Anticancer efficacy, tissue distribution and blood pharmacokinetics of surface modified nanocarrier containing melphalan.
Anticancer efficacy, tissue distribution and blood pharmacokinetics of surface modified nanocarrier containing melphalan.
复制标题
含美法仑表面修饰纳米载体的抗癌功效、组织分布和血液药代动力学。
DOI：
10.1016/j.ijpharm.2012.01.027
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发表时间：
2012
影响因子：
5.8
通讯作者：
K. Pathak
中科院分区：
文献类型：
--
作者：
Pooja Rajpoot;V. Bali;K. Pathak
本研究的目的是规避水分相关的不稳定性，提高生物利用度，并实现美法仑对卵巢的被动靶向增强。测定药物在各种赋形剂中的溶解度，以选择纳米乳的组分。用水滴定法绘制了拟三元相图。对从伪三元相图中选择的制剂进行热力学稳定性和稳定性研究，以选择最终的测试制剂，其特征在于平均小球尺寸、多分散指数（PDI）、ζ电位、粘度、折射率、体外药物释放和透光率百分比，以优化最终制剂。在雌性Balb/c小鼠上使用γ-射线衍射法进行优化制剂与纯药物混悬液相比的药代动力学和生物分布研究。还对Hela宫颈癌细胞系进行了体外细胞毒性研究，以比较开发的制剂与纯药物溶液的抗癌活性。使用适当的去卷积建立了药物释放量和药物吸收量的体外-体内相关性。在40±2°C和75± 5%RH下对最终制剂进行3个月的稳定性研究，并确定有效期。基于溶解度研究，分别选择Capmul MCM、Tween 80和Transcutol P®（Smix）作为油、表面活性剂和助表面活性剂。在所制备的17种制剂中，基于热力学应力和热稳定性测试选择6种制剂作为最终测试制剂。最佳处方组成为油（10%，v/v）、Smix（35%，v/v）和双蒸水（55%，v/v）。生物利用度研究表明，与混悬液相比，纳米乳的生物利用度提高了4.83倍。生物分布研究显示，与混悬液相比，卵巢对纳米乳剂中药物的摄取增加2倍以上。体外细胞毒性研究表明，与药物溶液相比，纳米乳剂制剂形式的药物具有增强的抗癌潜力。在药物释放量和药物吸收量之间建立了A级相关性。发现制剂的有效期为1.30年。结果表明，表面改性纳米乳是一种很有前途的方法，以提高稳定性，生物利用度和细胞摄取的药物。
The objectives of the present study were to circumvent the moisture-associated instability, enhance bioavailability and achieve enhanced passive targeting of melphalan to the ovaries. Solubility of the drug was determined in various excipients to select the components of nanoemulsion. Pseudoternary phase diagrams were constructed using aqueous titration method. Formulations selected from the pseudoternary phase diagram were subjected to thermodynamic stability and dispersibility studies to select the final test formulations which were characterized for average globule size, polydispersity index (PDI), zeta potential, viscosity, refractive index, in-vitro drug release and percentage transmittance to optimize the final formulation. Pharmacokinetic and biodistribution studies of the optimized formulation in comparison to the pure drug suspension were done using γ-scintigraphy on female Balb/c mice. In-vitro cytotoxicity study on Hela cervical cancer cell lines was also done to compare the anticancer activity of the developed formulation with respect to the pure drug solution. In vitro–in vivo correlation was established for the amount of drug released and the amount of drug absorbed using suitable deconvolution. Stability studies on the final formulation were performed at 40±2°C and 75±5% RH for 3 months and the shelf life was determined. Capmul MCM, Tween 80 and Transcutol P®(Smix) were selected as the oil, surfactant and co-surfactant respectively on the basis of solubility studies. Out of 17 formulations prepared, six formulations were selected as the final test formulations on the basis of thermodynamic stress and dispersibility tests. The optimized formulation composed of oil (10%, v/v), Smix(35%, v/v), and double distilled water (55%, v/v). Bioavailability studies revealed 4.83 folds enhancement in bioavailability of the drug from nanoemulsion as compared to that from suspension. Biodistribution studies revealed more than 2 folds increase in uptake of the drug from nanoemulsion by ovaries as compared to that from the suspension. In vitro cytotoxicity studies demonstrated augmented anticancer potential of the drug in the form of nanoemulsion formulation in comparison to the drug solution. Level A correlation was established between the amount of drug released and the amount of drug absorbed. The shelf life of the formulation was found to be 1.30 years. The results demonstrate surface modified nanoemulsion to be a promising approach so as to increase stability, bioavailability and cellular uptake of the drug.