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Drug ingredients considered inert might have biological activity

Systematic investigation of excipients reveals that most are inactive, but a few may act upon biological targets

by Bethany Halford
July 24, 2020

Although the therapeutic components of drugs get most of the attention, fillers called excipients make up the bulk of most drugs. Excipients act as preservatives or contain active ingredients within tidy tablets and slippery capsules. Though they are generally considered to be inactive, a new study suggests that some excipients can bind to biological targets, and may have pharmacological effects.

Structure of thimerosal.

Drugmakers put excipients through animal toxicity tests, but don’t typically study whether they interact with specific biological targets. To probe excipients’ biological activity, Brian K. Shoichet, a medicinal chemist at the University of California, San Francisco, and Laszlo Urban, a scientist at Novartis Institutes for Biomedical Research, did a systematic study of these supposedly inert ingredients (Science 2020, DOI: 10.1126/science.aaz9906).

Shoichet says he didn’t know much about excipients before doing this study. “That’s true of many medicinal chemists. It’s sort of a dark area of the art,” he says. “I started looking at the known excipients and thought, ‘Wow, these are crazy-looking molecules,’” he recalls. Shoichet began to wonder if they were truly biologically inert. “To a medicinal chemist, they look active,” he says.

Shoichet, Urban, and coworkers used computational modeling, enzymatic assays, and in vitro tests to narrow down which of more than 600 excipients might interact with important biological pathways. Two hits from these studies also showed potential biological activity in animal tests. Cetylpyridinium chloride is a preservative and surfactant used in several medicines, including the blood pressure drug dyazide. Thimerosal is a preservative used in some vaccines. Both reach blood concentrations in rats that are likely sufficient to interact with biological targets.

Structure of cetylpyridinium chloride.

That doesn’t mean these excipients are toxic—but they may not be inert, the researchers say. “It’s especially an issue for the population that takes the most drugs—and that’s the elderly population,” Shoichet says. Older people often take many drugs at once, getting higher doses of excipients than the general population. At the same time, they may not able to metabolize or excrete the excipients as efficiently as animal models suggest.

Novartis’ Urban points out that the study showed that about 70% of excipients are inert, so drug makers have plenty of options to turn to in order to replace those that might be problematic. “This is particularly important for drugs that are taken for a lifetime,” he says, like diabetes drugs and contraceptives.

Chris Moreton, a partner at the drug formulations consulting firm FinnBrit, points out that reformulating a drug isn’t trivial. It can take up to 2 years and easily cost upwards of $250,000. “I don’t dispute that there are some excipients where we’ve got to be careful, but those are known and have been known for some time,” Moreton says. “The industry is working to get away from those.”

“It is reassuring that this study demonstrated that the vast majority of excipients, when used at the maximum allowable amounts, appear to have limited pharmacological effects,” says Lynne S. Taylor, who studies drug formulation science at Purdue University.

Taylor adds that the study’s combination of in silico, in vitro, and in vivo testing could provide “a valuable framework for assessing the potential toxicology of the many new excipients currently under development as delivery aids for peptides and nucleic acid therapeutics.”


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