Viscosity-Lowering Effect of Amino Acids and Salts on Highly Concentrated Solutions of Two IgG1 Monoclonal Antibodies

详细信息    查看全文

• 作者：Shujing Wang ; Ning Zhang ; Tao Hu ; Weiguo Dai ; Xiuying Feng ; Xinyi Zhang ; Feng Qian
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：December 7, 2015
• 年：2015
• 卷：12
• 期：12
• 页码：4478-4487
• 全文大小：666K
• ISSN：1543-8392

文摘

Monoclonal antibodies display complicated solution properties in highly concentrated (>100 mg/mL) formulations, such as high viscosity, high aggregation propensity, and low stability, among others, originating from protein鈥損rotein interactions within the colloidal protein solution. These properties severely hinder the successful development of high-concentration mAb solution for subcutaneous injection. We hereby investigated the effects of several small-molecule excipients with diverse biophysical-chemical properties on the viscosity, aggregation propensity, and stability on two model IgG1 (JM1 and JM2) mAb formulations. These excipients include nine amino acids or their salt forms (Ala, Pro, Val, Gly, Ser, HisHCl, LysHCl, ArgHCl, and NaGlu), four representative salts (NaCl, NaAc, Na₂SO₄, and NH₄Cl), and two chaotropic reagents (urea and GdnHCl). With only salts or amino acids in their salt-forms, significant decrease in viscosity was observed for JM1 (by up to 30鈥?0%) and JM2 (by up to 50鈥?0%) formulations, suggesting charge鈥揷harge interaction between the mAbs dictates the high viscosity of these mAbs formulations. Most of these viscosity-lowering excipients did not induce substantial protein aggregation or changes in the secondary structure of the mAbs, as evidenced by HPLC-SEC, DSC, and FT-IR analysis, even in the absence of common protein stabilizers such as sugars and surfactants. Therefore, amino acids in their salt-forms and several common salts, such as ArgHCl, HisHCl, LysHCl, NaCl, Na₂SO₄, and NaAc, could potentially serve as viscosity-lowering excipients during high-concentration mAb formulation development.