Malekar Swapnil A, Sarode Ashish L, Bach Alvin C, Bose Arijit, Bothun Geoffrey, Worthen David R
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, 02881, USA.
Department of Chemical Engineering, College of Engineering, University of Rhode Island, 495M Pharmacy Building, 7 Greenhouse Drive, Kingston, Rhode Island, 02881, USA.
AAPS PharmSciTech. 2015 Dec;16(6):1335-43. doi: 10.1208/s12249-015-0323-z. Epub 2015 Apr 22.
This work was conducted in order to design, characterize, and evaluate stable liposomes containing the hydrophobic drug raloxifene HCl (RAL) and hydrophilic doxycycline HCl (DOX), two potentially synergistic agents for treating osteoporosis and other bone lesions, in conjunction with a radio frequency-induced, hydrophobic magnetic nanoparticle-dependent triggering mechanism for drug release. Both drugs were successfully incorporated into liposomes by lipid film hydration, although combination drug loading compromised liposome stability. Liposome stability was improved by reducing the drug load and by including Pluronics® (PL) in the formulations. DOX did not appear to interact with the phospholipid membranes comprising the liposomes, and its release was maximized in the presence of radio frequency (RF) heating. In contrast, differential scanning calorimetry (DSC) and phosphorus-31 nuclear magnetic resonance ((31)P-NMR) analysis revealed that RAL developed strong interactions with the phospholipid membranes, most notably with lipid phosphate head groups, resulting in significant changes in membrane thermodynamics. Likewise, RAL release from liposomes was minimal, even in the presence of RF heating. These studies may offer useful insights into the design and optimization of multidrug containing liposomes. The effects of RAL on liposome characteristics and drug release performance underscore the importance of appropriate physical-chemical analysis in order to identify and characterize drug-lipid interactions that may profoundly affect liposome properties and performance early in the formulation development process.
开展这项工作是为了设计、表征和评估含有疏水性药物盐酸雷洛昔芬（RAL）和亲水性盐酸多西环素（DOX）的稳定脂质体，这两种药物在治疗骨质疏松症和其他骨病变方面可能具有协同作用，并结合一种射频诱导的、依赖疏水性磁性纳米颗粒的药物释放触发机制。通过脂质膜水合作用，两种药物均成功载入脂质体，不过联合载药会损害脂质体稳定性。通过降低药物载量以及在制剂中加入普朗尼克（PL）提高了脂质体稳定性。DOX似乎未与构成脂质体的磷脂膜发生相互作用，在射频（RF）加热条件下其释放达到最大值。相比之下，差示扫描量热法（DSC）和磷-31核磁共振（³¹P-NMR）分析表明，RAL与磷脂膜发生了强烈相互作用，最显著的是与脂质磷酸头部基团相互作用，导致膜热力学发生显著变化。同样，即使在RF加热条件下，RAL从脂质体中的释放也极少。这些研究可能为含多种药物脂质体的设计和优化提供有用的见解。RAL对脂质体特性和药物释放性能的影响突出了适当的物理化学分析的重要性，以便在制剂开发过程早期识别和表征可能深刻影响脂质体性质和性能的药物-脂质相互作用。
