This study was undertaken to assess the
Introducing generic products from multiple sources into health care systems exist in many countries in an approach aiming to improving the overall healthcare system. However, this has been accompanied by a variety of problems, the most critical of which is the widespread distribution of counterfeit or substandard products.
Product selection of the same active ingredients from several generic products available in the market is very important step during the course of therapy and cause several concerns to a healthcare practitioner. Therapeutic equivalence must be insured by ascertaining the biopharmaceutical equivalency of such drug products [
Drug products that are therapeutically and chemically equivalent must have the same strength, quality, purity and content uniformity, and disintegration and dissolution rates [
To reduce the medicines expenditure burden on a healthcare system, the World Health Organization (WHO) has continuously advocated the use of generic products but this should be supported with sufficient evidence for the substitution of one brand for another. This could not be achieved without proving its efficacy through bioequivalence studies [
Bioequivalence studies for generic products are essential to ensure the absence of any significant difference in the rate and extent to which the active ingredients become available at the site of drug action administered under similar conditions in an appropriately designed study [
However, evidences reported in literatures and in clinical practice as well indicate that marketed products with the same amount of active ingredient exhibit marked differences in their therapeutic responses [
Dissolution testing, a surrogate marker for bioequivalence test, is a very practical and economic approach to identify bioavailability problems and assess the need for
The pharmaceutical market in the UAE is flooded with imported and locally manufactured generic products with no chemical/biopharmaceutical in-equivalencies have been reported so far. Raising this question, do these generic products have the same efficacy, quality, and safety? Quality control is the only answer to such question concerns of quality, safety, and efficacy of generic drugs in the market. Healthcare professionals are confronted with wide varieties of multisource generics and the only answer to their confusion will be performing quality control testing and bioequivalence testing for these products.
This study aims to assess the bioavailability of ciprofloxacin from selected generic products available in the UAE market. There are several brands of ciprofloxacin hydrochloride tablets available in the UAE market. The increasing use of ciprofloxacin hydrochloride tablets recently is a result of its versatility in the management of various cases of microbiological infections [
Ciprofloxacin (CFX) is one from the fluoroquinolone groups which are synthetic broad spectrum bactericidal anti-infective agents with outstanding antibacterial activity against Gram-negative and certain Gram-positive bacteria as well as some Chlamydia and Mycoplasma, and many mycobacterium species [
Its mode of action is the inhibition of the essential enzyme for DNA replication and synthesis (DNA gyrase) [
For the health care providers to use these brands interchangeably, the bioequivalence of these brands have to be ascertained. This means that there should be continued postmarketing surveillance of the drugs. The purpose of this study is to study the bioavailability and the pharmacokinetic properties of ciprofloxacin after single-dose oral administration and to compare the absorption characteristics of the different generic products for ciprofloxacin compared to the branded product in rabbits.
All chemicals were analytical grade. Ciprofloxacin and lomefloxacin were obtained as a gift from Gulf Pharmaceutical Industries (RAK, UAE). The different ciprofloxacin brands A, B, C, D, E, and F were purchased from retail pharmacies in the UAE. Dissolution apparatus (Copley dissolution 6000, Copley Scientific, U.K.) using a paddle stirrer and an UV-1700 spectrophotometer (Shimadzu, Scientific Instrument Division) was used. Acetonitrile, acetic acid, HCl (0.1 N), and methanol were from Sigma-Aldrich. All solvents were of HPLC grade.
The dissolution rates for all ciprofloxacin generic product as well as the reference product (Ciprobay) were tested (
Difference factor (
The compared dissolution curves are considered similar and bioequivalent, if
Twenty-four healthy white albino rabbits of either sex ranging in body weight from 1 to 1.2 kg were used. All the animals were maintained under similar conditions. The animals were fed with fresh green fodder and black gram in the morning and evening, while water was provided freely as much they required.
Pharmacokinetics of Ciprofloxacin from the different generic formulations was studied after administration of an oral dose in normal rabbits. The study was approved by the research and ethical committee in Dubai Pharmacy College.
Rabbits were randomly divided into four groups (
The blood samples were collected through the central vein of the rabbits in heparinized glass centrifuge tubes with the aid of sterilized disposable plastic syringes just before and at 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hrs after the drug administration. The blood samples were centrifuged at 5000 rpm for 10 min to separate the plasma for analysis.
The concentration of CFX in plasma was determined by the high performance liquid chromatographic procedure as described by Kordick et al. with some modifications [
Analysis of samples was performed using HPLC system equipped with Waters 1515 pump, Waters 2487 detector, Waters 717 P auto-samplers, and Waters C18 column (5.0
The ultraviolet (UV) detector was set at a wavelength of 279 nm. The column temperature was adjusted to be around 40°C in all cases.
The retention time for ciprofloxacin was 3.9 minutes with limit of detection (LOD) of 0.02
An equal amount of 5% perchloric acid was added to the plasma samples to separate proteins, vortexed for two minutes, and then centrifuged at 2000 rpm for 10 minutes. The aliquot was separated for injecting into the HPLC system.
Pharmacokinetic analysis was performed by both compartmental and noncompartmental approaches using WinNonlin PK software (Scientific Consulting Inc., Apex, NC). Plasma concentrations of ciprofloxacin versus time profile for selected generic formulation and the reference of each animal under nonsteady state condition were used to determine the disposition kinetic variables using compartmental model [
Results are expressed as mean ± S.D. for triplicate samples. The statistically significant difference among the groups was determined by one-way analysis of variance (ANOVA) using
The pharmacokinetic data derived by compartmental and noncompartmental methods were statistically compared applying Tukey’s
Figure
Dissolution profiles of ciprofloxacin (500 mg tablets) from the five tested generic products and the reference in 0.01 N HCl.
These results suggest that the formulation and/or the manufacturing process can affect the dissolution and thus the bioavailability of the drug product. Proper drug formulation will allow for the drug to reach its site of absorption, the upper part of the GI tract (duodenum/jejunum) in a solution form. The bioavailability will then be determined by its
Differences in the
The calculated similarity factor and difference factor for all ciprofloxacin dissolution profiles obtained from the 5 tested generic ciprofloxacin products compared to the reference.
Product |
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A | 44.63 | 13.55 |
B | 66.95 | 3.56 |
C | 58.17 | 0.78 |
D | 48.40 | 3.73 |
E | 58.43 | 5.90 |
From the presented data, it is noted the difference factor for all formulations compared to the reference data was within the range of 0–15 and the dissolution profiles for all formulations were comparable to that of the reference with a similarity factor
The mean drug plasma concentration after the administration of the five generic ciprofloxacin products as well as the reference product is shown in Figure
: Drug plasma concentration profiles after the administration of the 500 mg Ciprofloxacin dose from the five generic products and the reference in rabbits.
The plasma concentration-time data was best fitted to a biexponential equation corresponding to a two-compartment open model. The distribution
Two-compartment open model.
The noncompartmental and compartmental pharmacokinetic parameters (Mean ± SD) of ciprofloxacin after the oral administration of the different formulations in rabbits are presented in Tables
Noncompartmental analysis of ciprofloxacin from the tested products and the reference products after oral administration in rabbit.
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AUC last (hr·mg/L) |
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Lambda_z (1/hr) |
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HL_Lambda_z (hr) |
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AUC INF_obs (hr·mg/L) |
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Vz_F_obs (L) |
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Cl_F_obs (L/hr) |
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AUMClast (hr·hr·mg/L) |
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MRT last (hr) |
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Compartmental analysis of ciprofloxacin from the tested products and the reference product after oral administration in rabbit.
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Alpha (1/hr) |
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Beta (1/hr) |
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K12 (1/hr) |
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K21 (1/hr) |
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Alpha_HL (hr) |
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V1_F (L) |
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CL_F (L/hr) |
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The disposition kinetic parameters of ciprofloxacin based on the noncompartmental model of analysis are also listed in Table
Times to reach maximum drug concentration in plasma, maximum drug concentration, elimination rate constant, and renal clearance were not influenced by different generic products with a nonsignificant
Following compartmental model, the distribution and elimination half-lives of ciprofloxacin in rabbits were ranging between 0.34 and 3.63 hr and 2.99 and 4.32 hr, respectively. Time to reach maximum concentration was comparable with a maximum
Times to reach maximum drug concentration in plasma, maximum drug concentration, and renal clearance were not influenced by the different generic products with a nonsignificant
There was a statistically significant difference among the different formulations with respect to the estimated AUC with product B of smaller area under the curve (46.60 ± 2.54 hr*mg/L) compared to other products with a
The relative bioavailability of the different generic products compared to the reference was calculated as shown in Table
Relative bioavailability of the 5 tested generic products compared to the reference.
Bioavailability | A | B | C | D | E |
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(%) | 93.24 | 98.05 | 104.01 | 101.58 | 108.01 |
Six ciprofloxacin branded products were used and were within their shelf life as at the time of the study. The different brands of ciprofloxacin hydrochloride tablets were obtained from different retail pharmacy outlets within the UAE and were subjected to both
According to the FDA guidance for the industry concerning the dissolution testing of immediate release solid oral dosage forms, the biopharmaceutical classification system (BCS) suggests that drugs classified with class I and in some cases class III should release at least 85% of the drug upon drug dissolution in 0.1 N HCl in 15 min.; in this type, the bioavailability of the drug is not limited by dissolution [
To compare the dissolution profiles of the different generics versus the brand, a model independent approach of difference factor
In the present study, ciprofloxacin mean plasma concentrations in rabbits were determined and were between 9.57 and 10.89 mg/L, which are many times greater than the MICs for most susceptible organisms. The relative bioavailability of all ciprofloxacin formulations in rabbits was 93% to 108% after a 500 mg oral dose. Bioavailability was calculated by using AUC ratios corrected for dose. Following oral administration of the different ciprofloxacin formulations, ciprofloxacin plasma concentration versus time data in rabbits were best fitted to a two-compartment open model. This is comparable to the results of other studies in sheep [
The elimination half-life of ciprofloxacin after compartmental analysis in rabbits was determined to be within the range of 2.99–4.32 h and was longer than that of 2.44 h in preruminant calves [
The apparent volume of distribution
Based on the compartmental model of analysis, distribution kinetic parameters, namely, distribution rate constant, distribution half-life, and rate constants of the transfer of drug from central to peripheral compartment
From both studies, the
The high demand for having the different generic products is essential to reduce the pharmaceutical expenditure worldwide. However, postmarketing monitoring is very crucial to ensure better clinical outcome. The problem of fake and substandard medicines remains the big challenge that regulatory authorities may face and thus arises the need for adequate quality assurance and quality control of drugs. Assessment of bioavailability of the different generic products available in the market is very important to ensure that generic drugs being sold can be used interchangeably with the branded products. In the UAE, all tested ciprofloxacin generic products were proven to be of good quality and there is no fake or substandard medicine identified to be marketed in the UAE market.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors would like to thank Professor Saeed Ahmed Khan, Dean of Dubai Pharmacy College for facilitating this project. Special thanks also go to Lama Lozon, Maimona Jairoon, Arwa Kassim, and Samira Maher who helped in this research.