Development of a dissolution method for lumefantrine and artemether in immediate release fixed dose artemether/lumefantrine tablets

Background:Dissolution of artemether (ART ) and lumefantrine (LUM) active pharmaceutical ingredients (APIs) in fixed dose combination (FDC) ART/LUM tablets is one of the critical quality attributes. Thus, the verification of the release profile of ART and LUM from FDC ART/LUM tablets using a robust and discriminatory dissolution method is crucial. Therefore, the aim of this study was to develop and validate an appropriate dissolution method for quality control of FDC ART/LUM tablets.Methods:The dissolution medium was selected based on saturation solubility data and sink conditions. The effect of agitation speed, pH and surfactant concentration on the release of ART and LUM was evaluated by employing a two-level factorial experiment. The resulting final method was validated for linearity, precision, robustness and API stability. In addition, the discriminatory power of the method was evaluated using expired and unexpired FDC ART/LUM products.Results:A suitable dissolution profile of FDC ART/LUM tablets was obtained in 900 ml HCl (0.025 N, pH 1.6) with 1%Myrj 52 using paddle method at 100 rpm and 37 °C. ART and LUM were analysed using a HPLC method with UV detection at wavelengths of 210 and 335 nm, respectively. The results from the stability study showed that ART and LUM were sufficiently stable in HCl (0.025 N, pH 1.6) with 1%Myrj 52 at 37 °C. The method was linear (r2= 0.999) over the concentration range of 6.25–100 μg/ml. The results for precision were within the acceptance limit (%RSD 0.05) difference in release of ART and LUM observed between deliberately changed dissolution method settings (pH = 1.6 ±0.2 or agitation speed = 100 ±2) and optimized dissolution conditions revealed the robustness of the dissolution method. The method was capable to discriminate among different FDC ART/LUM products with different quality.Conclusions:The developed dissolution method is robust and discriminatory. It can be used in the quality evalua-tion of FDC ART/LUM tablets

Quality of fixed dose artemether/lumefantrine products in Jimma Zone, Ethiopia

Background: Malaria caused by Plasmodium vivax and Plasmodium falciparum is among the major public health problems in most endemic areas of the world. Artemisinin-based combination therapy (ACT) has been recommended as a first-line treatment for uncomplicated Plasmodium falciparum malaria almost in all endemic regions. Since ineffectively regulated medicines in resource limited settings could favour infiltration of poor quality anti-malarial medicines into pharmaceutical supply chain and jeopardize a positive treatment outcome, regular monitoring of the quality of anti-malarial medicines is critical. Thus, the aim of this study was to assess the quality of fixed dose combination (FDC) artemether (ART)/lumefantrine (LUM) tablets available in Jimma zone, Ethiopia. Methods: This study was conducted in Jimma zone, Ethiopia. A total of 74 samples of FDC ART/LUM (20mg ART/120mg LUM) tablets were collected from 27 public facilities. All samples were subjected to visual inspection and the relevant information was recorded. The samples were transported to Jimma University Laboratory of Drug Quality (JuLaDQ) and stored at ambient temperature (20 degrees C to 25 degrees C) until analysis. The Pharmacopoeial conform/non-conform methods and the risk-based Derringer's desirability function approach were employed to assess the pharmaceutical quality of the investigated products. Results: The visual inspection results revealed that there were no signs of falsified in the investigated products. Identification test results of samples indicated that all samples contained the stated active pharmaceutical ingredients (APIs). The results of uniformity of mass indicated that all samples complied with International Pharmacopoeial specification limits. The assay results, expressed as percent label claim (%lc) of ART (89.8 to 108.8%, meanSD=99.1 +/- 3.9%) and LUM (90.0 to 111.9%, mean +/- SD=98.2 +/- 3.8%) revealed that, all samples complied with International Pharmacopoeia acceptance specification limits (i.e. 90-110%lc), except one generic product (IPCA Laboratories Ltd., India) which contains excessive LUM (111.9 +/- 1.7%lc). The risk priority number (RPN) results revealed that assay (RPN=392) is relatively the most critical quality attribute followed by identity (RPN=280) and mass uniformity (40). Quality evaluation based on psycho-physical Harrington's scale revealed that more than 96% of samples were within the acceptable ranges (D >= 0.7-1.0). Conclusions: Both Pharmacopoeial and risk-based desirability function approaches to quality evaluation applied to the investigated products revealed that above 96% FDC ART/LUM tablets circulating in public settings of Jimma zone are of good quality

Assessment of efficacy and quality of two albendazole brands commonly used against soil-transmitted helminth infections in school children in Jimma Town, Ethiopia

Background : There is a worldwide upscale in mass drug administration (MDA) programs to control the morbidity caused by soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura and hookworm. Although anthelminthic drugs which are used for MDA are supplied by two pharmaceutical companies through donation, there is a wide range of brands available on local markets for which the efficacy against STHs and quality remain poorly explored. In the present study, we evaluated the drug efficacy and quality of two albendazole brands (Bendex and Ovis) available on the local market in Ethiopia. Methodology/Principal Findings : A randomized clinical trial was conducted according to the World Health Organization (WHO) guidelines to assess drug efficacy, by means of egg reduction rate (ERR), of Bendex and Ovis against STH infections in school children in Jimma, Ethiopia. In addition, the chemical and physicochemical quality of the drugs was assessed according to the United States and European Pharmacopoeia, encompassing mass uniformity of the tablets, amount of active compound and dissolution profile. Both drugs were highly efficacious against A. lumbricoides (>97%), but showed poor efficacy against T. trichiura (similar to 20%). For hookworms, Ovis was significantly (p < 0.05) more efficacious compared to Bendex (98.1% vs. 88.7%). Assessment of the physicochemical quality of the drugs revealed a significant difference in dissolution profile, with Bendex having a slower dissolution than Ovis. Conclusion/Significance : The study revealed that differences in efficacy between the two brands of albendazole (ABZ) tablets against hookworm are linked to the differences in the in-vitro drug release profile. Differences in uptake and metabolism of this benzimidazole drug among different helminth species may explain that this efficacy difference was only observed in hookworms and not in the two other species. The results of the present study underscore the importance of assessing the chemical and physicochemical quality of drugs before conducting efficacy assessment in any clinical trials to ensure appropriate therapeutic efficacy and to exclude poor drug quality as a factor of reduced drug efficacy other than anthelminthic resistance. Overall, this paper demonstrates that "all medicines are not created equal"

Quality of anthelminthic medicines available in Jimma Ethiopia

Soil-transmitted helminthiasis and schistosomiasis are major public health problems in Ethiopia. Mass de worming of at-risk population using a single dose administration of 400 mg albendazole (ABZ) or 500 mg mebendazole (MBZ) for treatment of common intestinal worms and 40 mg of praziquantel (PZQ) per kg body weight for treatment of schistosomiasis is one of the strategies recommended by World Health Organization (WHO) in order to control the morbidity of soil-transmitted helminthiasis and schistosomiasis. Since storage condition, climate, way of transportation and distribution route could all affect the quality of medicines, regular assessment by surveys is very critical to ensure the therapeutic outcome, to minimize risk of toxicity to the patient and resistance of parasites. Therefore, this study was conducted to assess the pharmaceutical quality of ABZ, MBZ and PZQ tablet brands commonly available in Jimma town (south west Ethiopia). Retail pharmacies (n = 10) operating in Jimma town were selected using simple random sampling method. Samples of anthelminthic medicines available in the selected pharmacies were collected. Sample information was recorded and encompassed trade name, active ingredient name, manufacturer's name and full address, labeled medicine strength, dosage form, number of units per container, dosage statement, batch/lot number, manufacturing and expiry dates, storage information and presence of leaflets/package insert. Moreover, a first visual inspection was performed encompassing uniformity of color, uniformity of size, breaks, cracks, splits, embedded surface spots or visual contaminations Finally, physico-chemical quality attributes investigated encompassed mass uniformity, quantity of active pharmaceutical ingredient (API), disintegration and dissolution, all following Pharmacopoeial test methods The physical characteristics of dosage form, packaging and labeling information of all samples complied with criteria given in the WHO checklists. The mass uniformity of tablets of each brand of ABZ, MBZ and PZQ complied with the pharmacopoeial specification limits, i.e no more than 2 individual masses > 5% of average tablet weight, and none deviate by more than 10%. The quantity of APIs in all investigated tablet brands were within the 90-110% label claim (l.c.) limits, ranging between 95.05 and 110.09% l.c. Disintegration times were in line with the pharmacopoeial specification limit for immediate release (IR) tablets, ranging between 0.5 and 13 min. However, the dissolution results (mean +/- SD, n = 6) of one ABZ brand (i.e. Wormin (R), Q = 59.21 +/- 0.99% at 30 min) and two PZQ brands (i.e. Bermoxel (R), Q = 63.43% +/- 0.7 and Distocide (R), Q = 62.43% +/- 1.67, at 75 min) showed poor dissolution, failing the United States Pharmacopoeia (USP) dissolution specification limit

Quality-by-design principles applied to the establishment of a pharmaceutical quality control laboratory in a resource-limited setting : the lab water

Quality-by-design (QbD) is defined as a systematic approach to design and develop a product/service based on sound science and quality risk management. It is already frequently applied in the pharmaceutical industry mainly in the development of pharmaceutical products and analytical methods but is not well established in the setup of facilities like quality control (QC) laboratory (lab).)erefore, lab QbD (lQbD) concept is introduced considering lab water purification system as an example.)e water purification system comprising distillation unit coupled with Nanopure Analytical Ultrapure Water System combined with a 0.2micron filter was established in Jimma University Laboratory of Drug Quality (JuLaDQ).)e consistent capability of the established water purification system was evaluated through routine monitoring of the critical quality parameters (i.e., physicochemical, HPLC-DAD chromatogram total peak area, and resistivity) of freshly prepared lab water for a period of one year. In addition, quality of different grade water (tap water, distilled water (before and/or after cleaning distillation unit), and fresh ultrapure water (18.2M Omega x cm at 25 degrees C)) used in JuLaDQ was evaluated.)e results of routine analysis of water quality revealed that HPLC global peak area at 210 and 254nm could serve as one of the discriminatory control strategies to evaluate the capability of water purification system to produce the desired quality of lab water; and thus, we proposed a specification limit of 5,000 mAU*s and 5,500 mAU*s for global peak area at 254 and 210 nm, respectively, as system suitability parameter

The in vitro Antibacterial Activity of Enrofloxacin-Trimethoprim Combination against Five Bacterial species

The aim of the current study was to investigate the combination effect of enrofloxacin and trimethoprim by their inhibitory and bactericidal activities against five bacterial species (E. coli, P. hemolytica, S. aureus, S. cholerasuis) and a field isolate S. typhimurium. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), fractional inhibitory concentration (FIC) and time killing rate were performed using these isolates. Both antibiotics has shown similar MIC ranging from equal to 3 fold dilutions difference for each of the bacteria tested except for E. coli where enrofloxacin has shown better activity with more than ten fold dilutions less than trimethoprim. The fractional inhibitory concentration index from the results of checkerboard for enrofloxacin and trimethoprim showed a synergistic effect for P. hemolytica and S. typhimurium (field isolate), while no difference was observed for the remaining tested bacteria. In the combination of the two antibiotics with different ratios, compared to the MICs of the two antibiotics tested alone, the concentration of the two antibiotics in the combination has shown a 2-8 fold reduction against all bacteria tested. Furthermore, as the concentrations of enrofloxacin increase and trimethoprim decrease the minimum inhibitory concentrations for E. coli, P. hemolytica and S. aureus has shown a decrease. The other two bacteria didn’t show any change. Although all the combined ratios had similar MIC and MBC values compared to MIC and MBC tested alone, the concentration of each antibiotic in the combined ratios was lower by more than ten-fold compared to the MIC and MBC alone for both antibiotics. The time kill rate study for the antibiotics alone or in combination against E. coli and S. aureus had revealed higher inhibitions of bacterial growth with a difference of 2-4 log cfu/ml bacteria by the combination antibiotics after 12 hrs of incubation than tested alone. In summary, combination therapy with these two antibiotics may serve additive to synergistic effect and broad spectrum activity against the tested bacteria