Impurities detection in ciclosporin capsules: a comparison with Neoral®

Badr Aljohani1,4, Essam Ghazaly2, David Perrett3, Atholl Johnston1. 1Clinical Pharmacology, William Harvey Research Institute, Queen Mary School of Medicine and Dentistry, London, UK, 2Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary School of Medicine and Dentistry, London, UK, 3Bioanalysis, William Harvey Research Institute, Queen Mary School of Medicine and Dentistry, London, UK, 4King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

Background: Ciclosporin is available in developing countries both as an original innovator’s brand and generic products. However counterfeit and substandard versions are also found in pharmacies. Poor quality medicines are a global problem affecting both developed and developing countries . Counterfeit medicines are fake, while substandard medicines are correct medicines that do not meet the requirements for quality, safety or efficacy of the original drug. Dissolution and impurity profiles affect the quality, stability and therapeutic efficacy of the product and there is potential toxicity from impurities. Therefore we have studied dissolution of, and the impurities in, ciclosporin capsules bought in different countries.

Method: Eight ciclosporin products (Brand A, Brand B, Brand C, Brand D, Brand E, Generic A, Generic B, Generic C) were obtained from hospitals and pharmacies from 8 different countries in the form of soft gelatine capsules (Five Neoral® and three generics). In-vitro dissolution testing was performed according to USP guidelines (n=5), with sampling at intervals up to 120 min (2). These samples were quantified by isocratic high performance liquid chromatography using acetonitrile plus 0.3% aqueous trifluoroacetic acid (70+30). The impurities were identified using accurate mass – mass spectrometry.

Results: All samples were compared to Brand A (reference product), which showed 100 mg of ciclosporin after 90 min in dissolution test. The ciclosporin products and two generics showed between 84 and 100 mg of 100 mg labelled amount. One generic had less than the minimum labelled amount (54 mg ± 10). Concentrations of inactive ingredients such as sorbitol were variable in different capsules. Up to 500 fold differences in sorbitol concentration were detected in different capsules. One of the product from South America, manufactured in central Asia, showed a contamination of Zizyphine A, a cyclopeptide product of the central Asian plant Ziziphus oenoplia. Ciclosporin H (CyH), a degradation product of ciclosporin was found up to 5 fold higher in generic product (generic C) compared to reference capsules (p<0.001)

Conclusion: Based on the results we conclude that some of the ciclosporin preparations did not contain the exact mass labelled. Other capsules were found to be contaminated with plant products. Degradation products were detected in all capsules including the reference capsule. This indicates problems with ciclosporin pharmaceutical production, and these could lead to harmful clinical effect on patients (3).

References:

1. Johnston A, Holt DW. Substandard drugs: a potential crisis for public health. British journal of clinical pharmacology. 2014;78(2):218-43.

2. The UNITED STATES PHARMACOPEIA, USP 35, 2012. Official Monographs/ Cyclosporine. United States: The United States Pharmacopeial Convention; pp 2793-2796.

3. Johnston A, Holt DW. Immunosuppressant drugs--the role of therapeutic drug monitoring. British journal of clinical pharmacology. 2001;52 Suppl 1:61S-73S.