Liu Peng, Viitala Tapani, Kartal-Hodzic Alma, Liang Huamin, Laaksonen Timo, Hirvonen Jouni, Peltonen Leena
Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
Pharm Res. 2015 Feb;32(2):628-39. doi: 10.1007/s11095-014-1491-3. Epub 2014 Aug 22.
The lack of effective screening methods and systemic understanding of interaction mechanisms complicates the stabilizer selection process for nanocrystallization. This study focuses on the efficiency of stabilizers with various molecular compositions and structures to stabilize drug nanocrystals.
Five structurally different polymers were chosen as stabilizers for indomethacin nanocrystals. The affinity of polymers onto drug surfaces was measured using surface plasmon resonance (SPR) and contact angle techniques. Nanosuspensions were prepared using the wet-ball milling technique and their physico-chemical properties were thoroughly characterized.
SPR and contact angle measurements correlated very well with each other and showed that the binding efficiency decreased in the order L64 > 17R4 > F68 ≈ T908 ≈ T1107, which is attributed to the reduced PPO/PEO ratio and different polymer structures. The electrostatic interactions between the protonated amine of poloxamines and ionized indomethacin enhanced neither the affinity nor the properties of nanosuspensions, such as particle size and physical stability.
A good stabilizer should have high binding efficiency, full coverage, and optimal hydrophobic/hydrophilic balance. A high affinity combined with short PEO chains (L64, 17R4) caused poor physical stability of nanosuspensions, whereas moderate binding efficiencies (F68, T908, T1107) with longer PEO chains produced physically stable nanosuspensions.
缺乏有效的筛选方法以及对相互作用机制的系统理解，使得纳米结晶稳定剂的选择过程变得复杂。本研究聚焦于具有不同分子组成和结构的稳定剂对药物纳米晶体的稳定效率。
选择五种结构不同的聚合物作为吲哚美辛纳米晶体的稳定剂。使用表面等离子体共振（SPR）和接触角技术测量聚合物在药物表面的亲和力。采用湿球磨技术制备纳米混悬液，并对其理化性质进行全面表征。
SPR和接触角测量结果相互之间具有很好的相关性，结果表明结合效率按L64 > 17R4 > F68 ≈ T908 ≈ T1107的顺序降低，这归因于PPO/PEO比例降低和聚合物结构不同。泊洛沙姆质子化胺与离子化吲哚美辛之间的静电相互作用既未增强纳米混悬液的亲和力，也未改善其诸如粒径和物理稳定性等性质。
一种良好的稳定剂应具有高结合效率、完全覆盖以及最佳的疏水/亲水平衡。高亲和力与短PEO链（L64、17R4）相结合会导致纳米混悬液的物理稳定性较差，而具有较长PEO链的中等结合效率（F68、T908、T1107）则产生物理稳定的纳米混悬液。
