Ito Daichi, Ge Dan, Kogure Noriyuki, Manaka Hitomi, Terui Yusuke, Takayama Hiromitsu, Linhardt Robert J, Toida Toshihiko, Higashi Kyohei
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Heliyon. 2020 Oct;6(10):e05168. doi: 10.1016/j.heliyon.2020.e05168. Epub 2020 Oct 6.
Physical mixtures of cationic polymers and heparin have been developed to overcome the limitations of unfractionated heparin. In this study, we found that heparin associates with natural polyamines in water, resulting in the generation of a poly-ion complex (PIC). PIC formation (or stability) was influenced by the concentration and ratio of heparin and polyamines, molecular weight of heparin, nature of polyamines, and pH conditions. Interestingly, the PIC obtained when heparin and tetrakis (3-aminopropyl) ammonium (Taa) were mixed exhibited stability and was sticky in nature. PIC formation was due to an electrostatic interaction between heparin and Taa. Heparin-Taa PIC was administered subcutaneously to mice, and the time to maximum heparin concentration within the therapeutic range of heparin was markedly increased compared to that after a single dose of heparin. These results suggest that the quaternary ammonium structure of Taa is critical for the preparation of a stable PIC, thereby allowing the sustained release of heparin into the blood.
阳离子聚合物与肝素的物理混合物已被开发出来，以克服普通肝素的局限性。在本研究中，我们发现肝素在水中与天然多胺结合，从而产生聚离子复合物（PIC）。PIC的形成（或稳定性）受肝素和多胺的浓度及比例、肝素的分子量、多胺的性质以及pH条件的影响。有趣的是，肝素与四（3-氨丙基）铵（Taa）混合时得到的PIC具有稳定性且具有粘性。PIC的形成是由于肝素与Taa之间的静电相互作用。将肝素-Taa PIC皮下注射给小鼠，与单次注射肝素后相比，在肝素治疗范围内达到最大肝素浓度的时间显著延长。这些结果表明，Taa的季铵结构对于制备稳定的PIC至关重要，从而使肝素能够持续释放到血液中。
