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 PS 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.

Role of Poloxamer 188 in Preventing Ice-Surface-Induced Protein Destabilization during Freeze–Thawing

“…Poloxamers, known by the trade name Pluronic, are nonionic triblock copolymers composed of a hydrophobic polyoxypropylene chain with two hydrophilic polyoxyethylene side chains . Poloxamer 188 (P188, Pluronic F-68), a popular grade with 75 ethylene oxide (on each side) and 30 propylene oxide monomers, has been used in protein products, including Gazyva, Norditropin, Hemlibra, and Orencia . Besides, P188 was also included in gene therapy products, such as Roctavian, Luxturna, and Zolgensma.…”

Injectable Devices for Delivery of Liquid or Solid Protein Formulations

“…Given protein specific behavior at high concentrations, further investigation will be required with for a specific candidate API. PEG-mediated protein solubility reduction as demonstrated in Schlesinger et al or alternate formulation methodologies may be required to retain acceptable protein stability over long durations. , …”

“…PEG-mediated protein solubility reduction as demonstrated in Schlesinger et al or alternate formulation methodologies may be required to retain acceptable protein stability over long durations. 26,41 Lastly, achieving sealed devices that maintain a cylindrical cross section without flattening and widening the device at the ends is of utmost importance for injectability. With suitably thin polymer membranes, self-collapsing seals may be suitable if processing can be effectively standardized.…”

Biomedical Applications of Lactoferrin on the Ocular Surface

“…CDs are cyclic oligosaccharides that show a good ability to form complexes with drug molecules and to improve their physicochemical properties without molecular modifications, via drug/host interaction [ 149 , 150 ]. The capacity of CDs to interact with proteins is well known [ 151 , 152 , 153 , 154 , 155 ]. Different mechanisms have been described by which cyclodextrins interact with proteins improving physical and chemical stability [ 154 ].…”

“…Different mechanisms have been described by which cyclodextrins interact with proteins improving physical and chemical stability [ 154 ]. CDs can form inclusion complexes with amino acids, mainly βCD derivatives and hydrophobic and aromatic residues of Phe, Tyr, His, and Trp, modulating the solvent exposure to hydrophobic amino-acidic residues [ 151 , 152 , 153 , 154 ]. Additionally, the surface activity of some CD-derivative can contribute to protein stabilization by reducing the protein surface adsorption [ 154 ].…”