Substandard and Counterfeit Medicines

Abstract

Counterfeit and substandard medicines are a global problem affecting both developed and developing countries. Governments and the health authorities are focusing on the spread of counterfeit medicines, as it is a threat to patients and funds criminal activities. Counterfeit medicines are fake, while substandard medicines are true medicines that do not meet the requirements for quality, safety and efficacy of the branded drug. Both counterfeit and substandard drugs can be life threatening and have caused deaths. Thus, it is important to have simple and rapid methodology for detecting counterfeit and substandard medicines. In this study, a capillary electrophoresis (CE) method used to detect impurities in lisinopril, high performance liquid chromatography (HPLC) to quantify ciclosporin active ingredients, and ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) for detecting impurities in both ciclosporin and azithromycin are discussed. A total of 44 lisinopril, 9 ciclosporin and 19 azithromycin products were obtained from hospitals and pharmacies from different countries. In vitro dissolution testing was used to identify differences between products. It was performed to the USP guidelines with sampling at intervals up to 120 min. The samples were quantified by CE, HPLC and UHPLC-MS for lisinopril, ciclosporin and azithromycin, respectively. Impurities were detected in all lisinopril tablets, ranging from 4% to 27%. For ciclosporin, all capsules met the USP requirements, rupturing within 15 min. Two ciclosporin generic products showed less than the minimum percentage of labelled amount, <80%. Statistical analysis showed significant differences (p<0.0001) of the mean percentage content between brand and generic products. Investigations were carried out to detect impurities in ciclosporin capsules using LC-MS. Concentrations of inactive ingredients such as sorbitol were variable between capsules. One from South America, manufactured in central Asia, showed contamination with a plant product (zizyphine A). The synthetic intermediate (delcorine) was found to be more than 1000-fold higher in the generic product compared to reference capsules (p<0.001). Based on the results we conclude that some of the ciclosporin preparations did not contain the exact mass labelled. Both ciclosporin and lisinopril preparations contained significant impurities. These results have important implications, especially with ciclosporin, which has a narrow therapeutic window. Switching among and between branded and generic ciclosporin may lead to irreversible kidney damage or acute rejection.