Trans-nasal zolmitriptan novasomes: in-vitro preparation, optimization and in-vivo evaluation of brain targeting efficiency
Trans-nasal zolmitriptan novasomes: in-vitro preparation, optimization and in-vivo evaluation of brain targeting efficiency
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DOI：
10.1080/10717544.2016.1183721
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发表时间：
2016-11-01
期刊：
影响因子：
6
通讯作者：
Bendas, Ehab R.
中科院分区：
文献类型：
--
作者：
Abd-Elal, Radwa M. A.;Shamma, Rehab N.;Bendas, Ehab R.
偏头痛发作是一种麻烦的生理状况，伴随着搏动，剧烈头痛，在头部的一半。佐米曲坦是一种有效的第二代曲坦，用于治疗偏头痛发作的患者，有或没有先兆，以及丛集性头痛。佐米曲坦口服给药的绝对生物利用度约为40%;由于肝脏第一代谢。经鼻给药将绕过全身前代谢，从而增加佐米曲坦的生物利用度。此外，由于存在微绒毛和高脉管系统，预计吸收比口服途径更快。然而，鼻腔给药药物的生物利用度特别受到膜渗透性差的限制。因此，这项工作的目的是探索新的纳米囊泡脂肪酸富集结构（novasomes）的潜力，有效和增强佐米曲坦的鼻腔给药，并研究其鼻脑靶向潜力。使用非离子表面活性剂、胆固醇以及游离脂肪酸制备Novasome。采用2（3）完全析因设计，研究了表面活性剂的种类、游离脂肪酸的种类以及游离脂肪酸与表面活性剂的比例对novasomes性质的影响。粒径，包封率，多分散指数，zeta电位和%佐米曲坦释放后2小时被选为因变量。使用Design Expert软件（版本7; Stat-Ease Inc.，Minneapolis，MN），并选择由Span（R）80：胆固醇：硬脂酸（比例为1：1：1）组成的优化制剂。该制剂包封率为92.94%，粒径为149.9nm，Zeta电位为-55.57mV，2 h后释放48.43%。使用透射电子显微镜进一步检查优化的制剂，其显示具有窄尺寸分布的非聚集多层纳米囊泡。DSC、XRD分析表明，药物以无定形状态均匀分散于纳米囊泡中。本文研究了~（99）Tc标记的佐米曲坦鼻腔给药诺伐他汀脂质体在小鼠体内的生物分布，并与~（99）Tc-佐米曲坦溶液静脉给药的药代动力学参数进行了比较。结果显示，佐米曲坦靶向脑的极大增强，与静脉内药物溶液相比，鼻内给药novasomes后的药物靶向潜力约为99%。因此，通过鼻途径施用的佐米曲普坦负载的novasomes可能构成急性偏头痛发作管理的进步。
Migraine attack is a troublesome physiological condition associated with throbbing, intense headache, in one half of the head. Zolmitriptan is a potent second-generation triptan, prescribed for patients with migraine attacks, with or without an aura, and cluster headaches. The absolute bioavailability of zolmitriptan is about 40% for oral administration; due to hepatic first metabolism. Nasal administration would circumvent the pre-systemic metabolism thus increasing the bioavailability of zolmitriptan. In addition, due to the presence of microvilli and high vasculature, the absorption is expected to be faster compared to oral route. However, the bioavailability of nasal administered drugs is particularly restricted by poor membrane penetration. Thus, the aim of this work is to explore the potential of novel nanovesicular fatty acid enriched structures (novasomes) for effective and enhanced nasal delivery of zolmitriptan and investigate their nose to brain targeting potential. Novasomes were prepared using nonionic surfactant, cholesterol in addition to a free fatty acid. A 2(3) full factorial design was adopted to study the influence of the type of surfactant, type of free fatty acid and ratio between the free fatty acid and the surfactant on novasomes properties. The particle size, entrapment efficiency, polydispersity index, zeta potential and % zolmitriptan released after 2h were selected as dependent variables. Novasomes were further optimized using Design Expert (R) software (version 7; Stat-Ease Inc., Minneapolis, MN), and an optimized formulation composed of Span (R) 80:Cholesterol:stearic acid (in the ratio 1:1:1) was selected. This formulation showed zolmitriptan entrapment of 92.94%, particle size of 149.9nm, zeta potential of -55.57mV, and released 48.43% zolmitriptan after 2h. The optimized formulation was further examined using transmission electron microscope, which revealed non-aggregating multi-lamellar nanovesicles with narrow size distribution. DSC, XRD examination of the optimized formulation confirmed that the drug have been homogeneously dispersed throughout the novasomes in an amorphous state. In-vivo bio-distribution studies of Tc-99m radio-labeled intranasal zolmitriptan loaded novasomes were done on mice, the pharmacokinetic parameters were compared with those following administration of intravenous Tc-99m-zolmitriptan solution. Results revealed the great enhancement in zolmitriptan targeting to the brain, with drug targeting potential of about 99% following intranasal administration of novasomes compared with the intravenous drug solution. Zolmitriptan loaded novasomes administered via the nasal route may therefore constitute an advance in the management of acute migraine attacks.