Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan 410013, PR China.
Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, PR China; Guangdong Institute of Semiconductor Micro-Nano Manufacturing Technology, Foshan 528200, PR China.
Eur J Pharm Biopharm. 2022 Oct;179:126-136. doi: 10.1016/j.ejpb.2022.09.002. Epub 2022 Sep 7.
Co-amorphous technology is an emerging approach for pharmaceutical engineering of drugs and drug leads with improved physicochemical properties and bioavailability. Platensimycin (PTM) is a promising natural antibiotic lead that acts on bacterial fatty acid synthase and exhibits excellent antibacterial activity. Despite great strides to improve its poor pharmacokinetics by medicinal chemistry and nanotechnology, there are no convenient oral delivery systems developed. Here, a co-amorphous system of PTM and berberine chloride (BCL) was developed for oral delivery of PTM. Co-amorphous PTM-BCL was prepared by rotary vacuum evaporation method, and systematically characterized by powder X-ray diffraction, temperature modulated differential scanning calorimetry, Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). Compared with PTM or BCL alone, the equilibrium solubility and dissolution rate of both of them in the co-amorphous systems decreased significantly, showing the characteristics of sustained release. The molecular interactions between PTM and BCL were mediated by strong charged-mediated hydrogen bonds, based on FTIR, XPS, and NMR-based techniques. The co-amorphous PTM-BCL system showed excellent physiochemical stability at room and elevated (40 °C) temperature under dry conditions. The combination of PTM and BCL showed increased killing of a clinical isolated methicillin-resistant Staphylococcus aureus strain in killing checkerboard assays. Finally, co-amorphous PTM-BCL exhibited 2- or 3-fold longer half-life in rats than that of crystalline and amorphous PTM upon oral administration, respectively. Our study suggests a rational approach to realize the full potential of potent antibiotic PTM, which may be conveniently adapted for engineering of other important pharmaceutics.
共晶技术是一种新兴的药物工程方法，可用于改善药物和药物先导物的物理化学性质和生物利用度。普拉地霉素 (PTM) 是一种有前途的天然抗生素先导物，作用于细菌脂肪酸合酶，具有优异的抗菌活性。尽管通过药物化学和纳米技术极大地改善了其较差的药代动力学特性，但尚未开发出方便的口服递送系统。在这里，开发了 PTM 和盐酸小檗碱 (BCL) 的共晶系统用于 PTM 的口服递送。通过旋转真空蒸发法制备共晶 PTM-BCL，并通过粉末 X 射线衍射、温度调制差示扫描量热法、傅里叶变换红外光谱 (FTIR) 和 X 射线光电子能谱 (XPS) 对其进行系统表征。与 PTM 或 BCL 单独相比，它们在共晶系统中的平衡溶解度和溶解速率均显着降低，表现出持续释放的特征。基于 FTIR、XPS 和基于 NMR 的技术，PTM 和 BCL 之间的分子相互作用由强带电介导氢键介导。在干燥条件下，共晶 PTM-BCL 系统在室温下和升高的（40°C）温度下表现出出色的物理化学稳定性。在棋盘式测定中，PTM 和 BCL 的组合显示出对临床分离的耐甲氧西林金黄色葡萄球菌菌株的杀伤作用增加。最后，与结晶和无定形 PTM 相比，共晶 PTM-BCL 在口服给药后在大鼠中的半衰期分别延长了 2 倍或 3 倍。我们的研究为实现强效抗生素 PTM 的全部潜力提供了一种合理的方法，这可能方便地适用于其他重要药剂学的工程。
