Lipid-based nanosystem of edaravone: development, optimization, characterization and in vitro/in vivo evaluation.
Lipid-based nanosystem of edaravone: development, optimization, characterization and in vitro/in vivo evaluation.
复制标题
DOI：
10.1080/10717544.2017.1337825
复制
发表时间：
2017-11
期刊：
影响因子：
6
通讯作者：
Zhou XF
中科院分区：
文献类型：
--
作者：
Parikh A;Kathawala K;Tan CC;Garg S;Zhou XF
依达拉奉（EDR）是一种公认的亲脂性自由基清除剂，用于治疗神经退行性疾病、心血管疾病和癌症。然而，由于口服生物利用度（BA）差，其口服使用受到限制。本研究的目的是通过开发基于脂质的纳米系统（LNS）使其能够口服使用。LNS的组分（包括油、表面活性剂和助表面活性剂）是根据其在胃肠道（GI）液中最大化溶解、降低其葡萄糖醛酸化和改善跨膜渗透性的潜力选择的。优化具有Capryol™ PGMC（油）、Cremophor® RH 40：Labrasol®：TPGS 1000（1：0.8：0.2）（表面活性剂）和Transcutol P®（助表面活性剂）的液体LNS（L-LNS）以形成具有液滴尺寸（16.25 nm）、多分散指数（0.039）、%透射率（99.85%）和自乳化时间（32 s）的微乳液。它显著改善了EDR负荷以及其在通过胃肠道转运期间的代谢和渗透性特征。为了克服L-LNS可能存在的缺点，使用Aerosil® 200配制固体LNS（S-LNS），并根据流动特性优化其浓度。通过固态表征、复溶能力和稳定性研究证实，S-LNS具有L-LNS的所有质量属性。L-LNS和S-LNS均能显著提高EDR在模拟胃液和肠液中的溶出速率。药代动力学研究显示，L-LNS和S-LNS相对于EDR混悬液的相对BA、Cmax和t1/2显著改善。此外，S-LNS在SH-SY 5 Y 695细胞系中显示出比EDR更上级的细胞摄取和神经保护作用。适当选择LNS的组分可以实现常规地通过肠胃外施用使用的挑战性治疗剂的有效口服递送。
Edaravone (EDR) is a well-recognized lipophilic free radical scavenger for diseases including neurodegenerative disease, cardiovascular disease, and cancer. However, its oral use is restricted due to poor oral bioavailability (BA). The aim of present research was to enable its oral use by developing a lipid-based nanosystem (LNS). The components of LNS including oil, surfactants, and co-surfactants were selected based on their potential to maximize the solubilization in gastrointestinal (GI) fluids, reduce its glucuronidation and improve transmembrane permeability. The liquid LNS (L-LNS) with Capryol™ PGMC (Oil), Cremophor® RH 40:Labrasol®:TPGS 1000 (1:0.8:0.2) (Surfactant) and Transcutol P® (Co-surfactant) were optimized to form microemulsion having droplet size (16.25 nm), polydispersity index (0.039), % Transmittance (99.85%), and self-emulsification time (32 s). It significantly improved the EDR loading as well as its metabolism and permeability profile during transport across the GI tract. To overcome the possible drawbacks of L-LNS, Aerosil® 200 was used to formulate solid LNS (S-LNS), and its concentration was optimized based on flow properties. S-LNS possessed all quality attributes of L-LNS confirmed by solid-state characterization, reconstitution ability, and stability study. The dissolution rate of EDR was significantly enhanced with L-LNS and S-LNS in simulated gastric, and intestinal fluids. The pharmacokinetic study revealed significant improvement in relative BA, Cmax, and t1/2 with L-LNS and S-LNS against EDR suspension. Moreover, S-LNS showed superior cellular uptake and neuroprotective effect compared to EDR in SH-SY5Y695 cell line. An appropriate selection of the components of LNS could enable effective oral delivery of challenging therapeutics that are conventionally used by the parenteral administration.
登录
查看更多内容
影响因子：
4.9
作者：
Collnot, Eva-Maria;Baldes, Christiane;Lehr, Claus-Michael
通讯作者：
Lehr, Claus-Michael
影响因子：
5.8
作者：
Cerpnjak, Katja;Zvonar, Alenka;Gasperlin, Mirjana
通讯作者：
Gasperlin, Mirjana
影响因子：
4.9
作者：
Bala, Vaskor;Rao, Shasha;Prestidge, Clive A.
通讯作者：
Prestidge, Clive A.
影响因子：
5.8
作者：
Ishak, Rania A. H.;Osman, Rihab
通讯作者：
Osman, Rihab
影响因子：
3.7
作者：
Jain, Amit K.;Thanki, Kaushik;Jain, Sanyog
通讯作者：
Jain, Sanyog