Furthering an incipient recognition of excipient effects, scientists based at Brigham and Women’s Hospital and MIT have shown that nearly all pills and capsules contain so-called inactive ingredients that can, despite that comforting label, bring discomfort to sensitive people. The scientists found that in frequently prescribed medications, inactive ingredients account for 71% of drug mass. Most worrisome are inactive ingredients such as lactose, peanut oil, and gluten, substances that can cause adverse effects in patients with conditions such as lactose intolerance or food allergies.

“When you’re a clinician, the last thing you want to do is prescribe a medication that could cause an adverse reaction or allergic reaction in a patient,” said Giovanni Traverso, PhD, a gastroenterologist affiliated with the Brigham and MIT. “This project was inspired by a real-life incident where a patient with Celiac disease was prescribed a medication and the formulation of the pill they picked up from the pharmacy had gluten in it. We wanted to understand the problem and drill down to characterize the entire universe of inactive ingredients across thousands of drugs.”

Traverso is the senior author of a perspective paper (“‘Inactive’ ingredients in oral medications”) that appeared March 13 in the journal Science Translational Medicine. This paper, Traverso and colleagues hope, will raise awareness of the potential for adverse effects posed by excipients, which are additives meant to improve the taste, shelf life, absorption, and other characteristics of oral medications such as pills and capsules.

“Using data analytics, we characterized the abundance and complexity of inactive ingredients in approved medications,” wrote the paper’s authors. “A majority of medications contain ingredients that could cause adverse reactions, underscoring the need to maximize the tolerability and safety of medications and their inactive ingredients.”

The paper describes how the scientists analyzed data on the inactive ingredients found in 42,052 oral medications that contained more than 354,597 inactive ingredients. Inactive ingredients are defined as substances that are added to a pill’s formulation but are not intended or expected to have a direct biological or therapeutic effect. Although such ingredients have been tested for safety at the population level, scattered case reports have suggested that inactive ingredients may cause adverse reactions in individuals who have allergies or intolerances.

“What is really striking about this data set is its complexity,” said Daniel Reker, PhD, a bioinformatics specialist at MIT researcher and a co-author of the current paper. “There are hundreds of different versions of pills or capsules that deliver the same medication using a different combination of inactive ingredients. This highlights how convoluted the possible choices of inactive ingredients are, but also suggests that there is a largely untapped opportunity today to specifically select the most appropriate version of a medication for a patient with unusual sensitivities.”

The scientists found a total of 38 inactive ingredients that have been described in the literature to cause allergic symptoms after oral exposure. The authors report that 92.8% of the medications they analyzed contained at least one of these inactive ingredients.

Specifically, they report:

  • About 45% of medications contained lactose
  • About 33% of medications contained a food dye
  • While only 0.08% of medications contained peanut oil, for certain drugs—such as progesterone—there are few alternatives that do not contain this inactive ingredient.

The authors note that inactive ingredients can cause an adverse reaction through an allergy (a histamine-related response that can trigger hives, difficulty breathing, and/or anaphylaxis) or an intolerance, in which difficulty absorbing a substance can cause gastrointestinal symptoms. It is unclear what amount of an ingredient is necessary to trigger a reaction in sensitive individuals—the content of lactose in a medication, for instance, may be too low to cause a reaction in many patients, except for those with severe lactose intolerance or those taking many medications containing lactose.

“While we call these ingredients ‘inactive,’ in many cases, they are not. While the doses may be low, we don’t know what the threshold is for individuals to react in the majority of instances,” said Traverso. “This pushes us to think about precision care and about the role for regulation and legislation when it comes to labeling medications that contain an ingredient that may cause an adverse reaction.”

“The future of inactive ingredient research will flourish with more detailed datasets,” the paper concluded. “Accounting for effects of excipients will enable advanced formulations for difficult-to-deliver medications and could lead to personalized medicine for vulnerable subpopulations. Such analysis will empower clinicians to make conscious selections of formulations focusing on their patients’ well-being.”

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