Sharma Puneet, Ganta Srinivas, Denny William A, Garg Sanjay
School of Pharmacy, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Int J Pharm. 2009 Feb 9;367(1-2):187-94. doi: 10.1016/j.ijpharm.2008.09.032. Epub 2008 Sep 26.
Lipid nanoparticles of the cancer drug Chlorambucil (CLB) were prepared by ultrasonication, using stearic acid as the core lipid. Four types of lipid nanoparticle formulations were studied: (i) stearic acid solid lipid nanoparticles (SLN); (ii) sterically stabilized SLN with pegylated phospholipids as stabilizer; (iii) nanostructured lipid complexes with oleic acid as adjunct lipid; (iv) lipid nanocomplexes with dimethyl dioctadecyl ammonium bromide (DDAB) as surface modifier (LN). Lipid nanoparticles were characterized for particle size, assay and encapsulation efficiency, particle morphology and physico-chemical stability over 90 days. All of the formulations were physically stable, with an average particle size of 147 (+/-10)nm. The drug encapsulation efficiency (DEE) of all the formulations except LN decreased significantly over time (p<0.05), probably due to the expulsion of CLB upon crystallization. This indicated that the presence of DDAB in stearic acid nanoparticles increases DEE, preventing CLB degradation in the aqueous disperse phase. Pharmacokinetic studies of the intravenous LN formulation revealed plasma clearance kinetics were comparable to that of CLB solution (p>0.01), indicating electrostatic charge mediated clearance, as reported earlier. In tissue and tumor distribution studies, lower AUC values of CLB were observed for LN compared to CLB solution in liver, kidneys, heart and lungs. However, higher AUC values of LN formulation as compared to CLB solution (p<0.01) in tumors suggested that the presence of DDAB on the lipid nanoparticles resulted in greater accumulation of the drug in tumors.
以硬脂酸为核心脂质，通过超声处理制备了癌症药物苯丁酸氮芥（CLB）的脂质纳米颗粒。研究了四种脂质纳米颗粒制剂：（i）硬脂酸固体脂质纳米颗粒（SLN）；（ii）以聚乙二醇化磷脂为稳定剂的空间稳定化SLN；（iii）以油酸为辅助脂质的纳米结构脂质复合物；（iv）以二甲基二十八烷基溴化铵（DDAB）为表面改性剂的脂质纳米复合物（LN）。对脂质纳米颗粒的粒径、含量测定和包封率、颗粒形态以及90天内的物理化学稳定性进行了表征。所有制剂在物理上都是稳定的，平均粒径为147（±10）nm。除LN外，所有制剂的药物包封率（DEE）均随时间显著下降（p<0.05），这可能是由于CLB在结晶时被排出。这表明硬脂酸纳米颗粒中DDAB的存在提高了DEE，防止了CLB在水相分散介质中的降解。静脉注射LN制剂的药代动力学研究表明，血浆清除动力学与CLB溶液相当（p>0.01），这表明如先前报道的那样，是由静电荷介导的清除。在组织和肿瘤分布研究中，与CLB溶液相比，LN在肝脏、肾脏、心脏和肺中的CLB的AUC值较低。然而，与CLB溶液相比，LN制剂在肿瘤中的AUC值更高（p<0.01），这表明脂质纳米颗粒上DDAB的存在导致药物在肿瘤中的积累更多。
