Department of Pharmaceutics, Rajiv Academy for Pharmacy, Mathura 2811001, Uttar Pradesh, India.
Department of Pharmaceutics, Rajiv Academy for Pharmacy, Mathura 2811001, Uttar Pradesh, India.
Int J Pharm. 2012 Apr 15;426(1-2):219-230. doi: 10.1016/j.ijpharm.2012.01.027. Epub 2012 Jan 24.
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 (S(mix)) 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), S(mix) (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.
本研究的目的是克服与水分相关的不稳定性，提高生物利用度，并实现对卵巢的增强型被动靶向。在各种赋形剂中测定药物的溶解度，以选择纳米乳的组成成分。使用水滴定法构建伪三元相图。从伪三元相图中选择的配方进行热力学稳定性和分散性研究，以选择最终测试配方，然后对其进行平均液滴大小、多分散指数（PDI）、zeta 电位、粘度、折射率、体外药物释放和透光率的测定，以优化最终配方。通过γ闪烁照相术在雌性 Balb/c 小鼠上对优化配方与纯药物混悬剂进行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。通过适当的反卷积建立了体外-体内相关性，以比较释放的药物量和吸收的药物量。在 40 ± 2°C 和 75 ± 5%RH 下进行最终配方的稳定性研究，持续 3 个月，并确定保质期。根据溶解度研究，Capmul MCM、Tween 80 和 Transcutol P（S(mix)）分别被选为油、表面活性剂和助表面活性剂。在制备的 17 种制剂中，有 6 种制剂根据热力学应激和分散性试验被选为最终测试制剂。由油（10%，v/v）、S(mix)（35%，v/v）和双蒸水（55%，v/v）组成的优化制剂。药代动力学研究表明，与混悬剂相比，药物从纳米乳中的生物利用度提高了 4.83 倍。生物分布研究表明，与混悬剂相比，药物从纳米乳中的卵巢摄取增加了 2 倍以上。体外细胞毒性研究表明，与药物溶液相比，药物的纳米乳制剂形式具有增强的抗癌潜力。在建立的体内外相关性中，释放的药物量与吸收的药物量之间存在 A 级相关性。该制剂的保质期为 1.30 年。结果表明，表面修饰的纳米乳是一种有前途的方法，可以提高药物的稳定性、生物利用度和细胞摄取。
