Comparative Bioequivalence Studies of Some Brands of Metronidazole Tablets Marketed in Zaria, Nigeria
CHAPTER ONE
Objectives of the Study
- To validate and modified the adopted UV spectrophotometric method for the analysis of metronidazole in a dosage form from a biological
- To establish the pharmaceutical, chemical and bioequivalence as well as interchangeability of various brands of metronidazole tablets marketed in Zaria metropolis with reference to comparator products (Loxagyl).
CHAPTER TWO
LITERATURE REVIEW
History of Metronidazole
Metronidazole is one of the examples of drug developed against parasite, which has since gained broad use as an antibacterial agent. Briefly, at Rhone-Poulenc in France, extracts of Streptomyces species were screen for activity against Trichomonas vaginalis, a cause of vaginal itching. A Nitroimidazole, Azomycin, was identified, and a synthetic derivative, metronidazole, was used to treat chronic trichomonad infections, beginning in 1959. The antibacterial activity of metronidazole discovered by accident in 1962 when metronidazole cured a patient of both trichomonad vaginitis and bacterial gingivitis. However, it was not until the 1970s that metronidazole was popularized (Samuelson, 1999).
Also, the isolation of the antibiotic, azomycin (2-nitroimidazole) from a Streptomyces by Maeda and collaborators in 1953 and the demonstration of its trichomonocidal properties by Horie in 1956 led to the chemical synthesis and biological testing of many nitroimidazole. One compound, 1-(β-hydroxyethyl)-2-methyl-5-nitroimidazole, now called metronidazole (FLAGYL®). It was observed that metronidazole has high activity in-vitro and in-vivo against the anaerobic protozoa Trichomonas viginalis and Entamoeba histolytica. Dunel and associates (1960) reported that oral doses of the drug imparted trichomonacidal activity to semen and urine and that high cure rates could be obtained in both male and female patients with trichomoniasis (Phillips and Stanley, 2006). Later studies revealed that metronidazole has extremely useful clinical activity against varieties of anaerobic pathogens that include both gram positive and gram negative bacteria, in addition to the protozoan Giardia lamblia. In 1964, a dentist known as Shinn noted that patient with gingivitist was cured with flagyl (Phillips and Stanley, 2006). It was also the first drug to have a cure rate approaching 100 % per cent with systemic treatment (Cudmore, et al., 2004).
Presently, metronidazole which is inexpensive has good penetration and produces relatively few side effects, is on the formulary at most hospitals for prophylaxis against anaerobic infection after bowel surgery, for treatment of wound abscess and for treatment of antibiotic associated colitis caused by clostridium difficile (Samuelson, 1999).
Chemistry of Metronidazole
Metronidazole is (2- (2 methyl-5- nitromidazole-1-yl) ethanol) (BP, 1993; Kolawole, 2004 and Usman et al, 2011). However it can be named as [1-(2-hydroxyethyl)-2-methyl-5- nitroimidazole] (Alves et al., 2007; Houghton, et al., 1982 and Phillips and Stanley, 2006). It is a synthetic antimicrobials agent with activity against obligate anaerobic bacterial and protozoa (Kolawole, 2004 and Mustapha, et al., 2006). It is a prototype of nitroimidazole class of antimicrobials (Ezzeldin and El-Nahhas, 2012). It is white or yellowish, odourless crystals or crystalline powder.
CHAPTER THREE
MATERIALS AND METHODS
Materials
The following were the materials used for the study.
Reagents and chemicals used
Analytical grade chemicals and reagents (BDH) were used.
Equipment and glass wares
Various types of glass wares, Analytical weighing balance (Mettler Analytical Balance Phillip Harris., England), Centrifuge Machine (Gallenkamph, England), Dissolution test apparatus (DT
80 – GmbH, Germany), Euweka Disintegration Time Test apparatus (Type ZT3, -GmbH, Germany), Euweka friabilator (Type TA-3R, GmbH, Germany)
Monsanto Hardness tester (Manesty Machines Liverpool, England), pH meter (Fisher Scientific, Singapore), Rotor mixer (Gallankamp, England), UV double beam spectrophotometer (MNF, Helious Zeta, Thermo Scientific England) and Water bath (model BJE 750A Gallenkamp, England)
Samples
Standard metronidazole powder from J. Link China with a batch number 10090704, manufacturing date of 9 September, 2010 and expiry date of 9 September, 2014.
Different brands of metronidazole tablets collected from Zaria metropolis.
Method
Sample collection
Different brands of metronidazole tablets were randomly purchased at different retail pharmacies and drug outlets in Sabon Gari, Zaria City, Tudun Wada, Samaru and Shika in the month of July, 2011. All the tablets were labelled to contain 200 mg of metronidazole as the active ingredient. The samples were coded and stored in the recommended conditions specified by the manufacturer in their original packs prior to the research. The details about the name, manufacturer, production and expiry dates, NAFDAC registration number and batch number were given in appendix I.
Assessment of in-vitro parameters of the samples
Physical Examination
A sachet containing10 tablets for each of the samples was randomly taken, the tablets were removed and examined for lustre, colour, texture, nature of surface and presence of score (Musa, et al., 2011).
CHAPTER FOUR
RESULT
The Results for both in-vitro and in-vivo studies of the samples of metronidazole were shown
Identification Test on the Samples of Metronidazole Tablet
All the Brands of Metronidazole (200 mg) Tablets revealed the presence of Metronidazole in the Tablet Dosage Form using BP 1993 method.
CHAPTER FIVE
DISCUSSION
All the samples of metronidazole tablets examined were registered with the NAFDAC and have reasonable shelf life as shown in table 4.1. This was an indication that the drug products met NAFDAC requirements for pharmaceutical products in Nigeria. All the samples have impressive appearance even though there was variation in organoleptic properties of the samples as shown in table 4.2. However, some of the tablets were scored and some were not scored. The scoring permit accurate subdivision of the tablet in order to provide doses of less than one tablet and also facilitate breaking of the tablet for ease of swallowing a dose consisting of one or more whole tablet (WHO, 2011).
SUMMARY, CONCLUSION AND RECOMMENDATIONS
Summary
- All the samples of metronidazole 200 mg tablets used for the study had good physical appearance.
- The presence of metronidazole was observed in each tablet of the
- Analysis of pharmaceutical equivalence revealed that all the samples of metronidazole tablets had acceptable level of weight variation, except samples MT05, MT08 and MT12 which deviated from the compendial specification. All the samples disintegrated within the BP, 2002 specification except MT07 with a value of 18.97 minutes. All the tablets had acceptable value for active ingredient with not less than 70% value at 45 minutes as specified in the BP, 2002. However, for the unofficial methods, all the sample except MT05, MT07, MT08 and MT11 passed the friability Only MT10 and MT11 failed the hardness test.
- The validated method adopted had good precision and accuracy with high percentage recovery which is an indication that the method is robust and capable for bioequivalence studies of metronidazole from saliva
- All the samples of metronidazole 200 mg tablets dosage form were bioequivalent with a point estimate ratios within 0.8-1.25 for bioequivalence
Conclusion
It has been shown from the validation parameters of the method that it was robust and reproducible with high degree of accuracy for detection of metronidazole from saliva samples. All the samples of metronidazole tablets collected revealed the presence of metronidazole in each of the tablets dosage form, the samples had acceptable level of bioequivalence and thus can be used interchangeably. This shows that there is no difference in the pharmaceutical, chemical and bio equivalences between Loxagyl® and other brands of metronidazole marketed in Zaria metropolis during the course of this research. However, there was variation in the pharmaceutical parameters of the samples. Sample MT05, MT08 and MT12 failed weight variation test. MT05, MT07, MT08 and MT11 failed friability test; while MT10 and MT11 failed the hardness test. However, statistical analysis of bioequivalence parameters shows no significant statistical difference. Thus, the samples have comparable bioavailability.
Recommendation
- More precise analytical methods such as HPLC, may be used to reassess the studies using a larger sample
- the Considering the recently introduced, Mega drug distribution system by federal government in the country, there is need to establish and maintain quality control laboratories in all state of the federation to ensure distribution of safe and effective drugs in all the distribution chain.
- There is need to have a guideline for bioequivalence study in the country by the regulatory agency as most of the drugs in use in the country are
- There should also be a need for routine post market surveillance of pharmaceuticals by the regulatory agencies to ensure the quality of drugs at different channels of
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