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Impact of Silicone Oil on Free Fatty Acid Particle Formation due to Polysorbate 20 Degradation
Pharmaceutical Research ( IF 3.7 ) Pub Date : 2020-10-07 , DOI: 10.1007/s11095-020-02936-3
Raphael Fish 1 , Jasper Lin 2 , Nidhi Doshi 2
Affiliation  

Purpose

Polysorbate 20 (PS20), a commonly used surfactant in biopharmaceutical formulations, can undergo hydrolytic degradation resulting in free fatty acids (FFAs) that precipitate to form particles. This work investigates the ability for silicone oil (si-oil) coated on the interior walls of prefilled syringes (PFSs) to act as a sink for FFAs and potentially delay FFA particle formation.

Methods

Myristic acid distribution coefficient was measured in a two-phase system containing si-oil and formulation buffer at a range of aqueous conditions. An empirical model was built from these data to predict distribution coefficient based on aqueous conditions. To verify the model, PS20 was degraded using model lipases side-by-side in glass vials and PFSs while monitoring sub-visible particles.

Results

The empirical model demonstrates that the partitioning of myristic acid into si-oil is maximized at low pH and low PS20 concentration. The model predicts that the presence of si-oil at levels typical in PFSs provides at most an 8.5% increase in the total carrying capacity for myristic acid compared to a non-coated glass vial. The time to onset of FFA particles was equivalent between degradations performed in two PFS models coated with differing levels of silicone oil and in non-coated glass vials.

Conclusion

Herein, we demonstrate that FFAs partition from aqueous solution into si-oil. However, the extent of the partitioning effect is not large enough to delay PS20-related FFA particle formation at typical formulation conditions (pH 5.0–7.5, 0.01% - 0.1% w/v PS20) filled in typical PFSs (<1.0 mg si-oil/mL aqueous fill).



中文翻译:

硅油对聚山梨酯20降解引起的游离脂肪酸颗粒形成的影响

目的

聚山梨酯20(PS20)是生物药物制剂中常用的表面活性剂,可发生水解降解,导致游离脂肪酸(FFA)沉淀形成颗粒。这项工作研究了涂在预填充注射器(PFS)内壁上的硅油(si-oil)充当FFA汇和可能延迟FFA颗粒形成的能力。

方法

在含有硅油和配制缓冲液的两相系统中,在一定范围的水性条件下测量肉豆蔻酸的分布系数。从这些数据建立了一个经验模型,以根据含水条件预测分布系数。为了验证模型,使用模型脂肪酶在玻璃小瓶和PFS中并排降解PS20,同时监测亚可见颗粒。

结果

经验模型表明,在低pH和低PS20浓度下,肉豆蔻酸在硅油中的分配最大。该模型预测,与无涂层玻璃小瓶相比,PFS中典型含量的si油的存在可使肉豆蔻酸的总承载量最多增加8.5%。在两种涂覆有不同水平的硅油的PFS模型中以及在未涂覆的玻璃小瓶中进行降解的过程中,FFA颗粒的形成时间相等。

结论

在本文中,我们证明FFA从水溶液分配到硅油中。但是,分配作用的程度不足以在填充典型PFS(<1.0 mg si-PS)的典型配方条件(pH 5.0-7.5,0.01%-0.1%w / v PS20)下延迟与PS20相关的FFA颗粒的形成。油/毫升水性填充液)。

更新日期:2020-10-07
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