Department of Pharmaceutical Technology, Institute of Pharmacy, Friedrich Schiller University Jena, Lessingstrasse 8, 07743 Jena, Germany.
Electron Microscopy Center, University Hospital Jena, Friedrich Schiller University Jena, Ziegelmuehlenweg 1, 07743 Jena, Germany.
Colloids Surf B Biointerfaces. 2018 Aug 1;168:10-17. doi: 10.1016/j.colsurfb.2018.02.023. Epub 2018 Feb 16.
Compared to conventional parenteral formulations injectable depot formulations, owing to a sustained drug release, offer several advantages, such as a reduced dosing frequency - and consequent improved compliance - or a predictable release profile. Additionally, fluctuations in the drug blood level may be smoothened and consequently side effects reduced. Because of their capability to encapsulate water soluble drugs and their very low toxicity profile liposomes comprising phospholipids, most certainly represent a vehicle of choice for subcutaneous (s.c.) or intramuscular (i.m.) administration typical for depot injections too. In the past, especially liposomes containing negatively charged phosphatidylserines were investigated regarding their aggregation and fusion behavior upon addition of calcium ions. Liposomes need to have a large size to prevent fast removal from the s.c. or i.m. injection site to make them useful as depot vehicle. In order to obtain such large liposomes, aggregation of smaller liposomes may be considered. Aim of the present study was to induce and investigate controlled aggregation of vesicles containing other negatively charged phospholipids besides phosphatidylserines upon mixing with a solution of divalent cations. L-α-phosphatidylcholine from egg (EPC) liposomes formulated with 25 mol% of 1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA) or 1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DSPG) proved to be possible lipid-based depot candidates due to their strong aggregation induced by calcium and magnesium cations. Different aggregation profiles with both cations could be observed. Morphological investigations of the aggregates showed that individual liposomes remain stable in the aggregates and no fusion occurred. A fluorescence-based fusion assay confirmed these results. Differential scanning calorimetry measurements supported the findings of the diverse aggregation profiles with calcium or magnesium owing to different binding sites of the cations to the lipid molecules.
与传统的注射制剂相比，注射用储库制剂由于药物释放持续时间长，具有许多优势，例如减少给药频率——从而提高顺应性——或可预测的释放曲线。此外，药物血药浓度的波动可能会变得平稳，从而减少副作用。由于其能够包裹水溶性药物，并且具有非常低的毒性特征，包含磷脂的脂质体无疑是皮下（s.c.）或肌肉内（i.m.）给药的首选载体，这也是储库注射的典型方式。过去，特别是含有带负电荷的磷脂酰丝氨酸的脂质体，其在添加钙离子时的聚集和融合行为受到了研究。脂质体需要具有较大的尺寸，以防止从皮下或肌肉内注射部位快速清除，从而使其成为有用的储库载体。为了获得如此大的脂质体，可以考虑较小脂质体的聚集。本研究的目的是在与二价阳离子溶液混合时，诱导并研究除磷脂酰丝氨酸以外的其他带负电荷的磷脂的囊泡的受控聚集。用 25mol%的 1,2-二棕榈酰-sn-甘油-3-磷酸（DPPA）或 1,2-二硬脂酰-sn-甘油-3-磷酸-(1'-rac-甘油)（DSPG）制成的来自卵（EPC）的α-磷脂酰胆碱脂质体由于钙离子和镁离子的强烈诱导聚集作用，被证明是可能的基于脂质的储库候选物。可以观察到两种阳离子的不同聚集曲线。对聚集物的形态学研究表明，单个脂质体在聚集物中保持稳定，没有融合发生。荧光融合测定证实了这些结果。差示扫描量热法测量结果支持了由于阳离子与脂质分子的不同结合位点，导致钙或镁具有不同的聚集曲线的发现。
