Drug Transport & Delivery Group, Department of Physics, Chemistry & Pharmacy, University of Southern Denmark, Odense, Denmark.
Drug Transport & Delivery Group, Department of Physics, Chemistry & Pharmacy, University of Southern Denmark, Odense, Denmark.
Eur J Pharm Sci. 2019 Jan 15;127:199-207. doi: 10.1016/j.ejps.2018.11.003. Epub 2018 Nov 5.
The current study documents enhanced apparent solubility of the BCS class II drug celecoxib (CXB) when formulated as solid phospholipid dispersion (SPD) with either mono- or diacyl-phospholipids by freeze drying from hydro-alcoholic solvent. The enhanced solubility upon dispersion in buffer or fasted state simulated intestinal fluid (FaSSIF) is interpreted to be due to two effects: (1) amorphization of CXB, inducing supersaturation, which is also observed when CXB is freeze dried in the absence of phospholipids and (2) association of CXB with spontaneously forming colloidal structures, such as vesicles and/or micelles, promoting solubilization. The latter effect depended on the CXB-to-phospholipid ratio, where monoacyl-phospholipid was a more efficient solubilizer than diacyl-phospholipid. In the case of diacyl-phospholipid, solubilization also depended strongly on the dispersion medium, where FaSSIF induced a more pronounced solubilization effect than buffer. In contrast, a significantly enhanced in-vitro permeability of CXB across a biomimetic barrier (Permeapad®) was found only with low lipid contents up to a CXB to phospholipid mass-ratio of 1:10 or in the absence of phospholipid; above this critical ratio, permeability was not enhanced, i.e. comparable to that observed with a suspension of non-processed (crystalline) drug. This non-linear dissolution-/permeation-behavior was observed independently of (1) the type of phospholipid (monoacyl- or diacyl-) employed and (2) the dispersion medium (buffer or FaSSIF), despite the fact that different patterns of co-existing colloidal states were observed from mono-/diacyl-phospholipid formulations in buffer/FaSSIF (small bile salt micelles, intermediate size mixed micelles and large vesicular structures), assessed by asymmetric flow field-flow fractionation/multi angle laser light scattering. A uniform mechanistic hypothesis is presented to describe the impact of phospholipids on CXB permeation behavior: Obviously, the critical drug-to-phospholipid ratio represents a compromise between optimal stabilization of the amorphous state-induced supersaturation and reduced thermodynamic activity of CXB due to association with colloidal states, where the type of colloidal state (vesicle or micelle) appears to be of minor importance.
当前的研究记录了当使用单酰-或二酰-磷脂通过冷冻干燥从醇水溶剂制备固体磷脂分散体（SPD）时，BCS 类 II 药物塞来昔布（CXB）的表观溶解度增强。在缓冲液或禁食状态模拟肠液（FaSSIF）中分散时，溶解度增强被解释为两个效应的结果：（1）CXB 的无定形化，诱导过饱和度，当 CXB 在没有磷脂的情况下冷冻干燥时也会观察到这种现象；（2）CXB 与自发形成的胶体结构（如囊泡和/或胶束）缔合，促进溶解。后一种效应取决于 CXB 与磷脂的比例，其中单酰磷脂比二酰磷脂更有效地增溶。在二酰磷脂的情况下，溶解也强烈依赖于分散介质，其中 FaSSIF 比缓冲液产生更明显的溶解效果。相比之下，仅在脂质含量低至 CXB 与磷脂的质量比为 1:10 或不存在磷脂的情况下，才发现 CXB 在仿生屏障（Permeapad®）上的体外渗透性显著增强；超过这个临界比例，渗透性没有增强，即与非加工（结晶）药物悬浮液观察到的渗透性相当。这种非线性的溶解/渗透行为独立于（1）所使用的磷脂类型（单酰-或二酰-）和（2）分散介质（缓冲液或 FaSSIF）观察到，尽管在缓冲液/FaSSIF 中观察到来自单/二酰磷脂制剂的共存胶体状态的不同模式（小胆盐胶束、中等大小的混合胶束和大囊泡结构），通过不对称流场流分离/多角度激光光散射进行评估。提出了一个统一的机制假设来描述磷脂对 CXB 渗透行为的影响：显然，临界药物与磷脂的比例代表了优化无定形状态诱导的过饱和度的稳定性和由于与胶体状态缔合而导致的 CXB 热力学活性降低之间的折衷，其中胶体状态的类型（囊泡或胶束）似乎不太重要。
