Institute of Pharmacy, Nirma University , Ahmedabad , India and.
Pharm Dev Technol. 2014 Mar;19(2):200-12. doi: 10.3109/10837450.2013.769566. Epub 2013 Feb 25.
In current exploration, systematic attempts have been made to improve the entrapment efficiency of a model hydrophilic drug substance, i.e. acyclovir, in poly (d, l) lactide (PLA) nanoparticles (NPs) using a modified nanoprecipitation technique.
Formulation parameters such as drug to polymer ratio, antisolvent selection, electrolyte (NaCl) addition, pH alteration and temperature were screened to improve the entrapment efficiency of acyclovir in PLA NPs. The temperature of the system (0-5 °C), phase volume ratio (1:2), stirring speed (2000 rpm), sonication time (5 min), etc. were kept constant during the preparation of NPs. Drug to polymer ratio and electrolyte addition emerged as critical formulation parameters affecting particle size as well as entrapment efficiency. Hence, in the present investigation a 3(2) full factorial design was used to investigate the combined influence of two factors, i.e. drug to polymer ratio (X1) and the amount of electrolyte, i.e. NaCl (X2) on particle size (Y1) and entrapment efficiency (Y2). The NPs were also evaluated for drug-excipient compatibility study by employing DSC and FT-IR analysis, whereas in vitro drug release studies were performed using dialysis bag technique in phosphate buffer pH 7.4.
Statistically significant models were evolved to predict entrapment efficiency and particle size. The effect of factors X1, X2 and [Formula: see text] was found to be statistically significant in nature. Response variables, i.e. entrapment efficiency and particle size, were simultaneously optimized using desirability function using Design Expert software. This process allowed the selection of most suitable level of factors to achieve desired level of particle size and entrapment efficiency. The results of multiple linear regression analysis revealed that for obtaining desirable particle size (less than 250 nm) and entrapment efficiency (more than 17%), the NPs should be prepared using 1:3 drug to polymer ratio and 0.04 M NaCl. Acyclovir was found to be compatible with PLA as indicated by DSC and FT-IR studies. The experimental values obtained from the optimized formulation highly agreed with the predicted values. The drug release from the optimized formulation exhibited biphasic pattern and the drug release kinetics was best explained by Weibull model.
In conclusion, results of the present study demonstrated that PLA NPs with expected particle size and entrapment efficiency can be obtained by adopting the concept of quality by design.
在当前的探索中，我们系统地尝试使用改良的纳米沉淀技术来提高模型亲水性药物物质（即阿昔洛韦）在聚（D，L）丙交酯（PLA）纳米颗粒（NP）中的包封效率。
筛选了制剂参数，如药物与聚合物的比例、反溶剂的选择、电解质（NaCl）的添加、pH 值的改变和温度，以提高阿昔洛韦在 PLA NPs 中的包封效率。在制备 NPs 时，系统温度（0-5°C）、相体积比（1:2）、搅拌速度（2000rpm）、超声时间（5min）等保持不变。药物与聚合物的比例和电解质的添加是影响粒径和包封效率的关键制剂参数。因此，在本研究中，采用 3(2)完全因子设计来研究两个因素（药物与聚合物的比例（X1）和电解质 NaCl 的添加量（X2））对粒径（Y1）和包封效率（Y2）的综合影响。通过差示扫描量热法（DSC）和傅里叶变换红外光谱（FT-IR）分析评估 NPs 的药物-赋形剂相容性，体外药物释放研究采用磷酸盐缓冲液 pH 7.4 中的透析袋技术进行。
成功建立了预测包封效率和粒径的统计学上显著的模型。发现因素 X1、X2 和 [Formula: see text] 的影响具有统计学意义。使用 Design Expert 软件中的适宜性函数对响应变量（即包封效率和粒径）进行了同时优化。该过程允许选择最合适的因素水平以达到所需的粒径和包封效率。多元线性回归分析的结果表明，为了获得理想的粒径（小于 250nm）和包封效率（大于 17%），应使用 1:3 的药物与聚合物比例和 0.04M NaCl 制备 NPs。DSC 和 FT-IR 研究表明，阿昔洛韦与 PLA 相容。从优化配方中获得的实验值与预测值高度吻合。优化配方的药物释放呈双相模式，药物释放动力学最好用 Weibull 模型来解释。
总之，本研究结果表明，通过采用质量源于设计的概念，可以获得具有预期粒径和包封效率的 PLA NPs。
