Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Institut Galien Paris-Sud, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
Int J Pharm. 2018 Sep 15;548(2):740-746. doi: 10.1016/j.ijpharm.2017.08.094. Epub 2017 Aug 25.
Chronic obstructive pulmonary disease (COPD) is a complex disease, characterized by persistent airflow limitation and chronic inflammation. The purpose of this study was to design lipid-polymer hybrid nanoparticles (LPNs) loaded with the corticosteroid, budesonide, which could potentially be combined with small interfering RNA (siRNA) for COPD management. Here, we prepared LPNs based on the biodegradable polymer poly(dl-lactic-co-glycolic acid) (PLGA) and the cationic lipid dioleyltrimethylammonium propane (DOTAP) using a double emulsion solvent evaporation method. A quality-by-design (QbD) approach was adopted to define the optimal formulation parameters. The quality target product profile (QTPP) of the LPNs was identified based on risk assessment. Two critical formulation parameters (CFPs) were identified, including the theoretical budesonide loading and the theoretical DOTAP loading. The CFPs were linked to critical quality attributes (CQAs), which included the intensity-based hydrodynamic particle diameter (z-average), the polydispersity index (PDI), the zeta-potential, the budesonide encapsulation efficiency, the actual budesonide loading and the DOTAP encapsulation efficiency. A response surface methodology (RSM) was applied for the experimental design to evaluate the influence of the CFPs on the CQAs, and to identify the optimal operation space (OOS). All nanoparticle dispersions displayed monodisperse size distributions (PDI<0.2) with z-averages of approximately 150nm, suggesting that the size is not dependent on the investigated CFPs. In contrast, the zeta-potential was highly dependent on the theoretical DOTAP loading. Upon increased DOTAP loading, the zeta-potential reached a maximal point, after which it remained stable at the maximum value. This suggests that the LPN surface is covered by DOTAP, and that the DOTAP loading is saturable. The actual budesonide loading of the LPNs was mainly dependent on the initial amount of budesonide, and a clear positive effect was observed, which shows that the interaction between drug and PLGA increases when increasing the initial amount of budesonide. The OOS was modeled by applying the QTPP. The OOS had a budesonide encapsulation efficiency higher than 30%, a budesonide loading above 15μg budesonide/mg PLGA, a zeta-potential higher than 35mV and a DOTAP encapsulation efficiency above 50%. This study shows the importance of systematic formulation design for understanding the effect of formulation parameters on the characteristics of LPNs, eventually resulting in the identification of an OOS.
慢性阻塞性肺疾病（COPD）是一种复杂的疾病，其特征是持续的气流受限和慢性炎症。本研究旨在设计负载皮质类固醇布地奈德的脂-聚合物杂化纳米颗粒（LPN），该纳米颗粒可与小干扰 RNA（siRNA）联合用于 COPD 的治疗。本研究采用双乳液溶剂蒸发法，以可生物降解聚合物聚（DL-丙交酯-共-乙交酯）（PLGA）和阳离子脂质二油酰基三甲基铵丙烷（DOTAP）为原料制备 LPN。采用质量源于设计（QbD）方法来确定最佳的制剂参数。基于风险评估，确定了 LPN 的质量目标产品概况（QTPP）。确定了两个关键的制剂参数（CFP），包括理论布地奈德载药量和理论 DOTAP 载药量。CFP 与关键质量属性（CQA）相关联，包括基于强度的水动力粒径（z-平均粒径）、多分散指数（PDI）、zeta-电位、布地奈德包封效率、实际布地奈德载药量和 DOTAP 包封效率。采用响应面法（RSM）进行实验设计，以评估 CFP 对 CQA 的影响，并确定最佳操作空间（OOS）。所有纳米颗粒分散体均显示出单分散粒径分布（PDI<0.2），z-平均粒径约为 150nm，表明粒径不受所研究 CFP 的影响。相比之下，zeta-电位高度依赖于理论 DOTAP 载药量。随着 DOTAP 载药量的增加，zeta-电位达到最大值，之后保持在最大值稳定。这表明 LPN 表面被 DOTAP 覆盖，并且 DOTAP 载药量是饱和的。LPN 的实际布地奈德载药量主要取决于布地奈德的初始量，并且观察到明显的正向作用，这表明当增加布地奈德的初始量时，药物与 PLGA 之间的相互作用增加。通过应用 QTPP 对 OOS 进行建模。OOS 的布地奈德包封效率高于 30%，布地奈德载药量高于 15μg 布地奈德/mg PLGA，zeta-电位高于 35mV，DOTAP 包封效率高于 50%。本研究表明，系统的制剂设计对于理解制剂参数对 LPN 特性的影响非常重要，最终确定了 OOS。
