Alternative Excipients for Protein Stabilization in Protein Therapeutics: Overcoming the Limitations of Polysorbates

Abstract

Given their safety and efficiency in protecting protein integrity, polysorbates (PSs) have been the most widely used excipients for the stabilization of protein therapeutics for years. In recent decades, however, there have been numerous reports about visible or sub-visible particles in PS-containing biotherapeutic products, which is a major quality concern for parenteral drugs. Alternative excipients that are safe for parenteral administration, efficient in protecting different protein drugs against various stress conditions, effective in protein stabilization in high-concentrated liquid formulations, stable under the storage conditions for the duration of the product's shelf-life, and compatible with other formulation components and the primary packaging are highly sought after. The aim of this paper is to review potential alternative excipients from different families, including surfactants, carbohydrate- and amino acid-based excipients, synthetic amphiphilic polymers, and ionic liquids that enable protein stabilization. For each category, important characteristics such as the ability to stabilize proteins against thermal and mechanical stresses, current knowledge related to the safety profile for parenteral administration, potential interactions with other formulation components, and primary packaging are debated. Based on the provided information and the detailed discussion thereof, this paper may pave the way for the identification or development of efficient excipients for biotherapeutic protein stabilization.

Keywords: excipient; polysorbate alternatives; protein biotherapeutic formulations; protein stabilization; surfactant.

Figure 1

(a) Idealized chemical structure of PSs and potential surfactant alternatives containing ester bonds. The ester bonds are highlighted in red, and the POE moiety in green; (b) Expected degradation mechanisms for ester bond/POE-containing surfactants [65].

Figure 2

Chemical structures of potential surfactant PS alternatives devoid of an ester bond: (a) Poloxamer, (b) Polyoxyethylene alkyl ether (Brij), (c) Dodecyl-β-D-maltoside, (d) Dodecyl glucoside, and (e) N-myristoyl phenylalanine Jeffamine M1000 diamide (FM1000).

Figure 3

Chemical structures of potential carbohydrate PS alternatives: (a) Disaccharides, (b) Sugar alcohols, (c) Cyclodextrins (CD), (d) Hydroxypropyl methylcellulose, and (e) Dextran.

Figure 4

Structures of low molecular weight polyamines used in the prevention of heat-induced aggregation and inactivation of proteins.

Figure 5

Chemical structures of synthetic amphiphilic polymers with potential to serve as PS alternatives: (a) Polyether polyols, (b) Sulfobetaine and its derivatives as examples of polyampholates.