Stabilizing effect of HP-β-CD on infliximab in liquid formulations and a solid formulation produced by electrospinning

Abstract

The development of stable biopharmaceutical formulations, such as monoclonal antibodies, poses a great challenge in the pharmaceutical industry. This study investigated the stabilizing effect of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in liquid and solid formulations of infliximab during processing and storage. The solid formulation was produced by a scaled-up high-speed electrospinning method, resulting in a product suitable for reconstitution with excellent dissolution properties. Liquid formulations contained exclusively HP-β-CD as a stabilizing excipient at different concentrations.

Both types of formulations were stored under various conditions for up to 6 months, and infliximab stability was compared based on monomer recovery and the analysis of fragments and aggregates. The solid formulation stored at low (-18°C, 4°C) temperatures and lower humidity conditions show the most promising results. Moreover, the monomer loss was less than 10% even at room temperature storage after 2 months, indicating a potentially good temperature tolerance. Increasing HP-β-CD content in liquid formulations significantly improved the long-term stability of infliximab while enhancing protection against mechanical stress.

Furthermore, to better understand the stabilizing mechanism of HP-β-CD on infliximab, the molecular interactions were investigated by bio-layer interferometry and isothermal titration calorimetry methods. The experiments proved that the presence of HP-β-CD decreased infliximab self-interaction, correlating with the aggregation-suppressing effect of HP-β-CD observed during the stress- and long-term stability studies. The results demonstrate the potential of HP-β-CD as a stabilizing excipient in liquid and solid formulations of infliximab.

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Materials

Model active agent (infliximab) was kindly provided by Janssen Pharmaceutica (Beerse, Belgium). The molecular weight of this particular antibody is 149.1 kDa (https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/REMICADE-pi.pdf). 2-Hydroxypropyl-beta-cyclodextrin (HP-β-CD) (Kleptose® HPB, MS nominal value: 0.62, average molecular weight 1387 g/mol) was received from Roquette Pharma (Lestrem, France). Sodium phosphate monobasic and sodium phosphate dibasic were purchased from Sigma-Aldrich (Budapest, Hungary). Infliximab stock solution at a protein concentration of 36 mg/mL in 10 mM sodium phosphate buffer at a pH of 7.2 was stored at -80°C before preparing different formulations. Ultrapure water was derived from a Zeneer UP S-UV (Human Corporation) equipment. All buffers were filtered through 0.22 μm PES membrane before usage (Millipore).

Fanni Angéla Geyer, Júlia Domján, Tibor Viktor Szalai, Zsolt Rapi, Zoltán Varga, György Marosi, Zsombor K. Nagy, Edit Hirsch, Stabilizing effect of HP-β-CD on infliximab in liquid formulations and a solid formulation produced by electrospinning, European Journal of Pharmaceutical Sciences, 2025, 107014, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107014.