Continental J. Pharmaceutical Sciences 5 (2): 20 - 24, 2011 4149 Wilolud Journals, 2011 http://www.wiloludjournal.

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ISSN: 2141 Printed in Nigeria

FORMULATION AND EVALUATION OF MOLEXICAM SUPPOSITORIES

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Maged Alwan Noman1 and Hussein Omer Kadi2 Depart. of Pharmaceutics, Faculty of Pharmacy, Sana'a University. Yemen University President 2 Depart. of Pharmacology, Faculty of Medicine Sana'a University. Hodeida University President

ABSTRACT Meloxicam suppositories non-steroidal anti-inflammatory drugs indicated for the treatment of musculoskeletal disorders and other syndromes involving pain. The goal of this study was formulation and evaluation various suppository bases containing molexicam and avoiding first pass effect of the drug. Molexicam suppositories was formulated using different bases like, cocoa butter, witepsol H15, witepsol E75, witepsol E76, witepsol S58, suppocire AM, and PEG. In-vitro performance evaluation of molexicam suppositories carried out includes uniformity of weigh, disintegration time, hardness, melting point, content uniformity and dissolution test. All Suppositories prepared with water soluble bases and oil soluble bases were within permissible range of all physical parameters. The results indicate that, polyethylene glycol showed an excellent drug release followed by witepsol S58 in the invitro dissolution study. All Suppositories prepared with water soluble bases and oil soluble bases were within permissible range of all physical parameters. Polyethylene glycol suppository bases exhibited a satisfactory dissolution profile for molexicam. So the release of meloxicam from water soluble bases was found higher than that from adeps solidus bases. KEYWORDS: molexicam, suppository bases, release and dissolution profile. INTRODUCTION Suppositories are an old form of medication that has been known from the time of Hippocrates (Abdou,1989). It have been recognized as an alternative to the oral route in situations such as when the patient is comatose, unable to swallow or when the drug produces nausea or vomiting. In the light of this, efforts have been made in recent times to present a good number of drugs in suppository form(Zuber, et al.1998; Adegboye and Itiola, 2003; Taha, et al. 2004; Pasztor, et al. 2007). Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of compounds characterized by a similar pharmacological profile encompassing anti-inflammatory, analgesic and antipyretic activities. They are indicated for the treatment of musculo-skeletal disorders and other syndromes involving pain(Brooks, 1991). Despite their well-known therapeutic efficacy, NSAIDs have the potential to cause adverse reactions, especially with regard to the digestive system and the kidney(Wallace, 1997). The topical administration of anti-inflammatory agent at inflamed site will alter the potential advantage of delivering drug directly to the surface area and producing a locally high concentration of the drug. Meloxicam is well absorbed after oral administration, with an absolute bioavailability of 89% that is not markedly affected by concomitant intake of food. Meloxicam reaches maximum plasma concentration (C max) at 9-11 hours after a 30mg dose and 2.5-7 hours after a 15mg dose. Meloxicam is strongly bound to plasma proteins (99.5%). Meloxicam displays linear pharmacokinetics, with a half-life of 20-24 hours(Dequeker and Degner, 2001). During distribution, meloxicam readily penetrates the synovial fluid, reaching concentrations that are 45-57% in plasma(Davies and skjodt, 1999). Inflammatory status was found to affect the distribution of meloxicam into synovial fluid, shifting the synovial fluid: plasma ratio from 0.58 acute inflammation to 0.38 no inflammation(Davies and skjodt, 1999). Rectal administration has been recommended as a non-invasive alternative for drugs which are largely metabolized by the liver or excreted in the bile and for those subject to degradation in the gastrointestinal tract(Jonkman, et al. 1979). Drug administered in suppository form can produce not only local effect but also systemic therapeutic action(Goodman, 2001). Rectal route of administration is specifically useful for infants and children who have difficulty in swallowing oral medicine. Aim of work is to get abettar quality of drug with lesser side effect thus by avoiding the first pass effect of the drug.

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Maged Alwan Noman and Hussein Omer Kadi: Continental J. Pharmaceutical Sciences 5 (2): 20 - 24, 2011 MATERIALS Meloxicam (Sheba Pharmaceutical Co., Yemen); Cacao-butter (Koch-Light Laboratories Ltd. Colnbrook Bucks England); witepsol H15, witepsol H75 and witepsol S58, (Huls AG, France); Suppocire AM (Delta Pharma Egypt); Poly ethylene glycol 1000 (Hi-Media Pvt. Ltd., Mumbai, India) and Poly ethylene glycol 4000 (Loba Chem. Pvt. Ltd., Mumbai, India). Ultraviolet spectrophotometer (Shimadzu UV-1601PC, Japan); Dissolution tester (Pharma test, type PTW, Germany); Disintegration tester type ST3 consisting of three vessels and hardness tester (ERWEKA, Germany). Preparation of suppositories: Suppositories of one gram containing 7.5 mg of meloxicam were prepared by the fusion method(Block, 2005; Adegboye and Itiola, 2003) using a metal mould with six cavities. Cocoa butter suppositories were prepared by melting the base and bees wax on water bath, and then the drug was incorporated. Suppositories were weighed and kept at room temperature for 24h after removal from the mould to allow for uniform solidification and crystal transformation. The prepared suppositories were wrapped in aluminum foil and stored in desiccators in a refrigerator until needed. Evaluation of physical properties of suppositories: The prepared suppositories were subjected to several physicochemical tests include uniformity of weight, hardness, melting point, disintegration time and content uniformity and the results were converted to a percentage of the whole. For determination of weight uniformity, twenty suppositories were weighed individually and the average weights were determined(BP, 1998). No suppositories should deviate from average weight by more than 5% except two which may deviate by not more than 7.5%. Hardness test or breaking strength test was carried out using Monsanto hardness tester to determine the tensile strength of the suppositories to access whether they will be able to withstand the hazards of packing and transporting(Coben and Liberman, 1989). Disintegration test of molexicam suppositories was carried out by modified method described by (BP, 1998) used for tablet disintegration. The suppository to be tested was placed in a cylindrical glass tube with perforated lower ends and immersed in 1000 ml of phosphate buffer solution pH 5.4 maintained at 37 0.5C. The tube was allowed to move up and down in the buffer medium. The time for disintegration was noted when the suppository has completely melted or dissolved then mean and standard divisions were calculated. Melting point method was used to determine the melting point of each type of suppositories(Mosbah, et al. 2010). In vitro release tests were carried out according to the USP XX basket method using the Pharma test, type PTW a Germany dissolution equipment. Each suppository was placed in the basket (USP, 1980) and lowered into a flask containing 500ml of phosphate buffer solution pH 7.5, maintained at a constant temperature 37 0.5C. The basket was rotated at a constant speed of 80rpm. Samples of 5 ml were withdrawn at specified time intervals. Fresh buffer solution maintained at experimental temperature was used to replace the same volume of withdrawn samples. The amount of meloxicam in each withdrawn sample was analyzed spectophotometrically at 275nm using Shimadzu UV-1601PC, Japan. The mean of three determinations was used to calculate drug release from each formulation. RESULTS AND DISCUSSION A standard curve was plotted and a good linearity was obtained (R2=0.999). Both the Poly ethylene glycol and the witepsol S58 showed excellent drug release in an in-vitro dissolution study. Results of all physical tests are presented in Table(1) which show that all prepared suppositories satisfied the BP requirement (BP, 1998) for weight uniformity and none of the individual weights deviating from the average by more than 5%.

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Maged Alwan Noman and Hussein Omer Kadi: Continental J. Pharmaceutical Sciences 5 (2): 20 - 24, 2011 All formulated suppositories were found to satisfy the British pharmacopoeia requirement for disintegration time which was less than 30 minutes for all lipophilic and hydrophilic bases. The hardness values of the tested suppositories range from 1.250.1 to 3.20 0.1 Kg. Witepsol E75 has the lowest value (1.25Kg.) and Poly ethylene glycol has the highest value (3.20 Kg.). Melting point range for all suppository bases containing molexicam can be arranged in the following order, cacao butter (33C) < witepsol H15(34.5C) < witepsol S58(35C) < witepsol E75 < witepsol E76(40.5C) < hydrous PEG(41C). Release data of molexicam from different suppository bases in phosphate buffer pH 7.4 is illustrated in Table (1). From the data obtained it was clear that the amount of the drug released from water soluble bases hydrous Poly ethylene glycol is greater than that from adeps solidus bases and this enhancement of the dissolution was due to enhanced solubility of the molexicam by water-soluble bases. Hence PEG bases with highest melting range (42 - 43 C) have good hydrophilic property and solubilizing effect (Verheyen, 2002; Betageri and Makarla, 1995) thus gave the highest amount of drug released (88.089 %) followed by witepsol H S58 a hydrophobic base with melting range (34-36C) which released about (49.492 %) of molexicam after 120 minutes. So the release pattern of molexicam from other suppository bases can be arrange as follows, witepsol S58 > suppocire AM > witepsol H15 > cacao butter > witepsol E75. The lowest amount of drug released was observed from witepsol E75 which exhibited the highest melting range (41-43C). Thus it could be concluded that softening point of these suppositories was the rate limiting step in release of drug from fatty bases. The cacao butter has low melting range (32-35C) but it gave slightly lower release of medicament compared with suppocire AM and witepsol H15. This is attributed to the presence of monoglycerides in the latter bases which acts as emulsifying agent, thus facilitating the dispersion of the medicament to the surrounding media. The lowest release was given by witepsol E75 base (37-39C). In studies of mechanisms underlying invitro availability of different drugs from suppositories, the water solubility of drugs was found to be the fundamental factor influencing the release rate and extent (Reglon, et al. 2001). The percentage drug contents of all the suppositories formulations were found to be between 93.5%1.40 105.50%1.01 which complied with the pharmacopoeia limits. Also, the mean drug content for the suppositories was found to satisfy the BP requirement for content uniformity for most suppository formulations where none of the suppository formulations had less than 90% and none had more than 110% of expected meloxicam content. CONCLUSION The release of meloxicam from water soluble bases was found higher than that from adeps solidus bases. REFERENCES Abdou H., 1989. In Dissolution, Bioavailability & Bioequivalence. Mack Printing Co., Pennsylvania, pp. 205. Adegboye T A and Itiola, O A., 2003. Formulation effects on the mechanical and release properties of metronidazole suppositories. Afr. J. Med. Med. Sci., 32: 247-251. Betageri G V., Makarla K.R., 1995. Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. Int. J Pharm., 126:155-160. Block L H., 2005. Medicated topicals. In: Gennaro AR. editors. Remington: The science and practice of pharmacy. 21st ed. Vol. 2. Noida: Lippincott Williams and Wilkins, p. 885-886.

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British Pharmacopoeia., 1998. I&II. London: Her Majestys Stationery Office. Maged Alwan Noman and Hussein Omer Kadi: Continental J. Pharmaceutical Sciences 5 (2): 20 - 24, 2011 Brooks P M., 1991. Day Ro.NSAIDs differences and similarities .N. Engl . J.Med., 324: 1716- 25. Coben L J, Liberman HA., 1989. Suppositories. In: Lachman L, Liberman HA, Kanig JL, editors. Theory and practice of industrial pharmacy. 3rd ed. Mumbai: Varghese Publishing House, p. 580. Davies N M, skjodt N.M., 1999. Clinical pharmacokinetics of meloxicam : a cylooxygenase2 preferntial (NSAID): Clin. Pharmacokinet, 36: 115-26. Dequeker J, Degner. F., 2001. Editorial. meloxicam inflamm. Res., 50 suppl. 1: 53-4. Goodman D O., 2001. Pharmacokinetics: Disposition and metabolism of drugs. In: Munson PL, Muller RA, Breese GR. editors. Principles of pharmacology. 1st ed. New York: Chapman and Hall, p. 47. Jonkman J., Van Bork, L., Wijsbeek, J., Bolhuis-De Vries, A., De Zeeuw, R, Orie, N. and Cox, H., 1979. Firstpass effect after rectal administration of thizinamium methylsulfate. J. Pharm. Sci., 68: 69-72. Mosbah A. El-Majri and Rakesh kumar Sharma, 2010. Formulation and evaluation of piroxicam suppositories. International Journal of Drug Delivery, 2, 108-112. Pasztor E, Csoka, G, Klebovich, I and Antal, I., 2007. Formulation study of metolose based on insitu gelling liquid suppository. Eur. J. Pharm. Sci., 6: 34-39. Reglon G, Deak D, Regdon G, Masko Z, Eros L., 2001. Preformulation experiences and in vitro model studies with spirinolactone-containing suppositories. Pharmazie, 56: 70 3. Taha R I, Zaghloul, AA, Samy, AM., Al-Saidan, S, Kassem, AA and Khan, MA., 2004. Bioavailiabilty assessment of salbuthamol sulphate suppositories in human volunteers. Int. J. Pharm., 279:3-7. United States Pharamcopoeia XX., 1980. 20th ed. Easton: Mark Publishing Company. 959. Verheyen S., 2002. Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions. Int. J Pharm., 249: 45-58. Wallace J.L., 1997. (NSAIDs) and gastro enteropalthy the second hudred years. Gastroenterology, 112: 100016. Zuber M, Pellion, B, Arnaud, P and Chaumeil, JC., 1998. Kinetics of theophyline release from suppositories in vitro: Influence of physicochemical parameters. Int. J. Pharm., 47: 31-36. Table (1): Physico-chemical parameter of molexicam in different suppository bases. Type of Base Cacao butter Witepsol H15 Witepsol E75 Witepsol E76 Witepsol S58 Suppocire AM PEG Physico-chemical parameter Disintegration Hardness Melting Time (min) (kg ) Point C 25.00 0.025 1.80 0.005 33.0 25.00 0.190 2.87 0.017 35.0 25.00 0.500 1.25 0.004 38.0 25.00 0.502 1.26 0.008 39.0 3.00 0.090 3.10 0.018 35.0 4.00 0.020 2.20 0.030 35.5 42.5 17.00 0.051 3.20 0.019

Uniformity of weigh (gm) 1.01 0.003 1.05 0.024 1.01 0.052 1.01 0.009 1.10 0.051 1.01 0.005 1.20 0.010

Content Uniformity % 100.94 0.64 99.80 3.431 101.43 1.002 101.18 0.936 100.85 1.790 100.47 1.233 102.14 0.575

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Maged Alwan Noman and Hussein Omer Kadi: Continental J. Pharmaceutical Sciences 5 (2): 20 - 24, 2011 Table (2): Dissolution profiles of molexicam from different suppository bases using phosphate buffer pH 7.5. Time(min) Bases 5 15 30 45 60 75 90 105 120 Cacao butter 0.699 0.033 1.256 0.013 1.268 0.063 1.366 0.010 1.711 0.009 2.102 0.013 2.232 0.011 2.626 0.105 2.398 0.119 % release of molexicam from different suppository bases (mg) Witepsol H15 Witepsol Witepsol S58 Suppocire E75 AM 0.309 0.015 0.366 0.002 5.008 0.100 1.156 0.046 1.425 0. 1.211 0.024 0.557 0.001 23.675 0.947 047 1.374 0.041 0.756 0.020 34.264 0.017 1.746 0.016 1.378 0.001 0.817 0.016 41.077 0.822 1.924 0.021 1.382 0.011 1.010 0.020 44.451 0.089 1.947 0.015 1.764 0.088 1.354 0.067 41.870 0.377 2.417 0.010 2.033 0.101 1.431 0.029 45.590 0.683 2.596 0.010 2.073 0.103 1.585 0.014 47.683 1.430 3.420 0.068 2.528 0.013 1.752 0.009 49.492 0.495 3.250 0.098 PEG 18.096 0.090 52.561 0.473 63.915 2.876 70.545 0.776 79.226 1.585 79.958 0.400 80.427 0.281 81.239 0.814 88.089 0.036

Received for Publication: 21/11/2011 Accepted for Publication: 14/12/2011 Corresponding Author Maged Alwan Noman Depart. of Pharmaceutics, Faculty of Pharmacy, Sana'a University. Yemen University President Republic of Yemen, Sana'a, Sana'a University, P.O. Box : 13893

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