Updated on May 4, 2023
“Take with food.”
“Take on an empty stomach.”
Most individuals have likely encountered these instructions at some point when using nutritional supplements. Many assume such directives are aimed at preventing gastrointestinal discomfort, and sometimes that is true.
Often, however, they are designed to optimize bioavailability, a critical function that can ultimately determine the success or failure of a supplement’s indication of use. This is because bioavailability dictates how much of a nutrient can interact with an individual’s physiology. High bioavailability results in a more powerful and more immediate physiological response.
Poor bioavailability, on the other hand, means larger amounts of the active ingredient is needed to experience the intended effect, increasing the risk of gastrointestinal irritation, as well as potentially causing a heavier load on the liver and generating more side effects. In some cases, the body will not absorb or make use of the nutrient at all, regardless of the amount taken.
While individuals can maximize the bioavailability of a nutritional supplement by adhering to its instructions, there is a limit to how much user compliance can impact the efficacy of the supplement’s active ingredients. Indeed, the bioavailability of most nutrients are affected by a plethora of factors, including the make-up of the encapsulant and the physical properties of the nutrient itself. Surprisingly, many nutritional supplements are manufactured using suboptimal formulations that fail to enhance both the absorption and the bioavailability of the product, diminishing the possibility of symptom management or maintenance of healthy function.
Additionally, some nutrients have such significant absorption and bioavailability challenges that it has not been possible to harness their therapeutic potential in meaningful ways using conventional formulations. But new technologies, such as cyclodextrin-based delivery systems, are paving the way for improved therapeutic efficacy and giving individuals a better opportunity to manage their health and wellness.
Ubiquitous Supplement Formulations Might Be Poorly Bioavailable
One of the primary determinants of a supplement’s bioavailability is the nature of the delivery mechanism embedded within the product. Unfortunately, the most popular delivery vehicles in the industry—mineral salts—might actually impede bioavailability. As such, an extraordinary number of supplements are unable to provide individuals with the best possible results.
Mineral salts are the most commonly used delivery vehicle because they tend to be palatable, easy to press into tablet format, and readily mix with the substances necessary for fat-solubility. Mineral salts, however, can prevent the active ingredients from being immediately dissolved and exposed to mucosal surfaces unintentionally. In mineral salt-based systems, an active ingredient is complexed with a powdered mineral like magnesium, which is flavorless, edible, and carries no significant health risks. However, some individuals struggle with swallowing powdery tablets.
More importantly, without additional ingredients, powdery tablets can become caked onto internal surfaces after ingestion, substantially delaying their absorption and causing irritation. To avoid this, manufacturers might add a chemical like stearic acid, which causes a tabletted supplement to become slippery, rather than sticky, when exposed to saliva or stomach acids and allows for the active ingredient to become suspended in fat particles. This supports user comfort and the ability of the active ingredients to cross through cell membranes.
Due to its low cost and high tolerability, the combination of magnesium and stearic acid has seen widespread use as the active ingredient carrier in nutritional supplements for more than 40 years. In fact, this practice is so common that it is referenced on ingredient lists as a single compound: magnesium stearate. However, magnesium stearate is problematic when it comes to bioavailability, because the molecular mechanics of stearates do not always lend themselves to efficient delivery.
Al Czap, CEO of Tesseract Medical Research and a pioneer in nutritional supplement formulation, was one of the earliest objectors to the use of magnesium stearate in manufacturing nutritional supplements precisely because of its unpredictable impact on bioavailability. “The more jagged the edges of the active ingredients are, the more they will shear the magnesium stearate, making a little Hershey’s kiss—and the active ingredient will have a shell of the stearate around it,” Czap explains. Significantly, the contents of each shell are not necessarily uniform; isolated active ingredients might be heavily obscured by a massive stearate shell, while other shells might contain large clumps of the supplement’s active ingredient.
When ingested, small clumps are absorbed and metabolized much faster than larger clumps, potentially leading to drastically delayed bioactivity and therefore unpredictable performance. Worse yet, the individual user might experience dips and peaks of the active ingredient’s concentration in their blood depending on how it has been metabolized. Additionally, magnesium stearate can trigger allergic reactions in rare instances, leading to tissue inflammation and breathing difficulties.
Despite such complications, many supplement manufacturers continue to include magnesium stearate and other similar additives to their supplements to provide physical bulk to their tablets. But similar to magnesium stearate, many of these manufacturing aids can impede nutrient efficacy and even cause adverse health effects. “They add hydrogenated oil, calcium phosphate, and magnesium stearate—which turns the product into a rock,” Czap explains.
Additionally, “patients who are environmentally sensitive can’t tolerate them.” In response to these concerns, Czap and other forward-thinking industry leaders have eliminated magnesium stearate and bulking manufacturing aids from their products, relying on safer and more functional alternatives, such as cellulose capsules and non-magnesium mineral salts. But the move away from magnesium stearate isn’t universal. “In the supplement industry, using magnesium stearate leaves you as a pariah,” Czap says. The pharmaceutical industry, on the other hand, has lagged behind in this transition toward better delivery mechanisms. “The pharmaceutical companies believe they can’t be wrong regarding magnesium stearate, but they are wrong.”
Malfunctional delivery systems aren’t the only factor to consider in making highly bioavailable products, however. Although capsules and non-magnesium mineral salts can work around palatability issues and provide a product with a measure of durability in the oral cavity and esophagus, they can’t improve bioavailability in and of themselves, and another delivery mechanism might still be needed to allow the active ingredient to enter the user’s bloodstream. Even for delivery systems that don’t sequester their active ingredient in shells of mineral salts, ensuring the solubility of the active ingredient such that it can enter the bloodstream can also present a challenge.
The Challenges of Solubility
For a nutritional supplement to be biologically active, it needs to be soluble in the fluids of the body to the point where the molecules of the active ingredient are dissociated from the inactive components, absorbed into the bloodstream after digestion, and metabolized by the liver. As Czap explains, “If a product isn’t soluble, then it gets broken down into its native components, which then sit around in the digestive tract until they’re excreted. In the absorption of things, it’s all about solubility.” However, the specific type of solubility matters.
For a variety of reasons, water-soluble nutrients are often particularly difficult to make bioavailable. Due to the high water content of body fluids, water-soluble nutrients can become extremely dilute very quickly, diminishing the probability of the nutrient accumulating at the specific tissues where it is needed. This is exacerbated by the fact that water-soluble nutrients are easy for the body to excrete. Many supplement manufacturers increase the amount of active ingredients to compensate for dilution and rapid excretion.
Unfortunately, this isn’t an ideal solution because it can place a heavier load on the liver, as well as have side effects, like stomach pain or kidney stress, caused by a higher burden of excreting the metabolized nutrient. Furthermore, dilution of water-soluble nutrients in bodily fluids can lead to interactions with other water-soluble physiological molecules, which could prevent the body from using them in some cases. Water-soluble nutrients are also more prone to exhibiting off-target effects; for example, even if a nutrient is intended to only operate on cardiac tissue, it might affect other tissues after it is dissolved in the bloodstream. These off-target effects are well-known for generating a plethora of undesirable side effects.
For most active ingredients in their supplements, manufacturers aim for fat-solubility to avoid the issues attendant to water-solubility and because fat-soluble nutrients can more easily cross cell membranes. But in some cases, fat-solubility alone doesn’t guarantee that the body will be able to utilize the nutrient. According to Czap, “If a nutrient is fat-soluble, then you have to find a way to make it attractive to the body.” Czap is referring to the efficiency of cellular uptake of fat molecules; if the fat molecules are cumbersome or inefficient for cells to internalize, then the active ingredient contained within the fat bubble will be absorbed at a slower rate and in a smaller quantity.
Thus, while fat-soluble nutrients are easier for the body to work with, there is still a strong incentive to create additional measures to improve bioavailability and address the issues which some fat-soluble nutrients might exhibit.
High Bioavailability Technology Opens New Frontiers
Generating a high bioavailability supplement often requires an advanced delivery system that goes beyond traditional formulations. In recent years, the development of delivery systems has been buoyed by breakthroughs in nanomachinery and nanotechnology, which have opened up new possibilities for optimizing therapeutic capabilities and benefits.
Czap’s approach to formulation has been profoundly shaped by these technologies, particularly when it comes to their potential for highly accurate, targeted, and distant delivery. “The question is, can we put these active ingredients in their own little ships so they can be utilized somewhere different where you take them out of the ship?” he asks. The answer is “yes”; Czap has already operationalized advanced techniques to provide stunning bioavailability and targeting.
For Czap, one of the most exciting advances in nutrient delivery is a substance called cyclodextrin, which allows for extraordinary precision of therapeutic action. Cyclodextrin is a group of molecules attached together in the shape of a ring, and it can be used as fiber in the body, which means it can be pressed into tablets or capsules either alone or alongside traditional fillers like the mineral salts. Importantly, cyclodextrin can be complexed with other structures made of cyclodextrin to form larger constructions.
Although researchers first discovered cyclodextrin’s unique chemical properties as early as 1891, turning it into a delivery mechanism required nearly 100 years of advancements in theory, experimental methods, and molecular engineering. In a cyclodextrin-based delivery system, therapeutic nutrients are encapsulated inside a large cyclodextrin structure. Because researchers can control the shape of the cyclodextrin structure that carries the active ingredient, they can make the structure into a shape much like the inside of a padlock.
Like a padlock, the cyclodextrin structure only opens to release the substance inside when it encounters the corresponding “key”—the cellular feature that is the intended target of the therapeutic effect. As such, only the intended target is exposed to the active ingredient, leading to a highly bioavailable therapeutic with superior efficacy, minimal side effects, and tunable duration.
With advances like cyclodextrin, even nutrients that previously presented operational challenges due to poor bioavailability or poor ability to localize to the correct physiological structure can now be used to support multiple structures and functions in the body. For example, chemicals like butyric acid can be complexed with cyclodextrin to achieve high bioavailability and harness butyric acid’s therapeutic potential as a supplement. In the body, butyric acid is a cellular energy source that is produced naturally in the gastrointestinal tract. Because it is an energy source, any butyric acid consumed for the purpose of therapeutic intent is instead rapidly consumed by whichever cells of the gastrointestinal tract encounter the butyric acid first.
Furthermore, butyric acid can affect a plethora of different types of cells in ways that individual users might not need. Historically, these factors have made butyric acid an inaccessible therapeutic nutrient, preventing individuals from experiencing its beneficial immunomodulatory effects.* Fortunately, butyric acid’s unique bioavailability issues can be resolved via cyclodextrin because the cyclodextrin prevents it from being utilized by cells other than the intended targets; i.e., until the butyric acid complexed with cyclodextrin arrives at the correct cell type in the correct tissue of the gastrointestinal tract, it remains locked inside. The molecular motif on the intended target tissue releases the butyric acid, passing it directly to the correct cell for maximum therapeutic benefit.
Additionally, the selectivity of cyclodextrin-encapsulated therapeutics means that nutrients that have historically had too many off-target effects to be therapeutically tolerable can now be used to support and promote health and wellness. Bioactive nutrients can also be delivered in smaller amounts because clinicians can expect fewer of the nutrient particles to be wasted on incorrect targets.
It is important to note that cyclodextrin doesn’t immediately solve major barriers to bioavailability, like solubility. However, the nutrients encapsulated in cyclodextrin are typically fat-soluble, which allows them to permeate cell membranes after they are delivered at their intended destination. This “doorstep delivery” massively increases the efficiency of these nutrients by reducing the chance that they will drift away from their intended target.
In contrast, water-soluble nutrients don’t form complexes with cyclodextrin as easily as fat-soluble nutrients do; instead of sitting neatly within the cyclodextrin’s structure like fat-soluble nutrients, water-soluble nutrients are repelled by molecular forces when they approach the cyclodextrin. Nonetheless, most water-soluble nutrients can still be complexed in cyclodextrin with enough effort, a capability that researchers are continuing to refine.
Ongoing research will continue to develop the potential of cyclodextrin, further honing specificity toward therapeutic targets, while exploring ways of tuning the duration of the therapeutic nutrients disbursed by the cyclodextrin. However, cutting-edge manufacturers like Tesseract Medical Research are already introducing cyclodextrin-based delivery systems and other bioavailability-enhancing features. With these new formulations, individuals can benefit from more—and better—therapeutic options available in nutritional supplement form than ever before.
Ariyasu A, Hattori Y, Otsuka M. 2016. International Journal of Pharmacy. 511(2):757-764.
Demuth B, Galata D, Szabo E, Nagy B. 2017. Molecular Pharmaceutics.
Erdogar N, Varan G, Bilensoy E. 2017. http://www.eurekaselect.com/148641/article.
Thatiparti TR, Shofstall AJ, von Recum HA. 2010. Biomaterials. 8:2335-2347.