Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel
Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel
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DOI：
10.1016/j.biomaterials.2012.05.026
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发表时间：
2012-10-01
期刊：
影响因子：
14
通讯作者：
Thanki, Kaushik
中科院分区：
文献类型：
--
作者：
Jain, Sanyog;Kumar, Dinesh;Thanki, Kaushik
通过聚电解质在脂质体上的逐层组装，制备了紫杉醇(PTX)的层状制剂。硬脂胺被用来为脂质体提供正电荷，然后用阴离子聚合物聚丙烯酸(PAA)包覆，然后再包覆阳离子聚合物聚烯丙基胺盐酸盐(PAH)。对各工艺参数进行了优化，优化后的处方粒径为226+/-17.61 nm，光密度指数为0.343+/-0.070，zeta电位为+39.9+/-3.79 mV，包封率为71.91+/-3.16%。所开发的配方进一步采用通用分步冷冻干燥循环进行冷冻干燥。冻干制剂在模拟胃肠液和加速稳定性条件下是稳定的。体外释药研究表明，层状制剂可持续释药24 h，释药规律为Higuchi动力学。此外，细胞培养实验显示，与游离药物相比，肺腺癌(A549)细胞系对层体的摄取更高。随后用四甲基偶氮唑盐比色法证实了这一点，结果表明，开发的层状制剂的IC50值为29.37mUg/ml，而游离药物的IC50值为35.42mUg/ml。体内药代动力学研究表明，与游离药物相比，PTX的整体口服生物利用度提高了约4.07倍。DMBA诱导的乳腺肿瘤模型体内抗肿瘤作用与对照组相比，肿瘤生长明显减少，与静脉注射相当。紫杉醇(R)。此外，还进行了毒性研究，以确认所开发的制剂的安全性，并发现其比紫杉醇(R)高得多。因此，开发的制剂策略可以有效地利用来提高难于给药的口服给药能力。(C)2012爱思唯尔有限公司。保留所有权利。
Paclitaxel (PTX) loaded layersome formulations were prepared using layer-by-layer assembly of the polyelectrolytes over liposomes. Stearyl amine was utilized to provide positive charge to the liposomes, which were subsequently coated with anionic polymer polyacrylic acid (PAA) followed by coating of cationic polymer polyallylamine hydrochloride (PAH). Optimization of various process variables were carried out and optimized formulation was found to have particle size of 226 +/- 17.61 nm, PDI of 0.343 +/- 0.070, zeta potential of +39.9 +/- 3.79 mV and encapsulation efficiency of 71.91 +/- 3.16%. The developed formulation was further subjected to lyophilization using a universal stepwise freeze drying cycle. The lyophilized formulation was found to be stable in simulated gastrointestinal fluids and at accelerated stability conditions. In vitro drug release studies revealed that layersome formulation was able to sustain the drug release for 24 h; release pattern being Higuchi kinetics. Furthermore, cell culture experiments showed higher uptake of layersomes from lung adenocarcinoma (A549) cell lines as compared to free drug. This was subsequently corroborated by MTT assay, which revealed IC50 value of 29.37 mu g/ml for developed layersome formulation in contrast to 35.42 mu g/ml for free drug. The in vivo pharmacokinetics studies revealed about 4.07 fold increase in the overall oral bioavailability of PTX as compared to that of free drug. In vivo antitumor efficacy in DMBA induced breast tumor model showed significant reduction in the tumor growth as compared to the control and comparable to that of iv. Taxol (R). In addition, the toxicity studies were carried out to confirm the safety profile of the developed formulation and it was found to be significantly higher as compared to Taxol (R). Therefore, the developed formulation strategy can be fruitfully exploited to improve the oral deliverability of difficult-to deliver drugs. (C) 2012 Elsevier Ltd. All rights reserved.