Department of Biochemical and Pharmaceutical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580-Bl.16, São Paulo, CEP 05508-000, Brazil.
AAPS PharmSciTech. 2019 Jul 12;20(6):251. doi: 10.1208/s12249-019-1465-1.
Polymersomes are versatile nanostructures for protein delivery with hydrophilic core suitable for large biomolecule encapsulation and protective stable corona. Nonetheless, pharmaceutical products based on polymersomes are not available in the market, yet. Here, using commercially available copolymers, we investigated the encapsulation of the active pharmaceutical ingredient (API) L-asparaginase, an enzyme used to treat acute lymphoblastic leukemia, in polymersomes through a quality-by-design (QbD) approach. This allows for streamlining of processes required for improved bioavailability and pharmaceutical activity. Polymersomes were prepared by bottom-up (temperature switch) and top-down (film hydration) methods employing the diblock copolymers poly(ethylene oxide)-poly(lactic acid) (PEG-PLA, PEG-PLA, and PEG-PLA) and the triblock Pluronic L-121 (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), PEG-PPO-PEG). Quality Target Product Profile (QTPP), Critical Quality Attributes (CQAs), Critical Process Parameters (CPPs), and the risk assessment were discussed for the early phase of polymersome development. An Ishikawa diagram was elaborated focusing on analytical methods, raw materials, and processes for polymersome preparation and L-asparaginase encapsulation. PEG-PLA resulted in diluted polymersomes systems. Nonetheless, a much higher yield of Pluronic L-121 polymersomes of 200 nm were produced by temperature switch, reaching 5% encapsulation efficiency. Based on these results, a risk estimation matrix was created for an initial risk assessment, which can help in the future development of other polymersome systems with biological APIs nanoencapsulated.
聚合物囊泡是一种多功能的纳米结构，具有亲水核，适合于大生物分子的封装和保护性稳定的冠层。尽管如此，基于聚合物囊泡的药物产品尚未在市场上推出。在这里，我们使用市售的嵌段共聚物，通过质量源于设计（QbD）的方法研究了活性药物成分（API）天冬酰胺酶在聚合物囊泡中的包封，天冬酰胺酶是一种用于治疗急性淋巴细胞白血病的酶。这使得提高生物利用度和药物活性所需的过程得到简化。聚合物囊泡通过自下而上（温度开关）和自上而下（薄膜水化）的方法制备，使用嵌段共聚物聚（乙二醇）-聚（乳酸）（PEG-PLA、PEG-PLA 和 PEG-PLA）和三嵌段 Pluronic L-121（聚（乙二醇）-聚（丙二醇）-聚（乙二醇），PEG-PPO-PEG）。讨论了质量目标产品概况（QTPP）、关键质量属性（CQAs）、关键工艺参数（CPPs）和风险评估，以作为聚合物囊泡开发的早期阶段。绘制了石川图，重点关注聚合物囊泡制备和天冬酰胺酶包封的分析方法、原材料和工艺。PEG-PLA 导致聚合物囊泡体系稀释。然而，通过温度开关制备的 Pluronic L-121 聚合物囊泡的产量要高得多，粒径为 200nm，包封效率达到 5%。基于这些结果，创建了一个初始风险评估的风险估计矩阵，这有助于未来开发其他包封生物 API 的纳米聚合物囊泡系统。
