The aim of the present work was the development of a novel glycosaminoglycan (GAG)-based injectable formulation intended for intra-articular administration that should best mimic the healthy synovial fluid. Hyaluronic acid (HA) was chosen among GAG polymers, since it is the most abundant component of the synovial fluid. A DoE (Design of Experiment) approach was used for the development of a formulation containing two HA (very high (VHMW) and low (LMW) molecular weight) grades. The rationale for this choice is that so far, no commercial product based on a single HA grade or even on binary HA mixture possesses optimal viscoelastic properties in comparison with healthy synovial fluid. A full factorial design was chosen to investigate the influence of concentration and relative fraction of the two polymer grades (retained as factors of the model) on formulation functional (viscosity and viscoelastic) properties, which are considered response variables. Thanks to the DoE approach, the composition of the optimized HA formulation was found. The addition to such formulation of an injectable grade fat-free soy phospholipid, which was rich in phosphatidylcholine (PC), resulted in improved lubrication properties. The final HA + PC formulation, packaged in pre-filled sterile syringes, was stable in long-term and accelerated ICH (International Council for Harmonisation) storage conditions. The overall results pointed out the formulation suitability for further steps of pharmaceutical developments, namely for the passage to pilot scale.

中文翻译：

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美国能源部协助开发的一种新的基于糖胺聚糖的粘胶补充剂。

本工作的目的是开发一种新的基于糖胺聚糖（GAG）的可注射制剂，旨在最佳模拟健康滑液，用于关节内给药。从透明质酸聚合物中选择了透明质酸（HA），因为它是滑液中含量最高的成分。使用DoE（实验设计）方法开发包含两种HA（非常高（VHMW）和低（LMW）分子量）等级的配方。这种选择的理由是，到目前为止，与健康滑液相比，没有基于单一HA等级甚至基于二元HA混合物的商品都具有最佳的粘弹性质。选择了全因子设计来研究两种聚合物等级的浓度和相对分数（保留为模型因素）对制剂功能（粘度和粘弹性）特性的影响，这些特性被认为是响应变量。由于采用了DoE方法，因此找到了优化的HA配方的组成。向这种制剂中添加富含磷脂酰胆碱（PC）的可注射级无脂大豆磷脂可改善润滑性能。最终的HA + PC制剂包装在预先填充的无菌注射器中，在长期和加速的ICH（国际协调委员会）储存条件下稳定。总体结果指出该制剂适合于药物开发的进一步步骤，即通过中试规模。