Cicognani Marta, Rossi Silvia, Vecchi Gabriele, Giori Andrea Maria, Ferrari Franca
R&D Department, IBSA Farmaceutici Italia Srl, Via Martiri di Cefalonia 2, 26900 Lodi, Italy.
Department of Drug Sciences, University of Pavia, Viale Taramelli, 12, 27100 Pavia, Italy.
Pharmaceutics. 2020 Jul 20;12(7):681. doi: 10.3390/pharmaceutics12070681.
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.
本研究的目的是开发一种新型的基于糖胺聚糖（GAG）的可注射制剂，用于关节腔内给药，该制剂应尽可能模拟健康的滑液。在GAG聚合物中选择了透明质酸（HA），因为它是滑液中最丰富的成分。采用实验设计（DoE）方法来开发一种包含两种HA（超高（VHMW）和低（LMW）分子量）级别的制剂。做出这种选择的理由是，到目前为止，与健康滑液相比，没有基于单一HA级别甚至二元HA混合物的商业产品具有最佳的粘弹性。选择全因子设计来研究两种聚合物级别的浓度和相对比例（保留为模型的因素）对制剂功能（粘度和粘弹性）特性的影响，这些特性被视为响应变量。借助DoE方法，找到了优化的HA制剂的组成。向该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制剂包装在预填充无菌注射器中，在长期和加速的国际协调理事会（ICH）储存条件下稳定。总体结果表明该制剂适合药物开发的进一步步骤，即进入中试规模。
