Enhanced Oral Bioavailability of The Hydrophobic Chemopreventive Agent (Sr13668) in Beagle Dogs
Enhanced Oral Bioavailability of The Hydrophobic Chemopreventive Agent (Sr13668) in Beagle Dogs
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DOI：
10.2174/1389201011314040012
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发表时间：
2013-03-01
影响因子：
2.8
通讯作者：
Lyubimov, Alexander V.
中科院分区：
文献类型：
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作者：
Banerjee, Aryamitra A.;Shen, Hao;Lyubimov, Alexander V.
SR 13668在癌症预防中的效力和活性已在几种体外和体内癌症模型中得到证实。然而，该化合物具有高度疏水性，其有限的口服生物利用度阻碍了其临床转化。在这项研究中，我们将SR 13668封装到聚合物纳米颗粒中，以增加化合物的水溶性，从而提高生物利用度。通过连续且可扩展的快速纳米沉淀与喷雾干燥相结合的工艺，生成了封装SR 13668的聚乳酸-乙醇酸共聚物（PLGA）纳米颗粒（100- 200 nm），具有窄粒度分布和高载药量。在8只比格犬中单次灌胃给予2.8 mg/kg SR 13668-PLGA纳米颗粒。在24小时内测量动物全血和血浆中的药物水平。据报道，与Labrasol（R）和0.5%甲基纤维素中的纯药物制剂相比，使用纳米颗粒增强了SR 13668的生物利用度。这是首次尝试在大型动物中经口给予纳米颗粒混悬液研究SR 13668的药代动力学。
Potency and activity of SR13668 in cancer prevention have been proven in several in vitro and in vivo cancer models. However, the compound is highly hydrophobic and its limited oral bioavailability has hindered its clinical translation. In this study, we encapsulated SR13668 into polymeric nanoparticles to increase compound aqueous solubility and therefore bioavailability. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (100-200nm) encapsulating SR13668 with narrow size distribution and high drug loading were generated by a continuous and scalable process of flash nanoprecipitation integrated with spray dry. A single gavage dose of SR13668-PLGA nanoparticles at 2.8 mg/kg was administered in eight beagle dogs. Drug levels in animal whole blood and plasma were measured over 24 hours. Enhanced bioavailability of SR13668 using nanoparticles compared with formulations of Labrasol (R) and neat drug in 0.5% methylcellulose is reported. This is the first attempt to study pharmacokinetics of SR13668 in large animals with orally administrated nanoparticle suspension.