Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackého 1946/1, Brno, Czech Republic.
Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackého 1946/1, Brno, Czech Republic.
Eur J Pharm Sci. 2018 Dec 1;125:120-129. doi: 10.1016/j.ejps.2018.09.022. Epub 2018 Oct 1.
Warfarin is intensively discussed in terms of generic substitution due to particular cases of bleeding, which are attributable to fluctuations in API content or the substitution of crystalline (WSC) for amorphous (WSA) warfarin. The aim of this study was to assess to what extent the in vitro release was affected by the form of API depending on the composition and technology. Bioequivalent tablets containing 5 mg of WSA or WSC prepared by wet granulation or direct compression were used. Furthermore, tablets of the same composition with WSC or WSA prepared by direct compression were evaluated. Raman spectroscopy was used to confirm the presence of WSA or WSC. The dissolution was more influenced by the technology than by the form of API but even tablets with dissimilar profiles were bioequivalent. This is probably due to the precipitation of WSA and WSC in the stomach on a poorly soluble acidic form, which subsequently dissolves in the neutral environment of the small intestine. Recrystallization was demonstrated in the in vitro assay at a pH of 1.2 and 4.5 using Raman spectroscopy and X-ray diffraction. In summary, the content uniformity appears to be the main factor affecting the safety of the treatment.
华法林由于特殊的出血病例而在仿制药替代方面受到了广泛讨论，这些出血病例可归因于 API 含量的波动或晶型（WSC）对华法林无定型物（WSA）的替代。本研究旨在评估 API 的形式在多大程度上取决于组成和技术而影响体外释放。使用了通过湿法制粒或直接压片制备的 5mg WSA 或 WSC 的生物等效片剂。此外，还评估了含有 WSC 或 WSA 的相同组成的片剂，通过直接压片制备。拉曼光谱用于确认 WSA 或 WSC 的存在。溶解更多地受技术而不是 API 形式的影响，但即使是具有不同特征的片剂也是生物等效的。这可能是由于 WSA 和 WSC 在胃中以难溶的酸性形式沉淀，随后在小肠的中性环境中溶解。使用拉曼光谱和 X 射线衍射在 pH 值为 1.2 和 4.5 的体外试验中证明了重结晶。总之，含量均匀度似乎是影响治疗安全性的主要因素。
