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Polysorbates HLB (PS) are the most commonly used surfactants in biopharmaceutical formulations, maximizing the reduction of aggregation, denaturation, and surface adsorption of therapeutic proteins. However, they themselves may undergo degradation due to the formulation composition, pH, and storage conditions, which may increase the challenges in controlling the heterogeneity, quality, and stability of the active pharmaceutical ingredients in biopharmaceuticals.
The core structure of polysorbates HLB is a sorbitan ester ring (sugar alcohol) with polyethylene oxide (PEO) conjugated to the hydroxyl groups. In various polysorbate molecules, the number of ethylene oxide subunits conjugated to the four hydroxyl groups of the sorbitan ester ring can vary. However, in all polysorbate structures, the total number of ethylene oxide repeat units is approximately 20. The chemical synthesis of polysorbates HLB involves two steps: 1) ethoxylation of sorbitan ester; 2) esterification with fatty acids such as lauric acid, palmitic acid, stearic acid, and oleic acid.
Polysorbates HLB are commonly named with a number that indicates the type of fatty acid ester bound to the sorbitan ethoxylate segment. For instance, Polysorbates HLB 20, 40, 60, and 80 are named after their fatty acid esters: laurate, palmitate, stearate, and oleate, respectively. The PEO segment in polysorbates HLB is hydrophilic, while the fatty acid portion is hydrophobic, making polysorbate HLB amphiphilic and efficient surfactants. Due to their amphiphilic nature, polysorbates HLB can self-assemble into micelles in aqueous solutions upon reaching the critical micelle concentration (CMC). These micelles generally have a nanoscale size and possess a strong drug-carrying capacity, making them widely used in drug delivery systems. They also serve as emulsifiers, solubilizers, and protein stabilizers for hydrophobic drugs. For example, Polysorbate HLB 80 is used as a stabilizer in certain COVID-19 vaccine formulations. Various polysorbates are also effective drug carriers for both hydrophobic and hydrophilic drugs and are widely used as emulsifiers in emulsion formulations. Polysorbate HLB 80 can act as an excipient in protein formulations to inhibit protein aggregation caused by stress conditions such as stirring.
Additionally, Polysorbate 80 and Polysorbate 20 exhibit good biocompatibility, low toxicity, and effective protein stabilization properties. Compared to charged surfactants (cationic, anionic, or amphoteric), non-ionic surfactants like polysorbates HLB generally have lower toxicity, better biocompatibility, and lower hemolytic potential. As such, polysorbates HLB are frequently used as drug carriers, improving the permeability of various drugs both in vitro and in vivo. They are commonly used in the production of therapeutic monoclonal antibodies (mAbs) and other therapeutic protein products.
During the production, processing, transportation, and administration of therapeutic biopharmaceuticals, therapeutic proteins may undergo adsorption, aggregation, or precipitation. Therefore, maintaining the stability of these proteins is critical. Adding polysorbates HLB to the formulation effectively protects proteins under all potential stress conditions, making the nature of the interaction between proteins and surfactants crucial in biopharmaceuticals.
Generally, polysorbates HLB competitively inhibit the adsorption of proteins onto hydrophobic interfaces, preventing protein aggregation through specific interactions with protein molecules. However, in some cases, this interaction may reduce protein stability or cause protein unfolding. Overall, polysorbates HLB protect proteins from the destabilizing effects of various interfaces, such as water-air, water-silicone oil, and water-container interfaces. Several factors influence their adsorption properties, including concentration, chemical potential at the interface, maximum surface excess, surface hydrophobicity, adsorption layer thickness, and temperature.
Therapeutic biopharmaceuticals, such as interferons, growth factors, and monoclonal antibodies (mAbs), are known for their high efficiency and specificity, which often results in wide therapeutic windows. These biologics have become standard treatments for many diseases. However, because the molecular weight of the biologically active molecules is large and their structures are complex, they are highly susceptible to external stress factors. Therefore, various excipients are typically added to their formulations to ensure the stability and drugability of the active molecules, with surfactants being one of the primary excipients.
Surfactants are ubiquitous in biopharmaceuticals, playing a key role in preventing aggregation, avoiding surface adsorption, and ensuring the long-term stability of tertiary structures. As a result, most commercially available biopharmaceuticals use Polysorbate HLB 20 or Polysorbate HLB 80 as surfactants.
