Formulation and Evaluation of Floating Mefenamic Acid Drug Delivery Tablet

International Journal of Pharmacy and Medical Sciences (1): 01-06, 01 ISSN -5854 IDOSI Publications, 01 DOI: 10.589/idosi.ijpms.01..1.641 Formulation and Evaluation of Floating Mefenamic Acid Drug Delivery Tablet 1 1 Shaimaa N. Abd Al Hammid, Alaa A. Abdul Rassol and Abdul-Wahab R. Hamad 1 College of Pharmacy, University of Baghdad, Baghdad, Iraq Zarka University College, Albalqa Applied University, Jordan Abstract: A new floating effervescent controlled-release drug delivery system having a density less than 1 was formulated in an effort to increase the gastric retention time of the dosage form, increase drug absorption and to control drug release. Different formulas were made as tablets by wet granulation technique, using polymers such as; Hydroxypropyl methylcellulose (HPMC) of different viscosity grades (HPMC100SR, HPMC4000SR, HPMC100000CP), carboxymethyl cellulose, methyl cellulose, sodium alginate and eudragit RS. The buoyancy was attributed to air entrapped in the polymer hydroxypropyl methyl cellulose (HPMC). Incorporation of a gas-generating agent together with polymer improved drug release, also the effect of citric acid on drug release and floating properties were studied. The study showed that tablet composition and mechanical strength have a great influence on the floating properties and drug release. It was found that HPMC viscosity had a significant effect on the release and floating properties of the delivery system. Ten formulas were prepared and it was that (F3) containing HPMC K4M mixed with sodium bicarbonate was selected as the best effervescent floating formula that gave sustained mefenamic acid release over 4hrs, with a short lag time (3 seconds) and floating duration 4 hrs. The stability of the prepared tablets F3 was studied at 50, 60 and 70 C for four months and the expected expiration date using Arrhenius plot was 3.1 years at 5 C. On the other hand, the in vivo radiographic studies were performed with Barium sulphate loaded formulation (F3) to justify the increased gastric residence time of the dosage form in the stomach, based on the floating principle was given to 3 male volunteers. X-ray studies showed that the appearance of the tablet in the upper part of the stomach confirms its floating behavior. The change in position of the formulations proves that they does not adhere to the mucous and remained floating for 4 hrs, indicated that gastric retention time was increased by the floating principle. Key words: Effervescent Floating Tablet Mefenamic Acid Comparative Bioavailability INTRODUCTION Floating drug delivery system can remain in the gastric region for several hours and hence significantly Gastric emptying occurs during fasting as well as fed prolong the gastric residence time of drugs. Prolonged states. The relatively short gastric emptying time can gastric retention improves bioavailability, reduces drug result in an incomplete release of drug from the drug waste and improves solubility for drugs that are less delivery system, leading to a diminished efficacy of the soluble in a high ph environment [3]. In addition to that administered dose [1]. floating drug delivery systems are classified depending Several approaches are currently used to prolong on the use of formulation variables: effervescent and gastric retention time. These include floating drug non-effervescent systems. delivery systems which are also known as Effervescent floating dosage forms which are matrix hydrodynamically balanced systems, swelling and types of systems are prepared with the help of swellable expanding systems, polymeric bioadhesive systems, polymers such as methylcellulose and effervescent modified-shape systems, high-density systems and other compounds, e.g., sodium bicarbonate. They are delayed gastric emptying devices []. formulated in such a way that when in contact with the Corresponding Author: Wahab Hamad, Zarka University College, Abalqa Applied University, Jordan. 1

Intl. J. Pharm. Med. Sci., (1): 01-06, 01 acidic gastric contents, CO is liberated and gets (Barlocher, GMBH, Germany), Poly oxyethyleneglycol entrapped in swollen hydrocolloids, which provides dodecyl ether Brij 35(Merck, Germany), methanol BDH buoyancy to the dosage forms [4, 5]. ethanol BDH, Hydrochloric acid, all other reagents were Mefenamic acid is a non steroidal anti-inflammatory of an analytical grade. drug acts by inhibiting isoforms of cyclo-oxygenase 1 and. It has an activity to treat inflammatory Experimental Design rheumatoid diseases and relieve acute pain [6]. The Preparation of Floating Drug Delivery System: drug has a relatively short half-life of about hours [7] Different formulas (Table 1) were prepared to get the and is, therefore, an ideal candidate for formulation as a most satisfactory ones using wet granulation sustained release dosage form. technique. The ingredients were weighed then the required quantities of mefenamic acid, polymer Aim of the Study: To prepare mefenamic acid as sustained and sodium bicarbonate were mixed together. PVP release floating tablets, to increase the bioavailability, 1% in Ethanol (99 % v/v) were used as a granulating optimize the efficacy, prolong the duration and decrease agent. mefenamic acid loss with an in vitro and preliminary The granules were prepared by passing the wet in-vivo study of the prepared formula in stomach coherent mass through a BSS # 16 sieve. The granules volunteers. then dried in hot air oven at a temperature of 40-45 C and passed through 0 mesh screen then, magnesium stearate MATERIAL AND METHODS was added as a lubricant. The granules were compressed using Erweka Tablet Machine manually using 1 mm Materials: Mefenamic acid powder (Shilton Chemicals, punch diameter. The quantities of polymer and excipients England). Hypromellose USP (Metolose 90 SH-4000SR) were adjusted in order to achieve a 4-hours extended (HPMC4000) Ex05097, Hypromellose USP(HPMC 100,000 release, with final tablet weight of 510 mg. The CP) substitution type 08 Metolose, Lot no.50546, compression was controlled to produce 3-4 kg/cm tablet Hypromellose USP (HPMC 100SR) substitution type 08 hardness [8]. Metolose grade 90 SH-100SR,Viscosity 100cp Lot no. 410540 (Shin-Etsu Chemicals Co. Ltd., Japan). Methyl Evaluation of Floating Drug Delivery System cellulose, Carboxy methyl Cellulose, Eudragit S 100 Physical Parameters: Weight variation test was done on Eudragit RS P14 (Barlocher, GMBH, Germany), Sodium tablets according to USP as well as the hardness of the alginate (Hopkin and Williams Ltd, Chadwell, Essex, prepared tablets was measured with Monsanto hardness England), Magnesium stearate (Peter Greven Nederland tester, in addition to that friability was measured using C.V., Venlo, Netherlands). PVP K90 (Kollidon 90F, Rosch friabilator. Dissolution time and rate were measured BASF, Ludwigshafen, Germany). Sodium bicarbonate in 900 ml 0.1 N HCl containing % Brij 35 using USP (NaHCO 3, Fisher Scientific, UK). Barium sulfate powder method [9]. Table 1: Schedule of Different Formulations for Mefenamic Acid as a Floating Drug Delivery Tablet Formula No.Ingredients (mg/tablet) F1 F F3 F4 F5 F6 F7 F8 F9 F10 Mefenamic acid 50 50 50 50 50 50 50 50 50 50 M C 50 - - - - - - - - - CMC - 50 - - - - - - - - HPMC4000SR - - 00 50-00 00 - - - HPMC100SR - - - - 50 - - - - - HPMC100000CP - - - - - - - 50 - - Eudragit RS - - - - - - - - - 50 Sodium alginate - - - - - - - - 50 - Sodium bicarbonate - - 50 - - 35 - - - - Citric acid - - - - - 15 - - - - PVP 5 5 5 5 5 5 5 5 5 5 Magnesium stearate 5 5 5 5 5 5 5 5 5 5 Total weight (Mg) 510 510 510 510 510 510 510 510 510 510

Intl. J. Pharm. Med. Sci., (1): 01-06, 01 Content Uniformity Test: Twenty tablets were accurately RESULTS AND DISCUSSION weighed and the average weight per tablet was determined. They were grounded to fine powder and Physical Parameters: Weight variation was performed for tablet powder equivalent to 50 mg mefenamic acid was all tablets and the results indicated that they were within weighed and mixed with 100 ml acidified methanol. After the required range 510 mg± 5%. In addition to that; filtering and appropriate dilution, the samples were hardness, friability, floating time and dissolution time and assayed spectro-photometrically at 80 nm [10]. rate are shown in Table () and Figure (1) while Figure () shows the floating behavior of the prepared mefenamic Floating Capability: A tablet was introduced in to beaker acid tablets. containing 100ml of 0.1N HCl. The time taken by the tablet Formulas 1,, 4, 9 and 10 were used to study the to come up to the surface and floated was taken as the effect of polymer type, by using methyl cellulose (MC), buoyancy time. An average of three determinations, from carboxymethyl cellulose, HPMC 4000, eudragit RS and which batch was taken for the floating forms [11]. sodium alginate respectively. The physical properties and drug release of mefenamic acid was significantly different Accelerated Stability Study: The effect of temperature (P<0.05) among these polymers as shown in Table (). on the degradation rate of mefenamic acid in selected MC fails to keep tablet floating, while CMC, HPMC100000 floating tablet F3 was studied at three different and sodium alginate gave a too long dissolution time than temperatures: 50 C, 60 C and 70 C for four months. required (30, 30 and 34 hr respectively). HPMC4000 was Samples were taken at different time intervals and the best polymer used. In fact, the floating time analyzed for mefenamic acid content (buoyancy) of the tablets is governed by two factors; spectrophotometrically at max 80 nm [10]. (first) the swelling (hydration) of the hydrocolloid particles on the tablets surface when the tablets contact In vivo Radiographic Studies: Three healthy male the gastric fluids, which in turn results in an increase in volunteers in the age group of 0-3years and weighing between 55-70 kg were selected for the study; they were made clear about the usage and adverse effects of the drug. BaSO was incorporated to make the tablets x-ray 4 opaque. The selected formula (F3) was mixed with barium sulfate 150mg in order to study its floating ability in vivo. Tablet Preparation for In vivo Studies: For in vivo tests tablets with the following composition were prepared: 50 mg mefenamic acid was mixed well with 150 mg BaSO 4:00 mg HPMC K4M:50 mg NaHCO 3and then 1% of PVP in ethanol in a sufficient quantity was added to make a wet mass and granulated using the same sieve utilized in the preparation of all formulas previously. The granules were mixed with 1 % magnesium stearate for minutes and compressed into tablets (average tablet weight 660 mg). Sufficient pressure was applied to keep the hardness at 3-5 kg/cm. The tablets loaded with barium sulfate were administered orally. During the study, volunteers fed with light meal, water was allowed to take. The X-ray photographs were taken at different periods of time to find the total residence time of the tablet in the stomach [1]. Radiographic images were taken with volunteers in standing position immediately after administration of the formulation (0.5 hr.) and at intervals of, 4, 6, 8 and 4 hrs. the bulk volume; and (second) the presence of the internal voids in the dry center of the tablet (porosity). These factors are essential for the tablet to acquire a bulk density less than 1 and remain buoyant on the gastric fluid [13]. Sodium bicarbonate was added as a gas-generating agent (F3), it improved dissolution it reacts with hydrochloric acid to create carbon dioxide whose bubbles were on the surface of the tablets, caused tablet floating in the fluids as shown in Figure (3). The gas generated is trapped and protected within the gel, formed by hydration of polymer, thus decreasing the density of the tablet. As the density of the tablet falls below 1, the tablet becomes buoyant [14]. Furthermore HPMC produced tablets with good gel strength; entrapping CO gas and imparting stable and persistent buoyancy also in contact with water it swells and increases their volume due to water diffusion through the matrix. The increasing water content dilutes the matrix until a disentanglement concentration is attained. At this point, the polymer molecules are released from the matrix, diffusing to the bulk of the dissolution medium. Then, the matrix volume decreases slowly because of polymer dissolution [15]. Polymeric matrices experience simultaneously swelling and polymer dissolution and diffusion. 3

Intl. J. Pharm. Med. Sci., (1): 01-06, 01 Table : Physical Properties of the Prepared Mefenamic Acid Floating Tablets (results are expressed as mean (n=3)) Formula no. Lag time (s) Floating time (hr) Hardness (Kg/cm ) Friability % Dissolution time (hr) Polymer type F1 10.0 1 5 0.9 1 MC F 75.0 30 4 0.5 30 CMC F3 3.0 36 3 0.9 4 HPMC4000+Na F4 1.0 48 5 0.6 8 HPMC4000 F5 30.0 1 4 0.6 1 HPMC100 SR F6 1.0 16 4 0.7 0 HPMC +Citric acid F7 0.5 1 4 0.7 16 HPMC +CaCo 3 F8 1.0 48 5 0.6 30 HPMC100000 F9 600.0 40 3 0.7 34 Na alginate F10 30.0 8 3 0.75 1 Eudrajit Fig. 1: The release of mefenamic acid from the prepared floating tablets in 0.1 N HCl dissolution media containing % Brij 35 Table 3: Rate Constants of Degradation (k) of Mefenamic Acid at Different Temperatures for the Prepared Floating Tablets (Formula 3). Fig. : Photographs of Mefenamic Acid Floating Matrix Tablet Before and After Floating in the 0.1 N HCl. Fig. 4: Degradation curves of effervescent mefenamic acid floating tablet at different temperatures (50, 60 and 70 C using the selected effervescent formula3. Fig. 3: Photographs of Effervescent Mefenamic Acid Floating Tablet in the Artificial Gastric Fluid Shows Carbon dioxide Liberation on the Surface of the Tablet Formula (F3) containing HPMC K4M mixed with sodium bicarbonate was selected as the best floating formula that gave sustained mefenamic acid release over 4hrs, with a short lag time (3 seconds) and floating duration >4 hrs. 4

Intl. J. Pharm. Med. Sci., (1): 01-06, 01 Fig. 5: Arrhenius plot for the estimation of expiration date of theprepared effervescent mefenamic acid floating tablet formula 3 Fig. 6: A representative radiographic image showing the presence of BaSO4 loaded floating tablet in the stomach of male volunteer 0.5,, 4, 6, 8 and 4 hr after administration ( The tablet is indicated with an arrow) Stability Studies: These were carried out for F3 for four Radiographic Studies: In the in vivo X-ray studies, the months at different temperatures to assess their long-term appearance of the tablet in the upper part of the stomach stability. The protocols of stability studies were in confirms its floating behavior. The tablet edges were compliance with the guidelines in the WHO document [16] sharp and no gel layer was seen after 0.5 h of the tablet for stability testing of products intended for the global administration. In the next picture taken at hrs market. After storage, the formulation was subjected to a significant changes were detected: the tablet had altered drug assay, floating behavior and in vitro dissolution its position. This provided evidence that the tablet did not studies. The expected accelerated expiration date was adhere to the gastric mucous, but, on the contrary, floated 3.1 years. The dissolution profile of the stored tablets did on the gastric fluid. Additionally the swelling of the tablet not show a significant change (p >0.05) after 16 weeks at is visualized very well together with the white dry core 5ºC. The inspection of tablets also did not exhibit any and translucent swelling layer around it. The position was change in their physical properties or appearance. th changed in formulations at the 4 hour x-ray. Also the 5

Intl. J. Pharm. Med. Sci., (1): 01-06, 01 swelling of the tablet can be visualized from the increase 7. British Pharmacopoeia volume 1 and. 009. in its size when compared to 0.5 hour, x-rays which are similar to the results of other researchers [17, 18]. As illustrated in Figure (6) the swelling continued and the glassy core diminished as well as the swelling layer eroded from the outer surface and a size reduction was seen [19]. CONCLUSION Increase the residence time in the stomach without contact with the mucosa was achieved through the preparation of floating drug delivery tablet, this leads to increase amount of drug absorbed. Mefenamic acid is a weak acid so increasing residence time of drug in stomach lead to increase total amount of drug absorbed. Formulation of mefenamic acid as effervescent floating tablet lead to sustained release of drug. Finally Formulation of mefenamic acid as effervescent floating tablet decrease frequency of dosing, patient compliance, side effect of drug, getting sustained release delivery with less amount, so more economic with better result. Floating drug delivery system promises with a good future in drug design. REFERENCES 1. Arora, S., J. Ali, A. Ahuja, R.K. Khar and S. Baboota, 005. Floating drug delivery system a review. AAPS Pharm. Sci. Tech., 06(03): 0-6.. Shishu, N. Gupta and N. Aggarwal, 007. A gastro retentive floating drug delivery system of 5- florouracil, Asian J. Pharmaceutical Sci., (4): 143-149. 3. Dave, B.S., A.F. Amin and M.M. Patel, 004. Gastroretentive drug delivery system of ranitidine hydrochloride: Formulation and in vitro evaluation. AAPS Pharm. Sci. Tech., 5(): 1-6. 4. Patel, D.M., N.M. Patel, N.N. Pandya and P.D. Jogani, 007. Formulation and optimization of carbamazepine floating tablets, Indian J. Pharmaceutical Sci., 69(6): 763-767. 5. Sanchez, P.E., A.H. Len and L.V. Robles, 008. Effect of sodium bicarbonate on the properties of metronidazole floating matrix tablets, Drug Development and Industrial Pharmacy, 34(): 171-180. 6. Lipincott, Williams and Wilkins. Remingtonõs, 006. st The Science and Practice of Pharmacy 1 edition, pp: 538. 6 Medicinal and Pharmaceutical Substances Mefenamic Acid. Crown Copyright, pp: 3743-3744. 8. Martinez, I.J., T.Q. Barreda and L.V. Robles, 008. Sustained delivery of captopril from floating matrix tablets. International Journal of Pharmaceutics, 36: 37-43. 9. Gad C. Sh., 008. Pharmaceutical Manufacturing Handbook Production and Processes. A John Wiley and Sons, Inc., Publication. Tablet Production, 966: 881-930. 10. Hussein, A.A., 1994. Effect of additives on the in vitro release of mefenamic acid from suspensions. Thesis on Degree of Master of Science of Pharmaceutics, pp: 5. 11. Adichwal, S. and B.K. Nanjwade, 009. Design and evaluation of floating matrix tablets of glipizide. Master s thesis of Pharmaceutics. J.N. Medical College, KLEUniversity, Belgaum-590010, Karnataka, India Ref., pp: 33. 1. Rahman, Z., M. Ali and R. Khar, 006. Design and evaluation of bilayer floating tablets of captopril. Acta Pharm., 56: 49-57. 13. Streubel, A., J. Siepmann and R. Bodmeier, 003. Floating matrix tablets based on low density foam powder: effects of formulation and processing parameters on drug release. European J. Pharmaceutical Sci., 18: 37-45. 14. Gambhire, M.N., K.W. Ambade, S.D. Kurmi, V.J. Kadam and K.R. Jadhav, 007. Development and in vitro evaluation of an oral floating matrix tablet formulation of diltiazem hydrochloride. AAPS Pharm. Sci. Tech., 8, 3 Articles 73: E1-E9. 15. Emilio, G.P., H.L. Alejandra and V.R. Leopoldo, 008. Effect of Sodium Bicarbonate on the Properties of Metronidazole Floating Matrix Tablets. Drug Development and Industrial Pharmacy, 34(): 171-180. 16. Mathews, B.R., 1999. Regulatory aspects of stability testing in Europe, Drug Development and Industrial Pharmacy, 5: 831-856. 17. Bomma, R., R.A. Naidu and M.R. Yamsani, 009. Veerabrahma, K. Development and evaluation of gastroretentive norfloxacin floating tablets. Acta Pharm., 59: 11-1. 18. Patel, A., M. Modasiya, D. Shah and V. Patel, 009. Development and in vivo floating behavior of verapamil HCl intragastric floating tablets. AAPS Pharm. Sci. Tech., 10(1): 310-315. 19. Bomma, R., R.A. Naidu, M.R. Yamsani and K. Veerabrahma, 009. Development and evaluation of gastroretentive norfloxacin floating tablets. Acta Pharm., 59: 11-1.