Chemicals & raw materials
polyethylene oxide and hydrophobic polypropylene oxide blocks. These components give them the properties required in a surfactant, and much like polysorbates, the stability, safety and tolerability of several products have been demonstrated in oral and parenteral applications. “Poloxamer 188 has even shown advantages over polysorbates in some special formulation cases,” adds Bollenbach. “Beside that, poloxamers have a less complex structure and composition than polysorbates, which is thought to be more manageable.”
The chemical formula for polysorbate 80, the most common surfactant found in pharmaceuticals, along with polysorbate 20.
), a chemical compound (and oxidative agent) used to disinfect and decontaminate cleanrooms used in drug production. Whether the risk of one or the other degradation pathways is higher depends on the formulation, but hydrolysis tends to occur more frequently in biologics, oxidation more so in small molecule drugs. In both cases, formulation scientists add other excipients to the reduce degradation risk, and the standards of procedure followed for manufacturing and storage are designed to reduce exposure to any stimuli that could excite molecules towards an oxidative or hydrolytic reaction.
(H2 O2
Bollenbach is eager to stress that this level of risk mitigation is par for the course for many excipients. “It’s not only polysorbates that can show instabilities that affect their shelf life and might impact the quality of the finished product,” he says. “These findings have led to the search for alternatives, but also to more research in the field of excipient stability.” The bar a surfactant must reach to become a viable alternative to polysorbates is high. After all, more than 90% of EU approved monoclonal antibodies (mAbs) are formulated with either polysorbate 20 or polysorbate 80. This is significant when mAbs constitute the majority of biologic drug approvals each year. But it hasn’t stopped researchers from evaluating alternative surfactants for potential advantages over polysorbates. “The choice of a sufficient surfactant for a biological is very complex,” explains Bollenbach. “Beside regulatory considerations, every biologic drug has its own specific characteristics, and finding the right surfactant candidate and concentration is something that must be evaluated.”
A promising candidate
One of the more promising candidates is poloxomers, a group of block copolymers composed of hydrophilic
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Poloxamers are particularly well suited for applications that require gel formation at lower temperatures and rapid dissolution at higher temperatures, meaning they’re often found in topical products. But the ability to transition from a liquid to a gel phase upon contact with physiological fluids or body heat also makes them ideal for slow-release formulations in both oral and parenteral drug delivery. In the gel phase, poloxamers can effectively trap and hold the drug molecules within their structure, and when formulated with other excipients, they can be used to tune the kinetics of drug release to achieve a specific dosing regimen. On the other hand, polysorbates are not designed to create a gel or matrix that can control the release of drugs over an extended period. Instead, they are used to improve drug solubility and dispersion, which can lead to relatively rapid drug release upon administration. It goes without saying that polysorbates and poloxomers aren’t the only surfactants about, and there are many other promising alternatives, like the highly biocompatible Lecithin found in egg yolk and soy beans, or cremophors – derivatives of castor oil shown to improve the solubility of drugs in lipids (fats) to a higher degree than polysorbates. These contextual differences help to illustrate how the use of surfactants in pharmaceuticals has developed as a result of research, and when we consider that a large amount of that research is on polysorbates, it’s not hard to understand why they’re the most common choice in small molecule and biologic formulations. Formulation science is an evolving discipline however, and with a growing interest in the study of excipient stability in pharmacologically relevant environments, like the human body or storage rooms, research developments might lead to new applications for surfactants, or the discovery of a new surfactant altogether. “As polysorbates have been used more often and for a longer time in protein formulations, there is more knowledge behind formulating with polysorbates,” says Bollenbach. “Poloxamers, as well as polysorbates, will be considered when new biologic drugs need suitable formulations. Meanwhile, the characteristics of both, as well as other surfactants will continue to be evaluated, especially regarding their stability and stabilising properties.” ●
World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net
Bacsica/
shutterstock.com
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