Documente Academic
Documente Profesional
Documente Cultură
Mekelle Ethiopia
Title: COMPARATIVE IN VITRO QUALITY EVALUATION ON DIFFERENT BRANDS
OF THE COMMONLY PRESCRIBED ANTHELMENTIC DRUGS, MEBENDAZOLE
TABLETS, FROM DRUG RETAIL OUTLETS IN MEKELLE TOWN, TIGRAY, ETHIOPIA
Helminths affect mostly school-age children from 1-14 years. In Cameroon and India more than
two thirds of children at this age group are affected (WHO, Eliminating soil transmitted
helminthiasis as a public health problem in children ; progress report 2001-2010 and strategic
plan 2011-2020., 2012). It is estimated that more than 610 million school-age children are at risk
of contracting helminths. The prevalence of these diseases in Cameroon and India is between
(WHO, Eliminating soil transmitted helminthiasis as a public health problem in children ;
progress report 2001-2010 and strategic plan 2011-2020., 2012).
Infection with intestinal helminthes is one of the most common health problems of children in
developing countries. Moreover, chronic intestinal helminthic infections have been identified as
one of the possible risk factors that contribute to the pathogenesis as well as the widespread of
other infectious agents such as HIV and mycobacterium in the tropical countries ( (Bentwich,
Kalinkovich, & Weisman, 1995)).
3. Literature review
It is imperative to gain a mebendazole tablet with good bioavailability and bioequivalence
properties. In this context, studies conducted on comparative in vitro quality evaluation on
different brands of mebendazole tablets is a prerequisite to get a good quality of mebendazole
tablet
Therapeutic effectiveness and quality of pharmaceuticals
For a drug to be effective, enough of it needs to reach its site(s) of action and stay there long enough to be
able to exert its pharmacological effects. Many factors have been found to influence the rate and extent of
absorption, and hence the time course of a drug in the plasma and, therefore, at its site(s) of action. These
include the foods eaten by the patient, the effect of the disease state on drug absorption, the age of the
patient, the sites of absorption of the administered drug, the co-administration of other drugs. In addition,
the physical and chemical properties of the drug, the type of dosage form, the composition and method of
manufacture of the dosage form, the size of the dose and frequency of administration are among the
factors, which are almost addressed in quality assessment studies (Ashford, 2002).
The presence of substandard pharmaceutical products in the drug distribution chain may produce a danger
to public health. Drug quality reports by the United States Pharmacopoeia Drug Quality and Information
Program in different countries e.g. Benin, Ghana, Nigeria, Bangladesh, Cambodia, China revealed that a
large number of drugs failed quality testing. Some of these drugs were found to contain active ingredients
outside the appropriate limits and most of them below the limits. Such drug products have therapeutic as
well as social and economic implications (World Health Organization, 1999).
Pharmaceutical quality
Pharmaceuticals play an important role in improving human health and promoting well- being.
However, to produce the desired effect, they have to be safe, efficacious and of acceptable quality, and
have to be used rationally. The use of ineffective and poor quality drugs will endanger therapeutic
treatment and may lead to treatment failures. Thus, the production, storage, and distribution of drugs in
each country need to be regulated by the government drug regulatory authority. Challenges to these drug
regulatory authorities are the flourishing of many pharmaceutical industries and distribution channels
during the past few years in the world, leading to an increased number of products circulating in national
and international drug markets. In the same manner, the presence of counterfeit and substandard drugs in
those markets has increased substantially as a result of ineffective regulation of the manufacturers and
trading of pharmaceutical products by both exporting and importing countries (World Health
Organization, 1999).
Marketing of poor quality drugs is high in developing countries, especially of Africa and Asia because of
weak drug regulatory systems. Thus, in countries like Ethiopia, where drug regulatory control is weak, the
quality of marketed drug products cannot be guaranteed. Quality assessment studies on some of the
marketed drug products could give an insight into the quality of the pharmaceutical products marketed
within the distribution chain and consumed. Such studies could provide basis for corrective measures
taken by drug regulatory authorities.
Quality control parameter and properties and properties of tablet dosage forms
The need for precisely defined and acceptable specifications for production control during
manufacturing processes and for the final products, in order to assure reproducibility in the wide
context of drug safety, is recognized. The assurance of quality of medicines is the primary
responsibility of the manufacturers (internal quality control).
However, it is recognized in most countries that the national health authorities must exercise
comprehensive surveillance by legislative methods over pharmaceutical manufacturers within
their jurisdiction, in order to ensure observance of good manufacturing practices and quality
control of products. During research, development and formulation, physicochemical analysis
and analytical profiles of drug substances provide good quality control data on which good
decisions can be established (deasy & Timoney, 1976).
Assessment of quality, safety and efficacy constitutes an important component of pharmaceutical
product evaluation, which is based on quality control tests. The minimum quality control tests for
pharmaceutical preparations are illustrated in Table1.1 (Ayeres G, 1981)
Tablets have some apparent features, like certain amount of hardness and resistance to friability,
tablet dosage form uniformity (weight variation, content uniformity), disintegration, and drug
dissolution. Each property will influence the other as hardness has influence on both friability and
drug dissolution. All are tablet properties that can be utilized as parameters for drug quality control.
The following physicochemical parameters (hardness and friability, content of uniformity,
weight variation, disintegration, assay of active ingredient, and dissolution test of tablet
have been taken directly from United State Pharmacopeia (USP, 2014)
Hardness and friability
Tablets require certain degree of strength and resistance to friability to withstand mechanical
shocks of handling during manufacturing, packaging, shipping and utilization by the patient.
Hardness is a force required to break a tablet across the diameter. The hardness of a tablet is an
indication of its strength. The hardness was measured using Schleuniger-2E Hardness tester. The
values were expressed in Newton (N).
The friability of tablets is determined by using ERWEKA TA Friabilator. Ten tablets will
weighed and placed in the Friabilator and rotated at 25 rpm for 4 minutes. Then the tablets will
take out, dusted and reweighed. The percentage friability of the tablets will calculated by the
formula, Percentage Friability = [(Initial Weight – Final Weight)/ Initial Weight] × 100. Three
trials per brand will perform.
This term includes both the mass of the dosage form and the content of the active substance in
the dosage form. These are expressed in terms of content uniformity or weight variation; which
are among the parameters of tablet quality control.
Weighed accurately 250 mg of drug then dissolve in 3 ml of anhydrous formic acid and 30 ml of
anhydrous glacial acetic acid and titrate with 0.1 M perchloric acid. The end point will
potentiometrically determined (1 ml of 0.1 M perchloric acid = 29.53 mg of C16H13N3O3).
Weight variation
Twenty tablets of each formulation were selected at random and weighed individually. The
weight of individual tablets was noted. Average weight was calculated and the individual
weights were compared with the average weight.
Disintegration
For the active medicinal agent in a tablet to become fully available for absorption, the tablet must
first disintegrate and discharge the drug to the body fluids for dissolution.
Disintegration test was carried out by using ERWEKA ZT 3 Disintegration test apparatus. One
tablet is placed in each tube, and the basket rack was positioned in a 1-litre beaker of distilled
water, at 37°C ±2°C. A standard motor-driven device is used to move the basket assembly
containing the tablets up and down through a distance of 5 to 6 cm at a frequency of 32 cycles
per minutes. The time taken for the tablet to disintegrate completely was noted.
Assay for the active ingredients
Assay is a critical step in analytical sciences. It is the determination of the strength or content of
the active ingredient within the dosage form. The quantitative determination of a drug dosage
form is preferentially performed by physicochemical methods. Such analytical techniques are
very diverse and successfully applied to the assay of the active medicinal agent in the
pharmaceutical tablets. The technique should provide specificity, accuracy, precision and
sensitivity to the particular ingredient of interest within the dosage form.
Dissolution Test as Quality Control Parameters
Drug absorption from a solid dosage form after oral administration depends on the release of the
drug substance from the drug product, the dissolution or solubilization of the drug under
physiological conditions, and the permeability across the gastrointestinal tract. Thus in vitro
dissolution may be relevant to the prediction of in vivo performance. In vitro dissolution tests for
immediate release dosage forms, such as tablets, are used to assess lot to lot quality of drug
product and ensure continuing drug product quality and performance after certain changes such
as changes in formulation, the manufacturing process and the site of manufacture (FDA, 1997).
In general, in vitro dissolution rate measurements have been used in a variety of ways including:
To study the effects of physicochemical variables of the pure drug on dissolution rates.
To study variables such as manufacturing processes, tablet coating, excipients, on
dissolution characteristics of the dosage form.
To screen potential dosage form candidates for in vivo bioavailability studies.
As a retrospective study to explain clinical failures of a particular dosage form.
As a sensitive quality control procedure to detect changes in the release characteristics
due to lot-to-lot variations, formulation changes, or storage conditions, which may or
may not be detected in less sensitive in vivo absorption.
Dissolution, Bioavailability and Bioequivalence
Literatures showed that there might be variations in clinical response among orally administered
drug products that contain chemically equivalent amounts of a drug due to differences in their
dissolution rates. This is a useful indication of the influence of dissolution rate on absorption and
bioavailability of drugs for clinical use (Banakar UV, 1992).
‘’Bioequivalence’’ is a comparison of the bioavailability of two or more drug products. Thus,
two products or formulations containing the same active ingredient are bioequivalent if their
rates and extents of absorption are the same. For a drug product to be considered bioequivalent to
a pioneer product there must be no statistical differences (as specified in the accepted criteria)
between their plasma concentration-time profiles, with some degree of acceptable tolerance
limits.
Bioavailability assessment and in vitro/ in vivo correlations
The term commonly used to describe such relationship is in vitro/in vivo correlation. If such
correlation could be established, it would be possible to use in vitro data to predict a drug’s in
vivo bioavailability. This would drastically reduce, or in some cases, completely eliminate the
need for bioavailability tests. The desirability for this becomes clear when one considers the cost
and time involved in administering drugs to healthy subjects or patients. It would certainly be
preferable to be able to substitute quick, inexpensive in vitro tests for in vivo bioavailability
studies (Banakar UV, 1992).
In vitro methods of assessing bioavailability
Evidences provided us with formulation variables that can greatly affect the bioavailability and
thus the clinical efficacy of many important therapeutic agents. Various in vivo and in vitro
physical methods have been developed to assess these effects. The release of a drug from the
dosage form into solution in the gastrointestinal fluids is often the rate-limiting step in
determining the rate and extent of absorption and thus in vitro measurements on disintegration
and dissolution provide a rapid, sensitive and reproducible means to study and assess the
bioavailability without involvement of human experimentation (Jollow, 1972).
Dissolution test for assessing bioavailability
Dissolution test is currently considered to be the sensitive and reliable in vitro parameter most
likely to correlate with bioavailability. Since dissolution of a dosage form in vivo is often a rate
limiting factor determining the physiologic availability of a drug, measurement of the in vitro
dissolution rate is more likely to offer a meaningful indication of physiologic availability.
Dissolution testing is implemented in the assessment and evaluation of the release rates and
bioavailability of a variety of conventional tablets. It is believed that if a tablet does not dissolve
properly in in-vitro test, it certainly will not do so in in-vivo tests for dissolution (Banakar UV,
1992).
Official dissolution methods
Dissolution tests provide an indication for differences in in-vivo absorption characteristics of the
drug and serve as a secondary standard to detect dosage forms with a potential for poor
bioavailability. It involves official methods. There are two official USP dissolution methods:
Apparatus-1 (Basket method) and Apparatus-2 (Paddle method) (Figure 1.5 and 1.6).
In Ethiopia The availability of numerous brands of mebendazole in our drug market today places
clinicians and pharmacists in a difficult situation of choice of a suitable brand or the possibility
of alternative use. Currently, large-scale deworming programs are intensifying, highlighting the
need to closely monitor the efficacy of anthelmintic drugs to detect changes in drug efficacy that
may arise through the evolution of anthelmintic drug resistance in the parasites (Bruno levecke,
2014) Therefore, the current study is aimed to evaluate the bioequivalence of the different brands
of mebendazole in Mekelle town, Tigray Regional State. To the best of my knowledge, this study
is the first to evaluate the bioequivalence of the different brands of mebendazole. It will also use
as a reference for further studies in the future.
5. Objectives
6. EXPERIMENTAL
6.1. Materials and Methods
6.1.1. Materials
6.1.1.1. Tablets and reference standards
6.1.1.2. Solvents / Chemicals/ Reagents
6.1.1.3. Instruments
6.1.2. Methodology
6.1.2.1. Identification
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