R&D, PLIVA Croatia Ltd, TEVA Group Member, Zagreb, Croatia.
Department of Pharmaceutical Analysis, University of Zagreb, Faculty of Pharmacy and Biochemistry, Zagreb, Croatia.
Drug Dev Ind Pharm. 2020 Aug;46(8):1298-1307. doi: 10.1080/03639045.2020.1788066. Epub 2020 Jul 7.
The compatibility of formulation components is crucial for safe and high-quality medicines. To detect the potential for incompatibility and to assess formulation stability, it is beneficial to conduct a compatibility study during the drug development phase. The therapy of tuberculosis normally consists of two or more medicines taken together. Consequently, different antituberculotic fixed-dose combination (FDC) formulations have been developed. Isoniazid is first-line medicine and present in several FDCs. Low bioavailability due to the active substances' incompatibility in acidic medium was reported for some of these FDC forms. Rifabutin, also a first-line antituberculotic, is available in the market as a single component formulation. This study presents compatibility testing of these two active substances for a new FDC and evaluates the impact of the most common solid dosage forms' excipients on the stability of two active substances. The potential for interaction between the formulation components was analyzed by the UHPLC method. One degradation product and one interaction product were observed and further characterized by high-resolution mass spectrometry. Still, significant degradation of two active substances, such as reported in marketed FDC formulations was not detected for this combination. The stability and drug delivery of the proposed combination were confirmed by the dissolution test in acidic medium.
制剂成分的相容性对于安全和高质量的药物至关重要。为了检测潜在的不相容性并评估制剂稳定性，在药物开发阶段进行相容性研究是有益的。结核病的治疗通常包括两种或多种药物一起使用。因此，已经开发了不同的抗结核固定剂量组合（FDC）制剂。异烟肼是一线药物，存在于几种 FDC 中。由于一些这些 FDC 形式中的活性物质在酸性介质中不相容，导致生物利用度降低。利福布汀也是一种一线抗结核药物，作为单一成分制剂在市场上销售。本研究对这两种活性物质进行了新的 FDC 的相容性测试，并评估了最常见的固体制剂辅料对两种活性物质稳定性的影响。通过 UHPLC 方法分析了制剂成分之间的相互作用潜力。观察到一个降解产物和一个相互作用产物，并通过高分辨率质谱进一步进行了表征。然而，对于这种组合，没有检测到与市售 FDC 制剂中报道的那样，两种活性物质的显著降解。通过在酸性介质中的溶出度试验证实了所提出的组合的稳定性和药物递送。
