The pharmaceutical industry has undergone a seismic shift toward biologics, enabling entirely new classes of active ingredients. But the discovery and use of inactive ingredients, or excipients, has failed to keep pace, leaving drug developers trying to optimize next-generation therapies with toolsets designed for a different purpose. Excipient innovation is long overdue, but new options are finally available to developers, helping biologics reach their potential for the first time.
Excipients are one of the most impactful advances in the history of the pharmaceutical industry, and yet their story is often ignored or minimized. Well before the modern pharma environment took shape, the healers of ancient civilizations in Asia, Europe, and the Middle East often combined herbal extracts with honey, wax, or animal fat to form salves and pills. They were also used to hide the unpleasant taste of certain herbal remedies, and serve as a preservative. Over a century ago, scientists at Bayer kicked off the modern age of pharmaceutical formulation by adding binders and fillers to acetylsalicylic acid (aspirin) to create the first tablets. This improved delivery method made aspirin dosing and administration much easier for the physician and patient.
Even today, excipients are largely used the same way — improving the taste and appearance of drugs and increasing their stability. Inactive ingredients are also utilized to increase absorption and bioavailability in the body, mitigate side effects to improve drug safety, and simplify the manufacturing process.
Today, most drugs have an average of eight to nine different inactive ingredients, far outweighing the number and concentration of the active drug. For traditional small molecule drugs, inactive ingredients are recognized as crucial components in drug delivery.
The biologics bottleneck
Biologics such as peptides and monoclonal antibodies now comprise nearly half of the total prescription drug spending, which is stunning given that the first biologics were developed in the 1980s. They are at the forefront of treating complex chronic diseases such as diabetes, cancer, Crohn’s disease, and rheumatoid arthritis. However, their size, complex structure, and sensitivity to breakdown pose significant challenges to their effectiveness.
To date, the focus of inactive ingredients for such biologic therapies has been on stabilizing the therapy for extended shelf life. Many peptides irreversibly bind, forming dimers and other complex structures, curbing the function of the drug. This is why one of the most commonly used classes of excipients in biologics are those meant to block that binding. The other is preservatives to prevent microbial growth.
Inactive ingredients can also assist with protecting the molecules from temperature and pH changes, as well as mechanical stress during manufacturing and administration to the patient. For oral drugs, excipients are also needed to protect from the acidity and enzymatic activity of the gastrointestinal tract. They can enhance absorption across cell membranes, minimize the immune response that some biologics can initiate, and slow drug release.
Scientists have engineered miraculous biologic therapies, but even after leveraging excipients that address the above challenges, the efficacy has often remained less than desired. To understand why, we need only look back at Bayer’s precedent with the tablet: the way aspirin was delivered determined its functionality.
Redefining drug delivery
A failure to leverage the history of excipient use has led to a number of issues that could be addressed by improving drug delivery inside the body. Many biologics are degraded and cleared quickly, leading to the need for higher doses, which can elevate off-target toxicity. Additional challenges in manufacturing have driven up biologics costs. Together, these limitations drastically hinder patient access.
New approaches are emerging that do more than simply carry a molecule from point A to point B. One key advance involves the use of polymer-based delivery systems, such as core shell spherification (CSS), which encapsulate large molecules within a mesh-like structure. Because these systems are chemically inert, they do not provoke immune responses, and they preserve the drug’s natural structure and function throughout injection and sustained release. Tunable characteristics allow the therapy to be released gradually over time or targeted to specific tissues, improving efficacy while reducing side effects. These controlled-release approaches could make extended-release biologics a practical reality for the first time, reducing dosing frequency and improving patient adherence.
Beyond traditional chemistry, more inventive strategies are gaining traction. “Bacterioboats” use harmless bacteria to transport drug-loaded nanoparticles through the digestive tract, anchoring them in place to allow sustained absorption. Metal-organic framework ‘cages’ can shield insulin and other fragile proteins from harsh stomach acids, making oral delivery possible where injections were once the only option.
The common thread across these innovations is a recognition that drug delivery is just as important as the active molecule itself. By optimizing carriers and excipients, developers can reduce dosing frequency, minimize immune reactions, improve patient convenience, and lower treatment costs — dramatically expanding access to complex therapies.
As biologic therapies continue to gain market share, formulation must mature in lock step. The end result will be drugs with better inactive ingredients that will shape the next generation of delivery, driving better uptake with fewer of the challenges currently associated with biologics.
