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Mona El Assal

Basic information

Name : Mona El Assal
Title: Associat Professor of Pharmaceutics at Pharmaceutics and Pharmaceutical Technology department at FUE University.
Google Schoolar Link: https://scholar.google.com.eg/citations?user=eABJu44AAAAJ&hl=en
Personal Info: Dr. Mona Ebrahim. Associat Professor of Pharmaceutics at Pharmaceutics and Pharmaceutical Technology department.She got her Master and Doctoral degree from Cairo University View More...


Certificate Major University Year
PhD Pharmaceutics and Clinical Pharmacy. Cairo University 2005
Masters Pharmaceutics and Clinical Pharmacy. Cairo University. 2000
Bachelor Pharmaceutical Sciences Cairo University 1984

Teaching Experience

Name of Organization Position From Date To Date
Military Medical Academy Consultant of Army Pharmaceutical Industry and Lecturer 01/01/1992 01/01/2011

Researches /Publications

Formulation, Optimization, and Evaluation of Solid Dispersions of metformin HCl Using Factorial Design - 01/1

Mona Ebrahim Abdel Tawab Ahmed Elassal

Mona El Assal, Mohammed mannaa, Ahmed Abdel Bary,


ABSTRACT The objective of this study is to achieve the controlling dissolution rate of Metformin HCl, a freely water soluble antidiabetic drug. Solid dispersions microcapsules were prepared using solvent evaporation method which enclosed preparation of a uniform dispersion of Metformin HCl in (Hydroxy propyl methylcellulose k100, Ethyl cellulose, Eudragit RL PO, RS PO & Compritol 888 ATO). A two-factor, General factorial statistical design was used to quantitate the effect of polymer type (X1) and drug: polymer ratio(X2) on the release profile. Where polymer type and drug: polymer ratio were selected as independent variables, while Y1 (cumulative drug release after 1 hr. ) and Y2 (cumulative drug release in 3 hrs. ), Y3 (cumulative drug release in 10 hrs.),Y4 (angle of repose ) and Y5 (Hausner ratio) were selected as dependent variables. The solid dispersions were characterized for their in vitro- release rate. The optimized formulation was further characterized by Drug scanning calorimetry, infrared spectrophotometry, X-Ray Diffractometer and SEM analysis. A convenient statistical model was made and a significantly controlled release rate was exhibited .the optimized formulation was investigated by DSC, XRD, FTIR and SEM data which showed the crystalline nature of Metformin HCl in a solid dispersion, the statistical model helped us to recognize the effects of formulation variables on the dispersion. Keywords: Metformin HCl, Solid dispersion, controlled release, factorial design, HPMC k 100, Ethyl cellulose, Eudragit RL, RS& Compritol ATO 888.

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Gelatine Based Nanoparticles as Drug Delivery System of Lornoxicam Gel - 01/1

Mona Ebrahim Abdel Tawab Ahmed Elassal


Abstract: The purpose of contemporary study was to project GNP by using of two step desolvation method. Biodegradable hydrophilic gelatin nanoparticles used as a delivery system of anti-inflammatory lornoxicam after gel formulation using each of hydroxyl propyl methyl cellulose (HPMC) and carbopol as gelling agent. The size and shape of the nanoparticles were examined by optical microscope and transmission electron microscopy, particles with a mean diameter of 240.6 nm and 0.1 poly dispersibility index PDI were produced and the percentage of entrapment efficiency was found to be 87.1%. The optimum amount of LOR loading was obtained. Four formulas were prepared F1 standard LOR carbopol gel, F2 standard LOR HPMC gel, F3 GNP –LOR containing carbopol as gelling agent and F4 GNP –LOR which has HPMC as gelling agent are GNP-LOR gel. Permeation of drug through membrane was determined by Franz diffusion cell. Further stability studies were carried out at 4Co for a period of 8 weeks. Vivo study was carried on white albino male rats to compare between different lornoxicam gel formulations. Conclusion: Results show that the two step desolvation is an appropriate method for preparing GNP. LORF3 which has carbopol as gelling agent was of lower release rate with maximum % inhibition of edema.

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Single dose Linezolid Pharmacokinetics in ill Patienys with Impaired Renal Function Epecially Chronic Hemodialysis Patients - 01/0

Mona Ebrahim Abdel Tawab Ahmed Elassal


ABSTRACT: Background and Objective: Renal failure patients were treated with linezolid (LZD) for proven or suspected infections by multi-resistant Gram-positive cocci. The aim of this study was to determine if dose adjustment of LZD is needed as a function of renal impairment or not, especially that a significant component of LZD is eliminated unchanged in urine. Methods: The single dose pharmacokinetics of LZD was investigated. Eighteen non-infected male subjects with various degrees of renal impairment ranged from normal to severe chronic impairment were enrolled, including end-stage renal disease (ESRD) patients maintained on hemodialysis (HD). LZD was administered as a single oral 600mg dose, and blood samples were drawn at different times and analysed by a validated HPLC assay method. Plasma profiles were evaluated by non-compartmental and compartmental approaches. Results and Discussion: A similar rate and extent of LZD absorption and elimination and comparable body exposure was observed in both healthy subjects and acute renal failure patients. The extent of LZD exposure was significantly increased by 3-fold in ESRD patients in their off-dialysis day. Furthermore, the t1/2 and MRT values were significantly increased by ~5- and 3-fold, respectively. The Vd/F values of LZD did not change with renal function. A significant decrease in CL/F by ~3-fold was observed in ESRD patients in their off-dialysis day however, CL/F was significantly increased by ~4-fold during HD. Approximately half of the administered LZD dose was removed during the HD session in these selected cohorts of ESRD patients. LZD was generally well tolerated. Conclusions: The dose of LZD did not need to be adjusted for patients with acute renal dysfunction or ESRD on HD. One of the twice-daily doses should be administered after the dialysis session because almost half of the LZD dose was substantially removed by HD. During the first three dialysis sessions of the treatment course, to avoid potentially ineffective therapy, a supplemental dose of LZD might be given if necessary or the dose of LZD should be administered 4 h before the beginning of the HD session. This was to keep LZD levels above the MIC for the organism causing the infection being treated.

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Post Marketing Bioequivalence Study of Six Brands of Ciprofloxacin HCl in Egypt Market and Evaluation as a Treatment of Human Periodontal Pockets - 01/0

Mona Ebrahim Abdel Tawab Ahmed Elassal


© Journal of Medical and Pharmaceutical Innovation, All Rights Reserved. Vol.1, Issue 6, 2014. Research Article Post Marketing Bioequivalence Study of Six Brands of Ciprofloxacin HCL in Egyptian Market and Evaluation as a Treatment of Human Periodontal Pockets Mai M.I.1, Mona I. El Assal2*, Mohamed A.K.3 1Military Medical Academy, Cairo, Egypt. 2Department of pharmaceutical technology, faculty of pharmaceutical science and pharmaceutical industries, Future University in Egypt. 3Department of Pharmaceutics, faculty of Pharmacy, Cairo University, Cairo, Egypt. ABSTRACT The availability of numerous brands of ciprofloxacin HCl 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. The aim of the present study was to evaluate physical standards of six brands of ciprofloxacin HCl tablets marketed in Egypt using in-vitro tests and then in vivo bioequivalence of best two brands of ciprofloxacin HCL, finally their evaluation in treatment of human periodontal pockets. The in-vitro dissolution study was carried out on six brands of ciprofloxacin HCl tablets using basket method according to US pharmacopoeia guidelines. Other general quality assessment tests like Weight variation, hardness, friability, drug content uniformity y and disintegration were also determined. Then brands of ciprofloxacin HCl were subjected to in-vivo efficacy studies in treatment of human periodontal pockets. Significant results were obtained with respect to both microbiological and clinical parameters. For evaluation of bioequivalence of best two brands of ciprofloxacin HCl, blood samples were taken, plasma concentration of ciprofloxacin HCl brands were determined by simple HPLC method. The pharmacokinetic parameters, Including peak plasma concentrations and time needed to reach the peak were obtained directly from plasma concentration–time profiles. The area under the curve was calculated using noncompartmental methods. Statistical analysis of in-vitro and in-vivo studies shows that ciprofloxacin brands are effective in treating periodontal pockets in order of ciprobay, cipromax, mifoxin, ciprocin, rancif and ciprofar. Statistical analysis of main parameters confirm the bioequivalence of the ciprofloxacin formulations in terms of pharmacokinetic characteristic, the results from this study demonstrate that Ciprobay and Cipromax are interchangeable in the clinical setting. Keywords: Bioequivalence, ciprofloxacin, periodontal pocket, Dissolution QR Code for Mobile Users Address for Correspondence: Mona I. El Assal Department of pharmaceutical technology, faculty of pharmaceutical science and pharmaceutical industries, Future University in Egypt. Email: drmona_2012@hotmail.com Conflict of Interest: None Declared! (Received 26 Novemberr 2014; Accepted 15 December 2014; Published 19 December 2014) ISSN: 2347-8136 ©2014 JMPI INTRODUCTION: Post-market surveillance or monitoring involves all activities undertaken to obtain more data and information about a product after it had been granted marketing authorization and made available for public use. The data and information so obtained Mona I. El Assal et al.: Journal of Medical and Pharmaceutical Innovation; 1 (6) 2014; 35-43 © Journal of Medical and Pharmaceutical Innovation, All Rights Reserved. Vol.1, Issue 6, 2014. 36 could be employed for product improvement, development of standards and regulations. Regulatory agencies rely on limited information obtained during clinical trials and to some extent scientific literature as guides to granting marketing authorization of medicines for public use. It is therefore imperative to conduct post-market surveillance or monitoring of approved medicines in order to adequately assess the quality, therapeutic effectiveness and safety of medicines for the larger public Post-market monitoring ought not to be a one off event rather it should be a continuous event throughout the life of a drug product. Activities of post market monitoring of a drug have been identified to include: review of product’s condition of approved study; evaluation and investigation of reported drug complaints; inspection of manufacturer’s processes and procedures for production and complaint handling; market surveys of technical and clinical documentation; review of product claims/labeling; public access to information taken and reported to the regulatory agency(ies); and in vitro testing of products for compliance to Standards (Garcia J, 2006). In vitro testing or quality control of drugs is a set of studies or experiments undertaken during production and occasionally ought to be undertaken post production by regulatory agencies and researchers. Routine laboratory testing of drugs in the market is crucial to protect public health especially in developing countries where counterfeit and substandard drugs have become a major challenge to health care services. Counterfeit and substandard medicines are a major cause of morbidity, mortality and loss of public confidence in drugs and health structures (Cockburn et al.,2005). Bioequivalence has been described as the absence of a significant difference in the rate and extent to which the active ingredient or moiety in pharmaceutical equivalents or pharmaceutical alternatives become availabl e at the site of drug action (that is ,a significant difference in the bioavailability of the 2 drug products) when they are administered at the same molar dose under similar conditions in an appropriately designed study (FDA,2003). Generic substitution could be considered when a generic copy of a reference drug contains identical amounts of the same active ingredient in the same dose formulation and route of administration as well as meet standards for strength, purity, quality and identity (Meredith, 2003). Bioequivalence studies may involve both in vivo and in vitro studies. In vitro Dissolution testing, a surrogate marker for bioequivalence test and may be vital in assessing in vivo performance. Dissolution testing also serves as a tool to distinguish between acceptable and unacceptable drug products (Ochekpe et al., 2006). In the present study the bioequivalence of two ciprofloxacin brands was evaluated in vivo by comparing the pharmacokinetic parameters derived from serum ciprofloxacin concentration-time profiles. Periodontal infection results either from the penetration of pathogenic microorganisms in the tissues, or even the activation of already existing germs, but not pathogenic under normal condition. This responsible flora is polymorphic, gram negative and microaerophilic or strictly anaerobic. Only ten or twenty species, regarded as pathogens, play a role in the pathogenesis of periodontal destruction (Darby et al, 2001). These poly¬microbial infections involve bacteria called periodontal pathogens, most of them gram-negative and strictly anaerobic, which act in synergy. Among these species, the most important are Aggregatibacter actinomycetem¬comitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Fusobacterium nucleatum, Prevotella intermedia ,Prevotella nigrescens , Campylobacter rectus , Eikenella corrodens and Peptostreptococcus micros ( Feng Z et al, 2006) . Ciprofloxacin is effective against several periodontal pathogens, including A. actinomycetemcomitans (Slots J et al, 1990). This antibiotic effectively penetrates the diseased periodontal tissues and can reach higher concentrations in the crev¬icular fluid than in the serum .Ciprofloxacin-metronidazole (500 mg of each, twice daily for 8 days) is indicated for periodontitis involving a mixture of enteric gram-negative facultative rods and anaerobic bacteria (Slots J, 2004). EXPERIMENTAL 1. Materials 1.1. In vivo evaluation: 6 different brands of ciprofloxacin as shown in Table 1 were purchased from different companies in Egypt pharmacies. The reagents utilized include hydrochloric acid and ferric chloride. Mona I. El Assal et al.: Journal of Medical and Pharmaceutical Innovation; 1 (6) 2014; 35-43 © Journal of Medical and Pharmaceutical Innovation, All Rights Reserved. Vol.1, Issue 6, 2014. 37 Drug Average Weight variation (mg) Average Hardness (kg/cm3) Friability % Average Drug Content (mg) Average Disintegration (min) ciprobay 781.4 9.3 0.19 500.02 3.1 Mifoxin 859.5 14.1 0.062 495.2 5.1 Cipromax 768.1 16.2 0.006 483.5 6.3 Ciprocin 634.8 16.9 0.014 475.01 6.9 Rancif 748.7 17.5 0.341 462.2 7.2 Ciprofar 930.6 29.7 0 458.9 8.2 Table 1: The quality control tests undertaken on six brands of ciprofloxacin 1.1.1 Determination of uniformity of weight 10 tablets from each of the 6 brands were weighed individually with an analytical weighing balance (Mettler). The average weights for each brand were obtained. 1.1.2 Hardness test The crushing strength was determined with a tablet hardness tester(Shital scientific, England). 4 tablets were randomly selected from each brand and the pressure at which each tablet crushed was recorded. 1.1.3 Friability test 10 tablets of each brand were weighed and subjected to abrasion by employing a Roche friabilator (Erweka Gmbh, Germany) at 25 rev/min for 4 min. The tablets were then weighed and compared with their initial weights and percentage friability was obtained. 1.1.4 Assay A solution of 1% w/v ferric chloride was freshly prepared as well as100 mcg/ml of pure ciprofloxacin. 5 tablets from each brand were crushed and 100 mg of the powdered samples were weighed,dissolved in 100 ml 0.1N hydrochloric acid (HCl) and further dilution was made to obtain 100 mcg/ml for each brand. To 5 ml of each brand and the pure sample, 1 ml of ferric chloride was added and made up to 50 ml with 0.1N HCl. The absorbance of each sample was taken at 438 nm against the blank reagent (1 ml ferric chloride solution made up to 50 ml with 0.1N HCl) with an ultraviolet spectrophotometer (Jenway, UK). The percentage content was calculated for each brand. 1.1.5 Disintegration test 6 tablets from each brand were employed for the test in a freshly prepared medium, 0.1 N HCl at 37°C using Educational Sciences Disintegration Apparatus (Es Eagle Scientific Limited, Nottingham,UK). The disintegration time was taken to be the time no particle remained on the basket of the system. 1.1.6 Dissolution test The dissolution test was undertaken using USP apparatus I (basket method) in 6 replicates for each brand. The dissolution medium was 1000 ml 0.1N HCl which was maintained at 37 ± 0.5°C. In all the experiments, 5 ml of dissolution sample was withdrawn at 0, 3, 8,15, 25, 35, 45 and 60 min and replaced with equal volume to maintain sink condition. Samples were filtered and assayed by ultraviolet spectrophotometry at 277nm. The concentration of each sample was determined from a calibration curve obtained from pure samples of ciprofloxacin. Data analysis The uniformity of weight, hardness test, friability test, drug content, disintegration test, dissolution test were analyzed with simple statistics using one way analysis of variance (ANOVA) and Dunnett’s test. 2. In vivo bioequivalence study 2.1 Study Design 12 Egyptian healthy male volunteers aged between 20 and 34 years (22.7 ± 3.6 years) and weighed from 51 to 93 kg (70.7 ± 10.3 kg) were enrolled in this study after providing written informed consent. The volunteers were examined and assessed for their eligibility to participate in the present study.The examinations and tests included medical history, physical examination, and measurement of weight, height and vital signs(heart rate and blood pressure). This study was a single-dose,randomized, open label, crossover. The 2 phases of study were separated by a 1 week washout period. The washout period was determined based on 5–7 times of the elimination half life (T 1/2 ) of ciprofloxacin . After an overnight fast for 12 h, the volunteers received 500 mg of either formulation of ciprofloxacin i.e ciprobay and cipromax, taken with 200 mL of water.5 mL of blood samples were obtained just before drug administration and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 hr after that. The plasma was separated by centrifugation at 10 000 rpm for 5 min at room temperature (20 °C), followed Mona I. El Assal et al.: Journal of Medical and Pharmaceutical Innovation; 1 (6) 2014; 35-43 © Journal of Medical and Pharmaceutical Innovation, All Rights Reserved. Vol.1, Issue 6, 2014. 38 by direct transfer into polypropylene tubes and storage at − 20 °C until analysis. 2.2 HPLC method In the present study plasma concentrations of ciprofloxacin were analyzed using a sensitive and selective HPLC method with ultraviolet detector. The HPLC instrumentation was manufactured by Knauer, Germany. 1 mL of sample was first deproteinized with an aqueous solution of trichloroacetic acid (10 % v/v). The mixture was vortexed for 10 s and centrifuged for 15 min. 20 μL of clear supernatant was injected onto the HPLC column. Short-term stability studies showed that CPR is stable in acidic media at least for 12 h at room temperature. The mobile phase consisted of 0.025 M phosphoric acid (pH = 3), acetonitrile, and triethylamine (88:12:0.1, v/v). Analytical column used for chromatographic separations was 5 μm Eurosphere C8 (150 × 4.5 mm) with a Eurosphere C8 (5 μm, 4.6 × 10 mm) guard column. The flow rate was 1 ml/min and the detector wavelength was set at 278 nm. Under these conditions the retention time for ciprofloxacin was 10 min. The method used was validated for specificity, precision and sensitivity. Validation parameters were according to the recommendation of the Center for Drug Evaluation and Research (CDER) and International Conference on Harmonisation (ICH) guidelines (Zakeri-Milani P, et al.2012). The precision, as the measure of intra-day repeatability,was expressed as the coeffi cient of variance (CV %) of 6 identically prepared and measured calibration samples during 1 day measurement series. Inter-day precision (reproducibility) was performed as a CV (%) of 6 consecutive days’ measurements of plasma samples (Valizadeh H, et al. 2010).The pharmacokinetic parameters for test and reference formulations were evaluated. The C max and the corresponding time of peak plasma concentration (T max) were taken directly from the individual plasma data. The elimination rate constant (k e) was estimated as the slope of the semi logarithmic plot of the 3–4 last points of the plasma concentration vs. time curve. The area under the plasma concentration vs. time curve, AUC 0–t, was calculated by linear trapezoidal method. T 1/2 was calculated as ln2/k e. For the purpose of bioequivalence analysis AUC 0–t, AUC 0–∞ and C max were considered as the primary variables. The values of AUC 0–t, AUC 0–∞ and C max were analyzed statistically using an analysis of variance (ANOVA). 3. In vivo efficacy study 3.1 Clinical procedure Thirty-five patients were enrolled in this study. Patients' dental and medical histories were obtained. The patients had no systematic diseases such as diabetes, blood pressure, and hematologic, cardiovascular or renal disorders. None of them had taken any antibiotics or used any kind of mouth rinses in the previous 3 months and had mild to moderate chronic periodontitis with pocket depths of 3-5 mm. The clinical indices of patients were recorded at baseline: attachment level, pocket depth (by William’s probe) and gingival bleeding (Ainano and Bay's method). (Newman MG, et al. 2002) 3.2 Microbiological Studies 3.2.1 Determination of MIC by agar plate dilution method Preparation of sterile stock solutions of Ciprofloxacin brands Weigh 102.4 mg of each brand placed in 10 ml volumetric flask and completed to 10 ml with distelled water to get conc of 10.24 mg/ml (10240 ug/ml). All stock solution were sterilized by filtration with Millipore bacterial filters (0.22 u Membrane Syringe Filter) and transferred into sterile tube with rubber cap, and stored away of light. Preparation of working dilutions for agar susceptibility tests: In 50 ml sterile falcon tube, using sterile pipettes, 1ml volume of the prepared dilution series added to 19 ml of sterile molten agar (Mueller-Hinton agar with 10% horse blood), mix thoroughly, and pour into 90 mm sterile Petri dishes to get final concentration in medium of (0.03-512 ug/ml). Bacterial Growth Inhibition Assay (Agar dilution susceptibility method) Two μl of staphylococcus aureus suspension was inoculated on agar plates containing different concentrations of drug. After 72 hrs of incubation, 37C, microaerobic atmosphere, the plates were examined visually, and the lowest concentration of antibiotics showing complete inhibition of bacterial growth was recorded as the MIC for each drug calculated by (ug/ml). 3.2.2 Evaluation of drug therapeutic effects on bacteria before and after treatment Each brand of ciprofloxacin has been given to six patients 500 mg twice daily for eight days Mona I. El Assal et al.: Journal of Medical and Pharmaceutical Innovation; 1 (6) 2014; 35-43 © Journal of Medical and Pharmaceutical Innovation, All Rights Reserved. Vol.1, Issue 6, 2014. 39 (Slots J, et al. 2002) and dental samples were taken before and after treatment. Sample Collection The samples were collected aseptically the supra gingival plaque was removed with the help of a Sterile Cotton Swap.With the help of paper point (No: 38) the sub gingival plaque was collected, by inserting the paper point into the deepest periodontal pockets for 20 seconds (Mane A.K., et al. 2009).The paper points were transferred into reduced Thioglycollate broth. The paper points were transported to the Microbiology Laboratory in reduced Thioglycollate broth. The bottle containing the paper point was shaken to dislodge the adhered bacteria on the paper point. Using standard loop technique culture was put on blood agar plate containing Hemin and Vitamin K (Slots J, et al. 1983). The plates were incubated in anaerobic jar Gas Pack for 6 days. The bacteria were identified based on Colony morphology, Gram Staining, pigment formation and biochemical tests (Baron E.J., et al. 1997). Probable pocket depth Probable pocket depth of the selected teeth was noted using Williams probe to the nearest mm at the baseline. Relative attachment level Sites of deepest pockets were selected for relative attachment level measurements. Williams probe was used to measure the relative attachment level to nearest mm. Plaque index Plaque was assessed on labial, buccal and lingual surfaces. Scoring criteria were followed as 0 for no plaque, 1 for separate flecks of plaque at the cervical margin of the tooth, 2 for a thin continous band (up to 1 mm) of plaque at the cervical margin of the tooth, 3 for a band of plaque wider than 1 mm, but covering less than one third of the crown of tooth and 4 for plaque covering at least one third, but less than two third of the crown of the tooth. The plaque index was calculated as: Plaque index = total score/ number of surfaces examined (F.J. Vander Quderaa. 1991). Gingival index All the tooth were examined on all four surfaces i.e., buccal, lingual/palatal, distobuccal, mesiobuccal and the amount of gingival inflammation was assessed by clinically examining the color, consistency and size of the gingival tissue, scoring criteria were followed as 1 for mild inflammation, slight edema, no bleeding on probing, 2 for moderate inflammation, redness, edema, bleeding on probing and 3 for severe inflammation, marked redness, edema, ulcerations and spontaneous bleeding. The gingival index was calculated as: Gingival index= [total score/number of tooth examined] x 4 (R.A. Seymour, et al.1995) Statistical analysis The obtained data was analyzed using different tests as T test, Paired Samples test, Crosstabs. RESULTS AND DISCUSSION As shown in Table I, all the brands complied with the compendia specification for uniformity of weight which states that for tablets weighing more than 324 mg, weights of not more than 2 tablets should not differ from the average weight by more than 5%. While all the brands complied with the USP specification for assay, brands ciprofar, ciprocin and rancif did not meet British pharmacopoeia (BP) standard. The USP specification is that the content of ciprofloxacin hydrochloride should not be less than 90% and not more than 110% while BP specifies that the content should not be less than 95% and not more than 105%. However, the result ascertains the presence of USP compendia quantity of ciprofloxacin hydrochloride in all the brands and so could not be judged as counterfeits without APIs. The hardness or crushing strength assesses the ability of tablets to withstand handling without fracturing or chipping. It can also influence friability and disintegration. The harder a tablet, the less friable and the more time it takes to disintegrate. As shown in Table I, brand Ciprobay required the least pressure before fracture (9.3 kg/cm3 ) while brand ciprofar break at (29.7 kg/cm3) with Monsanto hardness tester while the other brands were in between. A force of about 4 kg is the minimum requirement for a satisfactory tablet (Allen et al., 2004) . Hence the tablets of all brands were satisfactory. Friability test is used to evaluate the tablets resistance to abrasion, the compendia specification for friability is 1% . Friability for all the brands was below 1%. Disintegration could be directly related to dissolution and subsequent bioavailability of a drug. A drug incorporated in a tablet is released rapidly as the tablet disintegrates; a crucial step for immediate release dosage forms because the rate of disintegration affects the dissolution and subsequently the Mona I. El Assal et al.: Journal of Medical and Pharmaceutical Innovation; 1 (6) 2014; 35-43 © Journal of Medical and Pharmaceutical Innovation, All Rights Reserved. Vol.1, Issue 6, 2014. 40 therapeutic efficacy of the medicine. As shown in Table I, all the brands were film coated and complied with the compendia specifications for disintegration. The BP specification is that Table 2: Dunnett’s test on the six brands at 0.05 level (two-tailed) Mean difference is obtained by substracting mean % dissolved of brand ciprobay (reference)from mean % dissolved of other brands (test products). uncoated tablets should disintegrate within 15 min and film coated in 30 min while USP specifies that uncoated and film coated tablets should disintegrate within 30 min The USP and BP specifies that the amount of drug released (dissolution) should not be less than 80% of the labeled amount at 30 min. All brands complied except brand ciprofar which had 71% at 35 min as shown in Figure 1. Ciprofloxacin is a class III drug (Wu and Benet, 2005; Kasim et al., 2004) and from Figure 1, brand ciprobay released as much as 94% at 15 min and so it is envisaged that it will not have any bioavailability problems, brand cipromax released as much as 91%.The amounts released by the other brands were below 85%. Figure 1: Dissolution profiles of six brands of ciprofloxacin Hcl tablets The percentage dissolved was tested statistically to ascertain differences among brands using Dennett's test. The analyses were undertaken for time points 25 and 35 min. These time points were chosen because at least 5brands had released over 90% at these times. The results of Dennett's test as shown in Table 2 indicate that at 25 min and 35 min there is none significance difference between ciprobay and each of cipromax, mifoxin, rancif while there is significant difference between ciprobay and ciprofar. However brands rancif and ciprofar show the least departure from ciprobay at two time points. Bioequivalence is a comparison of the bioavailability of two or more drug product. The two chosen drugs containing the same active ingredient are bioequivalent if their rates and extents of absorption don’t show a significant difference. The mean plasma profiles of ciprobay and cipromax were visually very similar in shape and pattern as shown in (Figure. 2). Figure 2: Main plasma concentration time curve of ciprofloxacin following administration of ciprobay and cipromax to six volunteers Figure 3: Bacterial growth inhibition assay (the last conc. for each brand after which growth inhibition is obtained) The parameters AUC 0–∞ and T max were related to the extent and rate of drug absorption respectively, while C max was related to both of these processes (Valizadeh H, et al. 2010). After administration of ciprofloxacin the mean Cmax of 55.75 ± 0.65ng/ml and 46.36±0.99 were attained in about 2 hr for both of ciprobay and cipromax respectively. In the present study the mean value of AUC 0–t were 275.2 ± 23.01and 270.9 ± 1 6.06 ng.hr/mL and AUC0–∞ values were 339.61±48.7 and 304.04±40.37 ng.hr/mL for both ciprobay and cipromax respectively and as shown in Table III, Mann-Witney test statistical analysis for these parameters showed no statistically significant difference between two brands. Therefore confirming the bioequivalence of both brands of Time (min) Pair comparison Mean difference Significance 25 Cipromax vs ciprobay -1.27 0.785 Mifoxin vs ciprobay -4.73 0.194 Rancif vs ciprobay -2.00 0.081 Ciprocin vs ciprobay -3.37 0.075 Ciprofar vs ciprobay -54.97 0.016 35 Cipromax vs ciprobay -0.23 0.926 Mifoxin vs ciprobay 1.03 0.575 Rancif vs ciprobay -1.83 0.468 Ciprocin vs ciprobay 2.7 0.078 Ciprofar vs ciprobay -23.8 0 Mona I. El Assal et al.: Journal of Medical and Pharmaceutical Innovation; 1 (6) 2014; 35-43 © Journal of Medical and Pharmaceutical Innovation, All Rights Reserved. Vol.1, Issue 6, 2014. 41 ciprofloxacin. For evaluation of drug therapeutic effects on bacteria each brand of ciprofloxacin has been given to six patients 500mg twice daily for eight days (Slots J, et al. 2002) and dental samples were taken before and after treatment. As shown in Table V, regarding pocket depth there is a significant decline in pocket depth between before and after drug administration for each of ciprobay, cipromax, mifoxin, ciprocin and rancif at p≤0.05,regarding attachment level there is a significant decline for each of ciprobay, cipromax, mifoxin and rancif at p≤0.05,regarding plaque index there is a significant decline for each of ciprobay, cipromax, mifoxin, , and ciprofar at p≤0.05, regarding gingival index there is significant decline for each of ciprobay, cipromax, mifoxin , ciprocin and rancif at p≤0.05. Microbiological studies also include determination of the lowest concentration of each drug showing complete inhibition of bacterial growth which recorded as the MIC as shown in Table IV, the MIC of rancif and ciprofar were higher than the other brands (2 μgm/ml). Table 3: Mann- Whitney test statistical analysis of two brands of ciprofloxacin HCl Table 4: Comparison of antibacterial activities of different brands of Ciprofloxacin Drugs Dose Tmax Cmax Kel T½el AUC0-12 Auc0-end Vd CLtot ciprobay N 6'' 6 6 6 6 6 6 6 6 Mean 5.0000 2.0000 55.7533 0.1642 4.2367 275.1650 339.6117 10.1833 1.6683 Std. Deviation 0.00000 0.00000 0.65430 0.01203 0.29978 23.01198 48.68775 1.36144 0.21104 Median 5.0000 2.0000 55.4900 0.1618 4.2800 271.9950 338.3050 10.2500 1.7350 Minimum 500.00 2.00 55.27 0.15 3.78 248.37 278.94 8.61 1.41 Maximum 500.00 2.00 56.98 0.18 4.55 300.76 412.05 12.28 1.88 Cipromax N 6 6 6 6 6 6 6 6 6 Mean 5.0000 2.0000 46.3600 0.1535 4.6450 270.9700 304.0467 9.9750 1.4950 Std. Deviation 0.00000 0.00000 0.99874 0.02632 0.92531 16.06535 40.37101 2.15675 0.21296 Median 5.0000 2.0000 46.2600 0.1599 4.3400 272.8600 288.9300 9.0900 1.4800 Minimum 500.00 2.00 45.00 0.11 3.85 242.68 265.66 7.93 1.21 Maximum 500.00 2.00 47.65 0.18 6.32 288.96 353.86 13.00 1.79 P value 1.000 1.000 0.104 0.631 0.631 0.749 0.109 0.631 0.128 Drug Conc ug/ ml (MIC) No growth Ciprobay 1 Mifoxin 1 Cipromax 1 Ciprocin 1 Rancif 2 Ciprofar 2 Mona I. El Assal et al.: Journal of Medical and Pharmaceutical Innovation; 1 (6) 2014; 35-43 © Journal of Medical and Pharmaceutical Innovation, All Rights Reserved. Vol.1, Issue 6, 2014. 42 Table 5: T-Test statistical analysis of six brands of ciprofloxacin HCL in treatment of periodontal pockets CONCLUSION Post-market monitoring is very crucial for effective clinical outcome and this study has emphasized that all the brands of ciprofloxacin complied with the official specification for uniformity of weight, hardness, friability and disintegration. Drug content and in vitro dissolution studies among other tests are important pointers to the quality of drugs. This research shows that six brands can be used interchangeably with innovator brand ciprobay Drugs pocket depth(mm) before pocket depth(mm) after attachment level(mm)before attachment level(mm) after plaque indexbefore plaque indexafter gingival index before gingival index after ciprobay N 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Mean 4.67 3.00 6.50 4.33 4.50 3.00 2.83 0.03 Std. Deviation 0.82 0.00 0.55 0.52 0.55 0.00 0.00 0.00 Median 4.50 3.00 6.50 4.00 4.50 3.00 4.00 3.00 Minimum 4.00 3.00 6.00 4.00 4.00 3.00 2.00 3.00 Maximum 6.00 3.00 7.00 5.00 5.00 3.00 4.00 3.00 Pair diff P value 0.001 0.002 0.016 0.005 cipromax N 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Mean 5.50 3.50 6.50 3.50 3.67 3.00 2.5 1.17 Std. Deviation 0.84 0.84 0.55 0.55 0.52 0.00 0.00 1.03 Median 5.00 3.00 6.50 3.50 4.00 3.00 3.50 2.50 Minimum 5.00 3.00 6.00 3.00 3.00 3.00 1.50 1.00 Maximum 6.00 5.00 7.00 4.00 4.00 3.00 3.50 8.00 Pair diff P value 0.004 0.034 0.006 0.016 mifoxin N 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Mean 4.33 3.33 4.83 3.83 4.67 3.00 2.00 1.00 Std. Deviation 0.52 0.52 0.75 0.75 0.52 0.00 0.00 1.03 Median 4.00 3.00 5.00 4.00 5.00 3.00 1.5 1.00 Minimum 4.00 3.00 4.00 3.00 4.00 3.00 1.50 1.00 Maximum 5.00 4.00 6.00 5.00 5.00 3.00 3.50 2.50 Pair diff P value 0.005 0.002 0.010 0.005 ciprocin N 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Mean 4.83 3.50 5.17 3.83 3.33 3.00 3.00 1.00 Std. Deviation 0.75 0.84 0.75 0.41 0.52 0.00 0.00 0.82 Median 5.00 3.00 5.00 4.00 3.00 3.00 3.00 1.00 Minimum 4.00 3.00 4.00 3.00 3.00 3.00 2.00 0.00 Maximum 6.00 5.00 6.00 4.00 4.00 3.00 3.00 2.00 Pair diff P value 0.001 0.317 0.233 0.012 rancif N 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Mean 4.83 3.50 6.33 3.33 3.50 3.00 1.83 0.00 Std. Deviation 0.75 0.84 0.52 0.52 0.55 0.00 0.00 1.10 Median 5.00 3.00 6.00 3.00 3.50 3.00 2.30 1.00 Minimum 4.00 3.00 6.00 3.00 3.00 3.00 1.00 0.00 Maximum 6.00 5.00 7.00 4.00 4.00 3.00 2.50 1.00 Pair diff P value 0.014 0.022 0.359 0.001 ciprofar N 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Mean 3.83 3.50 3.33 3.33 4.50 3.00 2.5 2.5 Std. Deviation 0.75 0.84 0.52 0.52 0.55 0.00 0.00 1.03 Median 4.00 3.00 3.00 3.00 4.50 3.00 2.00 2.00 Minimum 3.00 3.00 3.00 3.00 4.00 3.00 2.00 2.00 Maximum 5.00 5.00 4.00 4.00 5.00 3.00 3.00 3.00 Pair diff P value 0.325 0.247 0.002 0.184 Mona I. El Assal et al.: Journal of Medical and Pharmaceutical Innovation; 1 (6) 2014; 35-43 © Journal of Medical and Pharmaceutical Innovation, All Rights Reserved. Vol.1, Issue 6, 2014. 43 in order of cipromax, mifoxin, ciprocin, rancif and ciprofar respectively.Statistical analysis of main parameters confirm the bioequivalence of the ciprofloxacin formulations in terms of pharmacokinetic characteristics in healthy volunteers after a single 500mg dose, the results from this study demonstrate that Ciprobay and Cipromax are bioequivalence and interchangeable in the clinical setting. Clinical studies indicated an improvement in the probable pocket depth, relative attachment level, gingival index and plaque index. Statistical analysis proved that ciprofloxacin brands are found to be effective in treating periodontal pockets in order of ciprobay, cipromax, mifoxin, ciprocin, rancif and ciprofar REFERENCES: 1. 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• Work shop of bioequevelancy & Drug Stability, Faculty of Pharmacy, Cairo University 7th December, 2013, Egypt. - 01/0

Mona Ebrahim Abdel Tawab Ahmed Elassal


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Certificate of Excellence Meletary Medical Services 2005

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