PEG 400 Menthol Azone sodium (%) (%) (%) (%) (%) C1 1.5 22.25 15.00 5.5 1.00 C2 1.5 20.15 15.00 5.75 1.00 *Above formulations contains carbopol (1% w/w), propylene glycol (40% w/w), triethanolamine (2.5% w/w), glycerin (10% w/w) and water (up to 100%).

In-vitro permeation profile of meloxicam sodium from optimal formulation C1 % Cumulative drug permeated
100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12

C1

Time (h)
Fig.1: In-vitro permeation profile of optimized formulation C1.

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