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Continental J. Pharmaceutical Sciences 5 (2): 20 - 24, 2011 ISSN: 2141 -4149

Wilolud Journals, 2011http://www.wiloludjournal.com ` Printed in Nigeria

FORMULATION AND EVALUATION OF MOLEXICAM SUPPOSITORIES

Maged Alwan Noman1 and Hussein Omer Kadi21 Depart. of Pharmaceutics, Faculty of Pharmacy, Sana'a University. Yemen University President2 Depart. of Pharmacology, Faculty of Medicine Sana'a University. Hodeida University President

ABSTRACTMeloxicam suppositories non-steroidal anti-inflammatory drugs indicated for the treatment of musculo-

skeletal disorders and other syndromes involving pain. The goal of this study was formulation andevaluation 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 ofmolexicam 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 resultsindicate that, polyethylene glycol showed an excellent drug release followed by witepsol S58 in the in-

vitro 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 asatisfactory 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). Ithave 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 recenttimes 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 ofcompounds 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 syndromesinvolving 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). Thetopical 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) at9-11 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% inplasma(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 noinflammation(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 todegradation 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 ofadministration 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 thedrug.

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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 BucksEngland); 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 (LobaChem. 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 hardnesstester (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 weighedand 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 weightswere 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 tensilestrength of the suppositories to access whether they will be able to withstand the hazards of packing andtransporting(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 pH5.4 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 standarddivisions 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 aflask 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 ofwithdrawn 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 drugrelease 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 bymore than 5%.

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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 thelowest 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) 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 inrelease 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 baseswhich 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 hadmore than 110% of expected meloxicam content.

CONCLUSIONThe release of meloxicam from water soluble bases was found higher than that from adeps solidus bases.

REFERENCESAbdou 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.


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. First-

pass 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 gellingliquid 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. Bioavailiabiltyassessment 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: 1000-16.

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 BasePhysico-chemical parameter

Uniformity of

weigh (gm)

Disintegration

Time (min)

Hardness

(kg )

Melting

Point C

Content

Uniformity %

Cacao butter 1.01 0.003 25.00 0.025 1.80 0.005 33.0 100.94 0.64

Witepsol H15 1.05 0.024 25.00 0.190 2.87 0.017 35.0 99.80 3.431

Witepsol E75 1.01 0.052 25.00 0.500 1.25 0.004 38.0 101.43 1.002

Witepsol E76 1.01 0.009 25.00 0.502 1.26 0.008 39.0 101.18 0.936

Witepsol S58 1.10 0.051 3.00 0.090 3.10 0.018 35.0 100.85 1.790

Suppocire AM 1.01 0.005 4.00 0.020 2.20 0.030 35.5 100.47 1.233

PEG 1.20 0.010 17.00 0.051 3.20 0.019 42.5 102.14 0.575

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Table (2): Dissolution profiles of molexicam from different suppository bases using phosphate buffer pH 7.5.

Time(min) % release of molexicam from different suppository bases (mg)

Bases Cacao butter Witepsol H15 Witepsol

E75Witepsol S58 Suppocire

AMPEG

5 0.699 0.033 0.309 0.015 0.366 0.002 5.008 0.100 1.156 0.046 18.096 0.090

15 1.256 0.013 1.211 0.024 0.557 0.001 23.675 0.9471.425 0.

04752.561 0.473

30 1.268 0.063 1.374 0.041 0.756 0.020 34.264 0.017 1.746 0.016 63.915 2.876

45 1.366 0.010 1.378 0.001 0.817 0.016 41.077 0.822 1.924 0.021 70.545 0.776

60 1.711 0.009 1.382 0.011 1.010 0.020 44.451 0.089 1.947 0.015 79.226 1.585

75 2.102 0.013 1.764 0.088 1.354 0.067 41.870 0.377 2.417 0.010 79.958 0.400

90 2.232 0.011 2.033 0.101 1.431 0.029 45.590 0.683 2.596 0.010 80.427 0.281

105 2.626 0.105 2.073 0.103 1.585 0.014 47.683 1.430 3.420 0.068 81.239 0.814

120 2.398 0.119 2.528 0.013 1.752 0.009 49.492 0.495 3.250 0.098 88.089 0.036

Received for Publication: 21/11/2011Accepted for Publication: 14/12/2011

Corresponding Author

Maged Alwan NomanDepart. 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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