盐酸苦参碱载药明胶纳米粒的设计及其体外溶血评价——一种治疗疟疾的新方法。
Design and in vitro haemolytic evaluation of cryptolepine hydrochloride-loaded gelatine nanoparticles as a novel approach for the treatment of malaria.
机构信息
School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
出版信息
AAPS PharmSciTech. 2012 Jun;13(2):568-81. doi: 10.1208/s12249-012-9775-6. Epub 2012 Apr 5.
Cryptolepine hydrochloride-loaded gelatine nanoparticles were developed and characterised as a means of exploring formulation techniques to improve the pharmaceutic profile of the compound. Cryptolepine hydrochloride-loaded gelatine-type (A) nanoparticles were developed base on the double desolvation approach. After optimisation of formulation parameters including temperature, stirring rate, incubation time polymer and cross-linker (glutaraldehyde) concentrations, the rest of the study was conducted at two different formulation pH values (2.5 and 11.0) and by two different approaches to drug loading. Three cryoprotectants--sucrose, glucose and mannitol--were investigated for possible use for the preparation of freeze-dried samples. Nanoparticles with desired size mostly less than 350 nm and zeta potential above ±20 were obtained when formulation pH was between 2.5 and 5 and above 9. Entrapment efficiency was higher at pH 11.0 than pH 2.5 and for products formulated when drug was loaded during the second desolvation stage compared to when drug was loaded onto pre-formed nanoparticles. Further investigation of pH effect showed a new isoelectric point of 6.23-6.27 at which the zeta potential of nanoparticles was zero. Sucrose and glucose were effective in low concentrations as cryoprotectants. The best formulation produced an EC(50) value of 227.4 μM as a haemolytic agent compared to 51.61 μM by the free compound which is an indication of reduction in haemolytic side effect. There was sustained released of the compound from all formulation types over a period of 192 h. Stability data indicated that the nanosuspension and freeze-dried samples were stable at 4 and 25°C, respectively, over a 52-week period, but the former was less stable at room temperature. In conclusion, cryptolepine hydrochloride-loaded gelatine nanoparticles exhibited reduced haemolytic effect compared to the pure compound and can be developed further for parenteral delivery.
盐酸 cryptolepine 载药明胶纳米粒的研制及其特性分析，旨在探索改善该化合物药物制剂特性的方法。盐酸 cryptolepine 载药明胶型（A）纳米粒是基于双重去溶剂法制备的。在优化了包括温度、搅拌速率、孵育时间、聚合物和交联剂（戊二醛）浓度等制剂参数后，本研究在两种不同的制剂 pH 值（2.5 和 11.0）和两种不同的载药方法下进行。三种冷冻保护剂——蔗糖、葡萄糖和甘露醇——被用于可能的冻干样品制备。当制剂 pH 值在 2.5 和 5 之间以及高于 9 时，得到了所需粒径大多小于 350nm 且 ζ 电位在±20 以上的纳米粒。在 pH 值为 11.0 时，包封效率高于 pH 值为 2.5 时，且在第二次去溶剂化阶段载药时的产品优于在预形成的纳米粒上载药时的产品。进一步研究 pH 值的影响发现，纳米粒的等电点为 6.23-6.27，此时 ζ 电位为零。蔗糖和葡萄糖在低浓度时作为冷冻保护剂是有效的。最佳制剂的 EC50 值为 227.4μM，作为溶血剂，而游离化合物的 EC50 值为 51.61μM，这表明溶血副作用降低。所有制剂类型在 192 小时内均有化合物持续释放。稳定性数据表明，纳米混悬液和冻干样品在 4°C 和 25°C 下分别稳定 52 周，而前者在室温下稳定性较差。综上所述，盐酸 cryptolepine 载药明胶纳米粒与纯化合物相比，溶血作用降低，可进一步开发用于注射给药。
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