From June 2015 to August 2015, Lexaria commissioned an independent, third-party laboratory to test our DehydraTECH technology under carefully monitored in vitro conditions. Specifically, we wanted to gain scientific evidence of two hypothesis. As it turned out, we learned that and more.
First, does our technological process yield an improvement in intestinal absorption? The answer was YES. Second, does our lipid formulation yield an improvement in intestinal absorption? The answer was also YES. In addition, we also learned that our DehyrdaTECH-enabled infused tea was absorbed at higher levels in the presence of “gastric juices” than in a more sterile environment without any “gastric juices”, suggesting though certainly not proving that our DehydraTECH™ technology may be effective in an actual gastrointestinal system rather than just in a simplified in vitro simulation.
Below, we explore why bioavailability is such an important consideration, and how it affects more than one might at first imagine. There are a number of important considerations to contemplate before making changes to one’s diet or consumption habits, but one vital fact outweighs all the others: the vast majority of many substances that are orally consumed without technology such as ours ends up being excreted as waste by the body without meaningful absorption and bioavailability.
Lexaria Bioscience Corp. has since 2015 conducted a number of in vitro studies, in vivo animal studies, and human clinical tests, and has done so chiefly with nicotine or with other plant-derived molecules of interest as the active pharmaceutical ingredient (“API”) under study.
A key part of the 2015 in vitro study evaluated how APIs are ingested and absorbed, assessing different delivery mechanisms, recent technological advances in bioabsorption, and how those advances offer users an alternative to smoking. In undertaking this study, it was important to understand what bioavailability is and how it differs from absorption. They are related and similar, but different. Absorption is just one component of bioavailability. To truly understand bioavailability, we have to speak briefly about how the human body digests food. The object of digestion is to transform large food particles into smaller molecules, which can more easily be absorbed into one’s water-soluble blood plasma. That is how humans get nutrients and energy.
Very little digestion actually occurs in the stomach, which is designed, in part, to kill pathogens and foreign substances that should not be ingested. In fact, roughly 95% of all digestion and absorption happens in the small intestine. Digestive enzymes intermingle with food during the roughly 2-hour journey to arrive at the small intestine, breaking down the food and preparing it for absorption. Unfortunately, hydrochloric acid in the stomach is also quite capable of destroying many nutritious, fragile molecules before they can ever be absorbed.
There are dozens of different potential API molecules under consideration for DehydraTECH processing. Many APIs do not tolerate acidic environments. Studies have shown poor recoveries, or even 0% recoveries in acidic environments (Source: Anal Chem. 2011 Jun 1; 83(11): 4228–4236. ).
The mouth and throat are a roughly neutral environment, with a pH of roughly 6.8. Stomach pH can be anywhere in the 1.0 – 3.0 range, which is highly acidic. In contrast, the small intestine has a highly alkaline environment conducive to molecular absorption, with a pH of about 8.5. Normal water is neutral or slightly alkaline and has a pH of 6.2 – 7.0. For scale, a pH of 8.0 is ten times more alkaline than a pH of 7.0; and a pH of 3.0 is 10,000 times more acidic than a pH of 7.0.
For these and other reasons, digestion, absorption, and bioavailability of mand APIs in their unprocessed form is very low. The molecules often do not survive their passage through the stomach undamaged and are not free to be absorbed in the alkaline environment of the small intestine.
Finally, the liver has a major role to play in that it regulates what molecules are allowed to reach the general circulation after ingestion, absorption through the small intestine, and finally passage through the liver’s filtration and processing systems. It often “wraps up” what it identifies as dangerous molecules in water-soluble chemicals that are identified for ejection through urine.
Bioavailability from both vaping and sublingual drops will generally be in the 14% – 40% range which is quite high but also associated with certain negative health impacts. Edible ingestion of API’s often drops to the 5%-6% range which is quite low, but with far fewer negative health impacts. Absorption of nicotine through smoking (burning is an oxidizing process) is relatively high because the molecules are not required to pass through the hostile stomach environment, and instead are absorbed into the bloodstream through the lungs – known as pulmonary absorption. Although smoking is a relatively efficient and quick acting process, it is also a well-known health hazard. Of the one billion people around the world who smoke, over six million people currently die each year from diseases caused directly by smoking. More on that below.
This is a good place to summarize what we know so far:
The goals of higher bioavailability of nicotine are thus threefold: to mollify objections to its smoking from non-smokers, to reduce unhealthy hazards of smoking, and to more efficiently and effectively deliver a higher proportion of useful molecules comprised from lower overall dosages that place less of a load on the liver. The challenges associated with efficient delivery of nicotine and the reduced harm to be experienced both by consumers and society through overcoming those challenges are now well understood.
Lexaria has focused on discovering new technologies that can more efficiently deliver molecular APIs to the bloodstream where they can have their desired effect. To this end, our lab and human experiments have greatly expanded our understanding of the most efficient ways to deliver APIs through ingestion.
In order to succeed in delivering a higher percentage of ingested cannabinoids into the human bloodstream, we needed to figure out how to protect the API molecule on its journey through the gastrointestinal system and into the bloodstream.
It is well known that ingesting fats (the terms “fats” and “lipids” can often, though not always, be used synonymously), while simultaneously ingesting other focused-upon substances can often lead to higher absorption levels of those key substances. “The US FDA recommended high-fat meals for food-effect studies because such fatty meals (800–1000 cal, 50%–65% fat, 25%–30% carbohydrates and 15%–20% proteins) affect GI physiology and maximize drug transfer into the systemic circulation.” (Food and Drug Administration, Guidance for industry: food-effect bioavailability and fed bioequivalence studies, food and drug administration. https://www.fda.gov/OHRMS/DOCKETS/98fr/5194fnl.pdf).
The reasons for this increased absorption have, in part, been previously discussed. Fats are emulsified by gallbladder secretions, breaking them down into more easily absorbed particles in the small intestine. And some types of fats take a different path into the human bloodstream than most other nutrients – they bypass the hepatic portal vein that otherwise goes straight from the intestine to the liver for filtering before nutrients are generally allowed to reach the majority of the body. Instead, the body re-assembles certain fats and shuttles them to the lymphatic circulatory systems where they enter the general bloodstream without passage through the liver. Many so called long chain fatty acid compounds, therefore bypass the portal vein “freeway” to the liver, whereas smaller fatty acids that are more water soluble do indeed go to the liver first.
As well, in order to prepare nicotine for higher bioavailability, the nicotine molecules can be manipulated in certain ways to connect them at a molecular level with various foods. Lexaria’s DehydraTECH technology “shuttles” the nicotine molecules “within” other food molecules, even unrelated to lipids. Then lipids, such the long chain fatty acids found in sunflower oil, can be added due to their well-known beneficial properties within the human GI system.
In the summer of 2015, the US laboratory we commissioned performed some of the first tests ever known to be conducted on long chain fatty acid processed with certain APIs that measured absorption into human intestinal cells. The results were astonishing. Utilizing a mixture of API, black tea and select lipids, processed using our patented dehydration synthesis technological method, the final result showed intestinal tissue API permeability 325% higher than API similarly processed with black tea and water but lacking our lipid incorporation. And when that same mixture of API, black tea and select lipids, processed with our DehydraTECH™ method was compared to the absorption of API suspended in water alone without any benefits of lipid incorporation and our processing techniques, the absorption levels into the human intestinal cells rose to a 499% improvement via our methodology.
This sort of vital scientific research adds to our cumulative understanding that APIs can indeed be ingested with bioabsorption levels that approach or perhaps even surpass those achieved from smoking. However much remains to be learned. For example, we did not know what ratio of API might be delivered to the liver for filtration via the portal vein as compared to delivery straight to the lymphatic and circulatory systems for higher bioavailability. And, additional laboratory testing with different individual lipids will have to be undertaken to determine which might perform best.
During 2018 Lexaria performed two separate animal studies that evaluated DehydraTECH and its ability to improve the deliver of nicotine into both blood plasma and brain tissue in rats. The studies were an overwhelming success that included certain results that were so significant, they have led to additional new patent filings by Lexaria Bioscience Corp.
In the study reported in Spring 2018, a small rat population of 12 animals was used. Blood was analysed at the 15min; 30min; 45min; 60min; 2Hr; 4Hr; 6Hr; and 8Hr time periods. Highlights from that study include:
At the dosing level of 10mg/Kg of nicotine polacrilix, the control formulation required nearly 3 hours to reach similar levels of blood absorption that the Lexaria formulation reached in only 15 minutes. The more rapid delivery and higher overall delivery level of the DehydraTECH-enabled formulation strongly evidenced the efficacy of DehydraTECH technology. Because the animal population was small, it was desirable to attempt to replicate the study results in a larger population.
In the second study reported in Summer of 2018, a rat population of 40 animals was used. Blood was analysed at the 2min; 4min; 6min; 8min; 10min; 12min; 15min; 30min and 60min time periods. Highlights from this study included:
The results were notable for several reasons. First, the population of test animals was considered large enough to generate statistically significant results. Second, the results corroborated those of the smaller initial study: even though the specific data generated differed, the data trend was similar. Third, much finer-grained and earlier blood data collection points illustrated for the first time ever, the ability to deliver nicotine to the blood in as little as 2 or 4 minutes.
This final point in particular is noteworthy. People who smoke cigarettes do so for a number of reasons, including a relatively immediate chemical delivery of nicotine to the bloodstream and the brain. In fact it is the immediacy of the delivery from the moment of dosing that contributes to the human feeling of dependency on the activity. A more delayed response – such as is usually delivered from a nicotine patch – is not as satisfying to most people.
So the fact that DehydraTECH is able to deliver nicotine to the blood in only minutes; and an average improvement of 70% over the critical first 15 minutes, is a good indication of the ability of this powerful technology to actually meet the needs of consumers.
In this second-generation study, confirmatory data was also generated regarding the ability of DehydraTECH technology to influence blood-brain-barrier penetration.
The FDA has repeatedly made mention of its desire to down-regulate the amount of nicotine available in cigarettes and, more recently, in vape devices. Lexaria’s technology utilized in a food, beverage, or capsule, could conceivably deliver lower levels of nicotine that still satisfy the cravings of the consumer, but do so at more acceptable overall dosing levels.
The benefits are obvious: a person requiring 10mg of a substance in order to achieve a desired outcome would have to consume 200mg of that substance if the bioavailability is only 5%. But raise the bioavailability rate to 30%, and the necessary consumption level drops to just 33mg. This is a massive reduction in intake with a lower risk of over-dosage and leads to a potentially lighter workload on the liver accompanied by certain reductions in waste and consumer cost.
Until recently, smoking was the most effective way to ingest nicotine, provided one was willing to overlook the unhealthy side effects and the social stigma. This creates a deadly paradox: “nicotine is pleasurable, but smoking is killing me”.
Smoking is an increasingly unacceptable activity in large segments of society. The toll from disease caused by smoking is unarguable. There is a large segment of society which reasonably argues that the act of smoking impacts non-smokers. The moment a smoker impacts a non-smoker, either through odor or second-hand smoke, smoking is no longer a personal decision, even though it may deliver a pleasurable user experience.
Now, because our understanding of bioavailability has increased, and with the new and exciting advances in technology, it is possible to deliver comparable bioavailability to that of smoking, but without the negative side effects. It is actually possible that one day, using disruptive, absorption enhancing technologies like DehydraTECH, foods and beverages will be reasonably able to replace smoking as the most effective delivery mechanism for nicotine, while also providing a powerful new way to deliver a host of other beneficial molecules more efficiently and effectively like pain relievers, vitamins, supplements and more.
Bioavailability matters… a lot. Improved bioavailability can lead to reduced social pressures associated with what are currently more common delivery methods such as smoking or vaping. Reducing smoking can lead to fewer societal objections for both cigarette and cannabis smoking. Positive community health outcomes are likely to be associated with lowered rates of smoking. And, higher bioavailability could be associated with lower overall dosages of certain molecules, which can itself be associated with reduced stress on the liver and other organs as well as financial cost savings for consumers.