Amino-Acid-Incorporating Nonionic Surfactants for Stabilization of Protein Pharmaceuticals

Abstract

With the rapid development of protein-based pharmaceutical products over the past decade, one of the biggest challenges in product development is maintaining the structural stability of proteins during purification, processing, and storage. In this work, the design of a new class of surfactants, polyethermodified N-acyl amino acids, is presented. One surfactant from this series, containing a phenylalanine moiety, demonstrated remarkable stabilization against aggregation of several model protein drugs. Dynamic light scattering, size exclusion chromatography, and circular dichroism all show the rate of thermally accelerated protein aggregation slowed. IgG aggregation was reduced by 3-fold compared to polysorbate controls. Testing of Orencia, a prescription biologic drug for rheumatoid arthritis, demonstrated a 36% improvement in monomer retention upon heat-aging.

Effects of Hydrophobic Tail Length Variation on Surfactant-Mediated Protein Stabilization

“…Surfactant synthesis was adapted from Katz et al Full synthetic procedures are included in the Supporting Information. In brief, phenylalanine was acylated with a hydrocarbon chain acyl chloride at room temperature in the presence of a base.…”

“…Previous research of Katz et al identified a new amino acid-based surfactant without ester bonds, commonly referred to as FM1000, that often outperforms the current surfactants on the market used for protein stabilization. , (For this paper, FM1000 will hereafter be referred to as 14FM1000, where the number in front of “FM1000” denotes the hydrophobic tail length.) FM1000 is currently in development by DuPont Pharma Solutions as a new excipient for the pharmaceutical industry.…”

“…FM1000 is currently in development by DuPont Pharma Solutions as a new excipient for the pharmaceutical industry. Importantly, compared to polysorbate 20 and 80, 14FM1000 led to a decreased rate of growth of immunoglobulin G (IgG) aggregates when protein–surfactant solutions were held isothermally at 65 °C . Katz et al hypothesized that the success of 14FM1000 was likely due to its ability to move and adsorb quickly to different interfaces such as aqueous–air and aqueous–oil, as shown by dynamic surface tension (DST) measurements .…”

Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness

“…Polymer excipients are inactive ingredients included in pill formulations that are frequently, but not exclusively, used to sequester small molecules and larger payloads through noncovalent interactions with active pharmaceutical ingredients (APIs), , proteins, − and polynucelotides . In oral, intravenous, or intramuscular administration, the polymer works with the active ingredients as a stabilizer, both on the shelf and in vivo.…”

Surfactant for better tomorrow: applied aspect of surfactant aggregates from laboratory to industry

“…The nonionic surfactant plays a pivotal role in stabilizing the protein in commercial formulations over the ionic surfactants; however, the mechanism of this stabilization is not clearly established [39,40]. Katz et al [41] reported that the amino acid-based nonionic surfactants are promising one for stabilization of protein pharmaceuticals. Kishore and coworkers recently focused on the understanding of interactions of nonionic surfactants with proteins in biotherapeutic formulations [42].…”