Flaten Gøril Eide, Skar Merete, Luthman Kristina, Brandl Martin
University of Tromsø, Institute of Pharmacy, Department of Pharmaceutics & Biopharmaceutics, N-9037 Tromsø, Norway.
Eur J Pharm Sci. 2007 Mar;30(3-4):324-32. doi: 10.1016/j.ejps.2006.11.017. Epub 2006 Dec 9.
Recently, we reported on the development and structural characterization of a phospholipid vesicle based barrier useful for medium throughput screening of passive drug permeability. Here, we investigate the physical and functional integrity of the phospholipid vesicle based barriers to agitation by stirring or shaking, and whether agitation affects drug permeability of sulpiride, metoprolol and testosterone. In addition, three drugs (caffeine, naproxen and sulphasalazine) which were shown in a previous study to affect the electrical resistance of the barriers, were investigated for their influence on the permeability of a simultaneously applied hydrophilic marker (calcein), and on the thermotropic phase transition of the phospholipid bilayers using differential scanning calorimetry (DSC). Electrical resistance measurements indicated that the barriers should withstand shaking speeds up to 150rpm without losing their integrity, but significant release of phospholipids from the membrane barriers to the donor and acceptor chambers was observed under agitation >or=150rpm. When using agitation up to 100rpm no increase in permeability was observed for sulpiride, metoprolol and testosterone. The phospholipid vesicle-based barrier thus differ from other permeability models in that agitation does not lead to an increase in permeability, not even for highly lipophilic drugs such as testosterone. This is explained by the different morphology of the vesicle-based barrier which is containing a 100microm thick layer of mostly aqueous compartments immobilised within a matrix of phospholipids vesicles. Sulphasalazine and naproxen were shown to decrease the electrical resistance and increase the permeability of the hydrophilic marker calcein. The DSC experiments showed that these two drugs probably interact with the head groups of the phospholipids. In contrast, caffeine gave an increase in electrical resistance and a decrease in permeability of calcein. From the DSC experiments no signs of interaction of caffeine with the phospholipid bilayer could be observed.
最近，我们报道了一种基于磷脂囊泡的屏障的开发及其结构表征，该屏障可用于被动药物渗透性的中通量筛选。在此，我们研究了基于磷脂囊泡的屏障在搅拌或振荡下的物理和功能完整性，以及搅拌是否会影响舒必利、美托洛尔和睾酮的药物渗透性。此外，在先前的一项研究中显示三种药物（咖啡因、萘普生和柳氮磺胺吡啶）会影响屏障的电阻，因此研究了它们对同时施加的亲水性标记物（钙黄绿素）渗透性的影响，以及使用差示扫描量热法（DSC）对磷脂双层热致相变的影响。电阻测量表明，屏障在高达150rpm的振荡速度下应能保持完整性，但在振荡速度≥150rpm时，观察到有大量磷脂从膜屏障释放到供体和受体室中。当使用高达100rpm的振荡时，舒必利、美托洛尔和睾酮的渗透性没有增加。因此，基于磷脂囊泡的屏障与其他渗透性模型不同，因为振荡不会导致渗透性增加，即使对于像睾酮这样的高度亲脂性药物也是如此。这可以通过基于囊泡的屏障的不同形态来解释，该屏障包含一个100微米厚的主要为水相隔室的层，固定在磷脂囊泡基质中。柳氮磺胺吡啶和萘普生被证明会降低电阻并增加亲水性标记物钙黄绿素的渗透性。DSC实验表明，这两种药物可能与磷脂的头部基团相互作用。相比之下，咖啡因会导致电阻增加和钙黄绿素渗透性降低。从DSC实验中未观察到咖啡因与磷脂双层相互作用的迹象。
