“Take with food.”
“Take on an empty stomach.”
Most patients have likely encountered these instructions when using medications and supplements at some point. 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 treatment. This is because bioavailability dictates how much of a chemical can interact with a patient’s physiology to treat their illnesses. High bioavailability leads to a more powerful and more immediate physiological response with lower doses of medication. Poor bioavailability, on the other hand, means patients need to take drastically larger doses before they experience the intended effect, increasing the risk of gastrointestinal irritation as well as potentially causing a heavier load on their liver and generating more side effects. In some cases, the body will not absorb or make use of a therapeutic at all, regardless of dose.
While patients can maximize the bioavailability of some supplements and medications by adhering to instructions, there is a limit to how much patient behavior can impact the efficacy of a therapeutic. Indeed, the bioavailability of a therapeutic is affected by a plethora of factors, including the make-up of the encapsulant and the physical properties of the active chemical. Surprisingly, many supplements and pharmaceutical drugs are manufactured using suboptimal formulations that fail to enhance the bioavailability of the product, diminishing the possibility of symptom relief or restoration of healthy function. Additionally, some ingredients have presented such significant bioavailability challenges that it has not been possible to harness their therapeutic potential in any meaningful way using conventional formulations. But new technologies, such as cyclodextrin-based delivery systems, are paving the way for improved therapeutic efficacy and giving patients a fresh chance to heal.
Ubiquitous Supplement Formulations May Be Poorly Bioavailable
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 chemicals necessary for fat-solubility. Furthermore, mineral salts can prevent therapeutic products from being immediately dissolved and exposed to mucosal surfaces unintentionally. In mineral salt-based systems, a therapeutic chemical is complexed with a powdered mineral like magnesium, which is flavorless, edible, and carries no significant health risks. However, some patients struggle with swallowing powdery tablets. More importantly, without additional ingredients, powdery tablets may become caked onto internal surfaces after ingestion, substantially delaying their absorption and causing irritation. To avoid this, manufacturers may add a chemical like stearic acid, which causes the supplement tablet to become slippery rather than sticky when exposed to saliva or stomach acids and allows for the therapeutic product to become suspended in fat particles. This greatly enhances patient comfort and the ability of the product 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 a carrier for supplements and medicines for over 40 years. In fact, it 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, as the molecular mechanics of stearate do not always lend themselves to efficient delivery.
Al Czap, CEO of Tesseract Medical Research and a pioneer in nutraceutical formulation, was one of the earliest objectors to the use of magnesium stearate precisely because of its unpredictable impact on bioavailability. “The more jagged the edges of the drug particles are, the more they will shear the magnesium stearate, making a little Hershey’s kiss—and the chemical particle will have a shell of the stearate around it,” Czap explains. Significantly, the contents of each shell are not necessarily uniform; isolated drug particles may be heavily obscured by a massive stearate shell while other shells may contain large clumps of the supplement’s active component. When ingested, small clumps are dissolved and metabolized much faster than larger clumps, potentially leading to drastically delayed bioactivity and unpredictable performance. Worse yet, the patient may experience dips and peaks of the chemical’s concentration in their blood depending on how it is metabolized. Additionally, stearate can trigger allergic reactions in rare instances, leading to tissue inflammation and breathing difficulties.
Despite such complications, many manufacturers continue to include stearate and other additives to their supplements or medications to provide physical bulk to their tablets. As with stearate, many of these additives can impede efficacy and 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 additives 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 hasn’t been 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 the transition toward better delivery mechanisms. “The pharmaceutical companies feel that they can’t be wrong regarding magnesium stearate, but they are wrong.”
Malfunctional delivery systems aren’t the only factor in making highly bioavailable products, however. 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, but they can’t improve bioavailability in and of themselves, and another delivery mechanism may still be needed to allow the product to enter the patient’s bloodstream. Even for delivery systems which don’t sequester their active chemical in shells of mineral salts, ensuring the solubility of the active component such that it can enter the bloodstream can be a challenge.
The Challenges of Solubility
For a medication or 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, 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 products are often particularly difficult to make bioavailable. Due to the high water content of body fluids, water-soluble chemicals can become extremely dilute very quickly, diminishing the probability of an active chemical accumulating at the specific tissue it is needed. This is exacerbated by the fact that water-soluble chemicals are easy for the body to excrete. Many supplement and drug manufacturers increase the amount of active ingredient 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 side effects like stomach pain or kidney stress caused by a higher burden of excreting metabolites. Furthermore, dilution of water-soluble chemicals in bodily fluids leads to interactions with other water-soluble physiological molecules, which may prevent the body from using them in some cases. water-soluble products are also more prone to exhibiting off-target effects; for example, even if a product is intended to only operate on cardiac tissue, it may affect other tissues once it is dissolved in the bloodstream. These off-target effects are well-known for generating a plethora of side effects.
For most therapeutics, manufacturers aim for fat-solubility to avoid the issues attendant to water-solubility and because fat-soluble chemicals can more easily cross cell membranes. Some chemicals, like the antibiotic medication ciprofloxacin, are already fat-soluble and can be taken without any additional considerations for bioavailability. But in other cases, fat-solubility alone doesn’t guarantee that the body will be able to use the chemical. According to Czap, “If a product is fat-soluble, 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, the therapeutic product contained within the fat bubble will be absorbed at a slower rate and in a smaller quantity. Thus, while fat-soluble chemicals 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 chemicals may exhibit.
High Bioavailability Technology Opens New Frontiers
Generating a high bioavailability product often requires advanced delivery systems that go 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 that they can be utilized somewhere different where you take them out of the ship?” he asks. The answer, of course, is “yes”; Czap has already operationalized advanced techniques to provide stunning bioavailability and targeting.
For Czap, one of the most exciting advances in drug delivery is a chemical 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 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.
While 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, therapeutics are encapsulated inside a large cyclodextrin structure. Because researchers can control the shape of the cyclodextrin structure which carries the active chemical, 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 chemical inside when it encounters the corresponding “key”—the cellular feature which is the intended target of the therapeutic effect. As such, only the intended target is exposed to the active chemical, leading to a highly bioavailable therapeutic with superior efficacy, minimal side effects, and tuneable duration.chemicals like butyric acid can be complexed with cyclodextrin to achieve high bioavailability and harness its therapeutic potential as a supplement product. In the body, butyric acid is a cellular energy source which is produced in the gastrointestinal tract. Because it is an energy source, any butyric acid consumed with therapeutic intent is rapidly consumed by whichever cells of the gastrointestinal tract encounter it first. Furthermore, butyric acid can affect a plethora of different types of cells in ways that patients may not need. These factors historically made butyric acid an inaccessible therapy, preventing patients from experiencing its beneficial immunomodulatory effects. Notably, butyric acid’s unique bioavailability issues can be resolved via cyclodextrin because the cyclodextrin prevents it from being used by cells other than the intended targets; 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 releases the butyric acid, passing it directly to the correct cell for maximum therapeutic benefit.
Additionally, the selectivity of cyclodextrin-encapsulated therapeutics means that chemicals which have historically had too many off-target effects to be therapeutically tolerable can now be used to help patients. Therapeutics can also be delivered in smaller dosages because clinicians can expect fewer of the therapeutic 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 chemicals encapsulated in cyclodextrin are typically fat-soluble, allowing them to permeate cell membranes once they are dumped at their intended destination. This doorstep delivery massively increases the efficiency of these chemicals by reducing the chance that the therapeutic molecules will drift away from the intended target. In contrast, water-soluble chemicals don’t form complexes with cyclodextrin as easily as fat-soluble chemicals do; instead of sitting neatly within the cyclodextrin’s structure like fat-soluble chemicals, water-soluble chemicals are repelled by molecular forces whenever they approach the cyclodextrin. Nonetheless, most water-soluble chemicals 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 therapeutics 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, patients can benefit from more—and better—treatment options than ever before.
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