TIFAC Centre of Relevance and Excellence, Centre of PG Studies and Research, Pharmacy Department, The Maharaja Sayajirao University of Baroda, Donors Plaza, Fatehgunj, Vadodara, Gujarat 390002, India.
Acta Biomater. 2011 Dec;7(12):4169-76. doi: 10.1016/j.actbio.2011.07.025. Epub 2011 Jul 30.
Olanzapine (OZ) is a second-generation or atypical antipsychotic which selectively binds to central dopamine D₂ and serotonin (5-HT(2c)) receptors. It has poor bioavailability due to hepatic first-pass metabolism and low permeability into the brain due to efflux by P-glycoproteins. The present investigation aimed to prepare a nanoparticulate drug delivery system of OZ using poly(lactic-co-glycolic acid) (PLGA) for direct nose-to-brain delivery to provide brain targeting and sustained release. PLGA nanoparticles (NP) were prepared by the nanoprecipitation technique and characterized by entrapment efficiency, particle size, zeta potential, modulated temperature differential scanning calorimetry (MTDSC) and X-ray diffraction (XRD) studies. The NP were evaluated for in vitro release, ex vivo diffusion, toxicity and pharmacokinetic studies. The NP were 91.2±5.2 nm in diameter and had entrapment efficiency 68.91±2.31%. MTDSC studies indicated broadening of the drug peak and a shift in the polymer peak, possibly due to physical interaction or H-bonding between the carbonyl groups of PLGA and the NH groups of OZ, and also due to the plasticization effect of OZ on PLGA. XRD studies indicated a decrease in the crystallinity of OZ or amorphization. In vitro drug release showed a biphasic pattern with initial burst release and, later, sustained release (43.26±0.156% after 120 h), following the Fickian diffusion-based release mechanism. Ex vivo diffusion through sheep nasal mucosa showed 13.21±1.59% of drug diffusion in 210 min from NP. Histopathological study of sheep nasal mucosa showed no significant adverse effect of OZ-loaded NP. In vivo pharmacokinetic studies showed 6.35 and 10.86 times higher uptake of intranasally delivered NP than OZ solution delivered through intravenous (IV) and intranasal (IN) route, respectively. These results proved that OZ could be transported directly to the brain after IN delivery of PLGA NP, enhanced drug concentration in the brain and would therefore be effective in improving the treatment of central nervous system disorders.
奥氮平（OZ）是一种第二代或非典型抗精神病药，它选择性地结合中枢多巴胺 D₂ 和血清素（5-HT（2c））受体。由于肝脏首过代谢和 P-糖蛋白的外排导致脑内通透性低，其生物利用度较差。本研究旨在使用聚（乳酸-共-乙醇酸）（PLGA）制备奥氮平的纳米药物递送系统，用于直接经鼻递送至脑，提供脑靶向和持续释放。PLGA 纳米粒（NP）通过纳米沉淀技术制备，并通过包封效率、粒径、Zeta 电位、调制温度差示扫描量热法（MTDSC）和 X 射线衍射（XRD）研究进行表征。NP 进行了体外释放、离体扩散、毒性和药代动力学研究。NP 的直径为 91.2±5.2nm，包封效率为 68.91±2.31%。MTDSC 研究表明，药物峰变宽，聚合物峰发生位移，这可能是由于 PLGA 的羰基与 OZ 的 NH 基团之间的物理相互作用或氢键，以及 OZ 对 PLGA 的塑化作用。XRD 研究表明 OZ 的结晶度降低或无定形化。体外药物释放呈两相模式，具有初始突释，随后为持续释放（120h 后释放 43.26±0.156%），遵循基于菲克扩散的释放机制。通过绵羊鼻黏膜的离体扩散研究显示，NP 在 210min 内有 13.21±1.59%的药物扩散。绵羊鼻黏膜的组织病理学研究表明，负载 OZ 的 NP 无明显不良反应。体内药代动力学研究表明，经鼻给予 NP 后，药物的摄取量分别比经静脉（IV）和经鼻（IN）途径给予 OZ 溶液高 6.35 倍和 10.86 倍。这些结果证明，PLGA NP 经鼻给药后，奥氮平可直接输送到大脑，增加大脑中的药物浓度，从而有效改善中枢神经系统疾病的治疗效果。
