Novel self-assembled nano-tubular mixed micelles of Pluronics P123, Pluronic F127 and phosphatidylcholine for oral delivery of nimodipine: In vitro characterization, ex vivo transport and in vivo pharmacokinetic studies
Novel self-assembled nano-tubular mixed micelles of Pluronics P123, Pluronic F127 and phosphatidylcholine for oral delivery of nimodipine: In vitro characterization, ex vivo transport and in vivo pharmacokinetic studies
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DOI：
10.1016/j.ijpharm.2015.07.075
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发表时间：
2015-09-30
影响因子：
5.8
通讯作者：
Shamma, Rehab N.
中科院分区：
文献类型：
--
作者：
Basalious, Emad B.;Shamma, Rehab N.
蛛网膜下腔出血(SAH)是中风患者死亡的主要原因。尼莫地平是FDA批准的唯一治疗蛛网膜下腔出血引起的血管痉挛的药物。然而，NM的口服生物利用度较低(5-13%)，这是因为它的水溶解度低，首过代谢广泛，消除半衰期短(1-2小时)。本研究的目的是研制NM-Pluronic/磷脂酰胆碱/聚山梨酯80混合胶束(PPPMM)，该胶束在稀释后仍能在水介质中溶解NM，延长其循环时间，提高其生物利用度，最终有助于将其靶向于脑组织。采用薄膜水合技术制备了PPPMM制剂，并对其载药量、增溶效率、胶束大小、Zeta电位、透射电子显微镜和体外大鼠肠道转运进行了评价。当PC与Pluronics(R)的摩尔比为75：25时，其载药量、SE、胶束尺寸和Zeta电位分别为1.0 6+/-0.0 3 mg/m L、99.2+/-2.0 1%、571.5+/-11.87 nm和-31.2+/-0.0 6 mV。所选择的处方具有更大的疏水核心体积，用于增溶NM，并表现出最高的NM传输。电子显微镜照片显示了高度柔韧的纳米管混合胶束(NTMM)的形成。体内药代动力学研究表明，与药物溶液相比，NM在大鼠血浆(232%)和脑(208%)中的生物利用度更高，这是因为柔性NTMM能够促进NM从肠粘膜的吸收。NTMM的药物溶解度显著增加，药物吸收增强，循环时间长，有望改善NM的口服和肠外给药。(C)2015爱思唯尔B.V.保留所有权利。
Subarachnoid hemorrhage (SAH) is a major cause of death in patients suffering from stroke. Nimodipine (NM) is the only FDA-approved drug for treating SAH-induced vasospasm. However, NM suffers from poor oral bioavailability (5-13%) due to its low aqueous solubility, extensive first pass metabolism and short elimination half-life (1-2 h). The objective of this study was to develop NM-loaded Pluronic/phosphatidylcholine/polysorbate 80 mixed micelles (PPPMM) that can solubilize NM in aqueous media even after dilution, prolong its circulation time, improve its bioavailability and eventually help in targeting it to the brain tissue. PPPMM formulations were prepared using the thin film hydration technique, and evaluated for drug payload, solubilization efficiency (SE), micellar size, zeta potential, transmission electron microscopy (TEM) and ex vivo transport through rat intestine. The selected NM-loaded PPPMM, containing PC to Pluronics (R) molar ratio of 75:25, showed a drug payload, SE, micellar size and zeta potential of 1.06 +/- 0.03 mg/mL, 99.2 +/- 2.01%, 571.5 +/- 11.87 nm and -31.2 +/- 0.06 mv, respectively. The selected formulation had a much larger hydrophobic core volume for solubilization of NM and exhibited the highest NM transport. TEM micrographs illustrated the formation of highly flexible nanotubular mixed micelles (NTMM). The in vivo pharmacokinetic study showed greater bioavailability of NM in plasma (232%) and brain (208%) of rats from NM-loaded PPPMM compared to that of the drug solution due to the efficiency of flexible NTMM to enhance absorption of NM from the intestinal mucosa. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NTMM could be promising to improve oral and parenteral delivery of NM. (C) 2015 Elsevier B.V. All rights reserved.