Improving cannabinoid bioavailability through proprietary delivery technologies

Maximizing and Understanding the Benefits of Proprietary Delivery Technologies For Increasing Bioavailability of Cannabinoid Molecules

Human beings and marijuana have long had a varied and overlapped history together. The first emergence of a hemp cord in pottery was found at an ancient village site at around 8,000 BCE in an area that is known today as Taiwan (AHH.org). Locating a hemp product as an agricultural good that was deliberately cultivated, highlights it as one of the first and oldest known agricultural crops. The “First pharmacopeia of the East lists medical marijuana. Chinese surgeon Hua T'o uses marijuana as an anesthetic” (AHH.org). This usage of marijuana for medicinal purposes occurred as early as the year 200 CE. One hundred years later, in the year 300CE, it is documented that a woman in Jerusalem was given medical marijuana as she went into labor (AHH.org). One can conclude from these well-documented pieces of history, that marijuana has been a part of the human experience for as long as humans have been existed. The usage of marijuana for medicinal uses goes back thousands of years.
In recent times, given the greater societal acceptance of marijuana and countless studies proving its medicinal use for anything from pain relief to insomnia to cancer therapies, there’s been more momentum for such cannabis medical-grade products. There is an increased interest in creating, and expanding pharmaceutical-grade cannabinoid products. With this heated discussion, there’s more and more focus on improving the bioavailability of cannabinoid molecules through different delivery methods. With the increased number of competitors in this field, there’s more focus on the most effective route of these active ingredients such as tetrahydrocannabinol (THC) and cannabidiol (CBD) into the bloodstream and related systems of the human organism.
Since both these substances have such well documented ways of helping human beings achieve greater health and wellness and relieving suffering, determining the best route of delivery is crucial for he further development of this field.

Oral Delivery Method
As so many are already aware, one of the most common ways to ingest cannabis is through oral delivery methods such as the pill, caplet, or medical-grade edibles. The oral consumption of edibles impacts the human organism in a very specific manner.
“The GI tract gradually absorbs cannabinoids, including cannabidiol (CBD), one of at least 60 active cannabinoids identified in cannabis to possess significant medical benefits. Orally delivered cannabis requires four to ten times the amount of the smoked version in order to achieve the same effect. The reduced psycho-activity of CBD-rich cannabis may make it an appealing treatment option for patients seeking anti-inflammatory, anti-pain, anti-anxiety, anti-psychotic, and/or anti-spasm effects without the high or euphoric feeling” (UPG.com). In this manner, patients feel like their pain is being adequately treated without feeling like they’re suffering any mental impairment. The symptoms that medical marijuana is designed to treat are adequately treated with this particular method.
However, the oral consumption of marijuana isn’t perfect. As a result of the fact that it’s going through a person’s metabolism, and every individual’s metabolism is different, means that the rate at which the results manifest are generally less predictable. For some people the onset of pain relief can take 30 minutes, for other people, it can take longer. Again, other patients have found that medical marijuana orally consumed, works on them faster.
It’s also important to note that via this delivery method, one has the presence of the GI tract, and with it, the liver. The liver can’t help but metabolize and further degrade CBD—that’s just what the liver does. However, given the presence of the liver and its undeniable activity, it does mean that patients consuming medical marijuana through oral methods are getting a less potent version of its medicinal qualities and effectiveness. This means there are inherent challenges when it comes to pinpointing the best dosage per patient and per condition. Post oral ingestion, “…systemic absorption is relatively slow resulting in maximum ?9-THC plasma concentration within 1-2 hours which could be delayed by few hours in certain cases (56, 58). In some subjects, more than one plasma peak was observed (52, 59). Extensive liver metabolism probably reduces the oral bioavailability of ?9-THC by 4-12% (53). After oral administration, maximum ?9-THC plasma concentration was 4.4-11 ng/mL for 20 mg (50) and 2.7-6.3 ng/mL for 15 mg (58, 60). Much higher concentration of 11-OH THC was produced after ingestion than inhalation (56, 58).Following assimilation via the blood, ?9-THC rapidly penetrates in to fat tissues and highly vascularized tissues including brain and muscle resulting in rapid decrease in plasma concentration (61, 63)” (Sharm et al., 2012). Hence, once the THC is delivered to tissues, there’s a subsequent redistribution of it that is more gradual: this type occurs from the deeper fat reserves of the human body, returning it to the blood stream.
The liver reduces THC to a more diminutive metabolite, referred to as 11-hydroxy-THC. This metabolite is considered to be possibly more bioavailable that THC and more capable of passing the blood-brain border, which is a membrane of cells that are a more selective filter for blood that crosses onto the brain (Wilcox, 2017). Decades ago a study that administered THC or 11-hydroxy-THC to male volunteers found that the latter substances kicked in faster, making them consider it to be a more active metabolite (Huestis, 2007). However, it is worth noting that even with oral delivery of cannabis, there’s still something known as the “first pass” phenomenon. Essentially, this just refers to the fact that the liver is so good at filtering out toxins and breaking down foreign materials, it might break down the THC so much that users don’t feel anything—no pain relief, no appetite stimulation, no desired relief from insomnia. Sometimes consuming a meal before the oral consumption of medical marijuana products can help minimize the first pass effect, but that can also mean that it takes longer for one to feel an impact from THC.
It’s noteworthy that given the many intensive benefits of the oral route, scientists have already fine-tuned its usage. “A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the ‘first-pass’ effect” (Atsmon et al., 2018). This substance, PTL401, was so promising, that there are no safety concerns connected to its administration, but that it also has a much more rapid absorption to the human body and a more successfully bioavailability, when compared with the oromucosal spray (Atsmon et al., 2018), helping to justify subsequent research and eventual acceptance and use in society.
Furthermore, the oral route still offers a host of benefits, making it the preferred means for some patients and certain conditions. One of the overwhelming benefits of the oral route is that it generally lasts for a longer period of time, which means that patients aren’t obliged to constantly consume medication, once they are able to determine the best dosage (UPG.com). Another major advantage of the oral method is that the host of medical marijuana dispensaries available today offer a wide array of baked goods, snacks, sweets, drinks and other items for consumption, at a range of doses for patients. Patients can safely experiment with the best dosage for their condition in a more effective manner. Furthermore, more cannabis-centered cooking means that patients can consume cannabis products and THC in the form of pizza, chicken, breads. Additionally, cannabis butter is great for cooking and baking and another simple way for patients to consume marijuana medicinally. The oral methods via which marijuana can be consumed are literally boundless. Of course, the patient is expected to be responsible when it comes to experimenting with these items and their dosage, so the impetus is on them when it comes to trying new products. For example, with cookies made with cannabis butter, it might be hard at first to determine the appropriate dosage so experimenting with care is essential.
Sublingual Delivery Methods
Sublingual delivery of cannabis products refers to the absorption of the drug via the tissue directly underneath the tongue, allowing it to access the bloodstream very rapidly, as this particular vessel contains many vessel-rich tissues (Smith, 2017). “Sublingual dosing is the quickest form of relief; ideal for patients whose conditions require them to rely on fast-acting therapeutic effects, such as those who are in chronic pain. Sublingual application delivers the effects of cannabis in as little as 30 seconds up to 2 minutes” (Smith, 2017). There is much debate and discussion among experts regarding the best consumption of medical marijuana products: oral versus sublingual delivery. Many consider the sublingual delivery method to be a superior choice because of the liver and the entire digestive tract—and the contributions these two entities have to creating decreased bioavailability. Some argue that when relying on the oral administration of edibles, one is only absorbing around 20% of the THC or CBD, due to the liver breaking down so many of these substances (Smith, 2017). Thus, for pain patients who require medical marijuana for much needed relief will have to suffer until the oral delivery kicks in. Sublingual delivery method doesn’t have those restrictions.
  Medicating with edibles only lets you absorb around 20% of the cannabinoids, and these have to first be processed by the liver before they make it to the bloodstream (Smith, 2017). This is why edibles takes a significantly longer time to hit (30 to 60 minutes or more), which doesn’t make it ideal for patients who need fast-acting relief. However, in some cases patients medicate with edibles after sublingual application; doing so can provide a more holistic and longer-lasting therapeutic experience.
The sublingual application involves holding drops from a medical marijuana tincture under the tongue. It’s important to note that this sublingual tissue absorbs fats more readily than lipids, “as lipids do not hold an electrical charge-an optimal method for absorption at the surface of oral mucosa (under your tongue). Because of this, oil-based products are optimal for sublingual absorption, especially those that contain essential fatty acids such as Omega-3, 5, 6, 7 and 9” (Dope Magazine, 2017). Hence, these fats are better recognized by the body, a fact that helps with their own absorption into the bloodstream. As a result, many manufacturers of sublingual methods of cannabis rely on MCT, also known as Fractionated Coconut Oil, because MCT is made up of medium-chain triglycerides, such as Capric and Caprylic Triglycerides; neither of these substances have omega fatty acids (Dope Magazine, 2017). This is largely because, the more delicate the emulsification, the speedier and more efficiently the body will be able to take in and effectively use the medicinal substance (Dope Magazine, 2017). Some experts praise sunflower lecithin as being one of the more superior fats for the under-the-tongue method of absorption (Dope Magazine, 2017). Fats are so commonly used in this method that their use is known as liposomal delivery: “Our cells have a phospholipid outer layer, so when there is a lipid (or fat/oil) delivery, it aids dramatically in the body’s ability to absorb and utilize cannabis. Essentially, the lipids surround the medicinal molecules (such as CBD and THC) and the body recognizes it as a natural compound to uptake”(Dope Magazine, 2017).
Of course, the sublingual delivery method isn’t perfect. A study conducted to determine the use of cannabis to reduce intraocular pressure found that a 20mg does of CBD administered sublingually did not reduce this intraocular discomfort (Tomida, et al, 2006). However, this method is very notable and effective in numerous other studies in the art and science of removing pain. For example, in the study, “Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination” the researchers found that the regular dosage of sublingual cannabis helped to improve the participants physical health, general vitality and ability to function socially with females afflicted with HPV (Palmiereri et al., 2017). The only arena where there was no improvement was in the participants emotional reactions. Largely this study is one of the many cases of evidence that show the overall promise of CBD-rich hemp oil in being both safe and well-tolerated in patients for a variety of pain and medical conditions.
In addition to being the answer to “first pass” metabolism that reduces the bioavailability of orally consumed cannabis, supports of the sublingual method of consumption praise not only the speed at which the cannabis is consumed but also the fact that there are literally no negative health effects. Smokers and vaporizers of cannabis simply cannot give that same assurance. Also the sublingual delivery method empowers physicians and other healthcare providers with a level of accuracy that oral consumption just doesn’t allow. Sublingual delivery also empowers the patient to keep a high level pharmaceutical grade solution at home through their own cannabis tincture or comparable solution. The dosing accuracy is nothing to underestimate. Being able to engage in accurate dosing means that patients have a much safer process when engaging in this form of medication. Furthermore, it’s a more discrete form of consumption, which can be beneficial for users who need frequent dosages.

Buccal Delivery Method
A delivery method of medical marijuana that is comparable to the sublingual method is known as the buccal method: this is where the dosage is placed between the gums and inner cheek for around three to ten minutes, allowing as much of the substance to absorb as humanly possible. In terms of comparison between the intraoral buccal versus the intraoral sublingual method, the buccal delivery method is considered somewhat inferior. “The buccal mucosa is considerably less permeable than the sublingual area, and does not provide the rapid absorption and superior bioavailability of sublingual administration. In several comparative studies, sublingual delivery was more effective than buccal delivery” (Kaufman, 2013). However, despite these drawbacks, experts still believe that when used in conjunction with sublingual methods, there’s still promise for the buccal delivery process. Furthermore, researchers think that even outside of CBD and THC consumption, more and more vaccines and antigens will be given via the sublingual and buccal (Senel et al., 2012). While buccal delivery methods might be less ideal at this time, there’s more talk in the field of science that CBD and THC will be better processed to work in a more superior way so that drug delivery is more effective by this particular means (Senel et al., 2012). There’s increasing talk about the best ways to process medical marijuana products to make them more suitable for buccal absorption. At this time, buccal absorption is a sound alternative for patients who cannot tolerate the sublingual delivery method.
Buccal mucosa has nevertheless received a host of attention over the last quarter of a century, and market demand has created many buccal delivery items. For example, “Nabiximols, an oral buccal spray, is a combination of THC and CBD. It was approved in Canada in 2005 for pain management in cancer patients and for multiple sclerosis–related pain and spasticity. It is not currently available in the US” (Cavalet, 2016). Buccal drug delivery still offers clear benefits and drawbacks, offering opportunities for the future for developmental substances in the cannabis and related health fields. Oral mucosa does offer pathways for increased drug absorption, though as already stated, the sublingual method is superior to buccal.
When it comes to dealing with the possibilities in connection with the oral mucosa, nanospheres are widely agreed upon to be where the future is headed.
“The solution for delivering nutritional supplements and nutraceuticals through the oral mucosa lies in encapsulating biological compounds into highly permeable lipid nanospheres. These are easy to administer to the mouth’s sublingual oral mucosa via an eyedropper for rapid uptake into the circulatory system” (Kaufman, 2013). These findings offer many implications for the future and for subsequent developments of cannabis related products for health and medicine.

Transdermal Delivery Method
Many consider the transdermal method to be the most innovate and unique form of marijuana consumption. The cannabis patch adheres to an area of the body near veins and this allows the marijuana to get to work immediately with access to the bloodstream. Transdermal patches have received a positive response because they are discrete and long lasting, and users can get an exact dose. Furthermore, patients can select a patch with various forms of isolated cannabinoids such as THC, CBD, CBN or in mixes of several (Llan,d 2017). This allows the user to select cannabis to address their specific condition. For some, transdermal patches are ideal because they can provide slow and steady relief over a period of time. This factor is another inherent element about them that makes them appealing to those in the health and medicine community: their slow and steady release of a cannabis means that they are less likely to be abused.
The transdermal method comes with numerous considerations: “Cannabinoids are highly hydrophobic, making transport across the aqueous layer of the skin the rate-limiting step in the diffusion process… In vitro diffusion studies may underestimate in vivo transdermal flux…After application of a dermal patch, mean steady-state plasma concentration of ?8-THC was 4.4 ng/ml within 1.4 h, and was maintained for at least 48 h. Permeabilities of CBD and CBN were found to be 10-fold higher than for ?8-THC. In vivo studies of transdermal drug delivery in guinea pigs noted the presence of significant amounts of plasma metabolites after topical application of THC” (Huestis, 2009). What this means is that there is still more research and experimentation that needs to occur in order to determine the overall viability of the transdermal method and to find the best solutions to many of the common problems that prevent transdermal patches from being more effective. For example, if transdermal patches were developed with more combinations of substances, it might increase the overall drug absorption.
Furthermore, the transdermal delivery of cannabinoids is viewed as something that should minimize the negative effects of other forms of consumption. A major benefit of this method is that the first pass metabolism from the liver is inconsequential. The implications of this method for patients who have serious afflictions, like cancer are immense. A patient could apply a transdermal patch before something unpleasant like chemotherapy, or use it in anticipation of painful periods of healing or to help stimulate the appetite. When examined for its potential benefits for arthritis sufferers, the results were very promising. The transdermal application of cannabis showed that it could do more than just relieve pain: it was able to relieve a whole host of negative symptoms that often go hand in hand with arthritis. “Transdermal CBD gel significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner. PWL recovered to near baseline level. Immunohistochemical analysis of spinal cord (CGRP, OX42) and dorsal root ganglia (TNF?) revealed dose-dependent reductions of pro-inflammatory biomarkers” (Hammell et al., 2015). What’s significant about these findings was that all of these benefits observed in rats occurred without any foreseeable side effects that the researchers were able to notice or document. The complete absence of side effects is a very promising factor, when further testing on humans becomes relevant. It’s also important to note that these lack of side effects also include a lack of psychoactive behaviors in the animals (Hammell et al., 2015).
Nasal Delivery Methods
Cannabis-based nasal sprays offer much promise when it comes to nullifying the significance of the first pass of the liver. As this paper has stated, more common delivery methods of cannabinoid medications often depend on inhalation or eating of the solutions or capsules, taking the substance immediately into the bloodstream, but then forcing them to be passed on to the liver, for further degradation. As this paper has discussed, this creates a host of issues, as the cannabis products aren’t able to directly target the areas of disease or discomfort because of the filtering effect of the liver. Furthermore, this can also cause the potency and release times of the drug to be unpredictable and inconsistent (prnewswire, 2018). Furthermore, many cannabis products at this time don’t fully dissolve in water, which can add issues to dosing them properly and can create other such discrepancies (prnewswire, 2018). “The blood brain barrier also presents a major challenge in delivering targeted, consistent therapeutic relief. The blood brain barrier has historically stymied drug delivery because the capillaries that carry blood to the brain filter and block the passage of certain substances hindering therapeutic treatments” (prnewswire, 2018).
Many people in the science community view this challenge as an opportunity to develop a cannabis product that is able to overcome the blood-brain barrier, and many believe this opportunity lies in developing nasal-based cannabis products. For example, one company by the name of PreveCeutical developed a gel-based nasal spray that starts to act upon contact with the mucosal tissue, allowing greater targeted drug delivery directly to the brain (prnewswire, 2018). Hence the body’s bloodstream and metabolism are generally circumvented, enabling more precise doses to reach their targets without the filtering and metabolism that happens in the liver (PRNewswire, 2018). This means that the overall bioavailability of a nasal-centered product is extremely promising, as it can remain on the mucosal tissue for an extensive release. As a result, nasal administration is one of the most successful strategies for deliver of cannabis as it offers a generous surface area and advanced vascularization of the nasal cavity. Other products such as fine-mist sprayers empower the cannabis substances to make contact with this area, ensuring a rapid uptake and reliable results as the mist is able to permeate this area in a manner that ensures rapid uptake as it spreads throughout the nasal membrane (Smith, 2017). Because of this ideal situation, nasal sprays and gels can be formulated without any undesired plant substances or chemicals: this part of the body can accept it readily. As Paul Johnson, one of the developers of a nasal cannabis spray for a company called Verra Wellness, argues that this transmucosal delivery of cannabinoids is safer and it exposes the body to a host of compounds that are active within the raw plant material (Rogers, 2017). Experts like these argue that nasal delivery has better solubility, particle sizes and don’t have the typical impurities or dangers that are present when smoking or inhaling cannabis.
Dr. David Casarett, head of palliative care at Duke University, explains that nasal-centered cannabis products don’t always create the most predictable reaction in the human body. For example, Casarett argues that things like a cold or allergies or another state causing inflammation can impede absorption (Rogers, 2017). Casarett also made the point that “...the nasal membrane has high concentrations of enzymes that CBD has been found to deactivate, causing the body to temporarily not be able to metabolize other drugs, including THC” (Rogers, 2017). This means that the dosing method for nasal based products isn’t as clear cut as many would like one to think. Hence, experts advise the one still experiment with dosing modestly, starting slowly with the lowest dose (Rogers, 2017).
Encapsulation Technologies
Many experts, scientists and researchers within the medical cannabis industry view encapsulation technologies to be the last frontier of exploration. Encapsulation technology is nothing new: many companies have been working on improving the overall bioavailability of plant-based phytochemicals that the body has difficult absorbing into the circulatory system (Etter, 2018). Many biotech companies have been able to work on encapsulating vitamins, minerals, super-nutrients and nutraceuticals as nano-sized lipid spheres that move vital nutrients into the bloodstream and to the cells that needs them rapidly and with great efficiency (Etter, 2018). This growing trend has caused many scientists to wonder if the same thing could be done with medical cannabis products.
Encapsulated technologies are able to address many of the pervasive issues that plague the medical marijuana industry: there’s no lung damage from inhalation, they are able to create a standardized dose, and there’s no delay or variability within the onset of the medication (Etter, 2018). More and more biotech companies are experimenting with the best methods of encapsulation as this will allow clinicians to engage in more accurate dosing with patients and more purity of the cannabis reaching the bloodstream and going to work right away, without being degraded by the human body. Microencapsulation is becoming less expensive and less complicated. Methods at this time involve, “…the coplanar/coaxial process is based on Astrophysics and employs an all-natural phase change material, e.g., Beeswax, which is dispersed along coplanar/coaxial elliptical pathways, falling between 8 to 20 Degrees of Radian, to create uniformly-shaped, nearly-perfectly rounded excipient manufactures in sizes ranging from +or- 1um to 5000um that do not require sifting, drying/sieving (Resnick, 2017). More and more experiments of recent times have been able to successfully encapsulate CBD oils, THC extracts, a range of essential oils and other cannabis products (Resnick, 2017). Encapsulation means that these topical or comparable products are higher quality and have a time-release feature (Resnick, 2017).
Furthermore, their high quality material means they will not prematurely break down the compounds so that there is more controlled dosing (Resnick, 2017). As many experts and researchers have argued, this form of cannabis delivery is truly exciting because of the potency and precision that it promises. Live-cell encapsulation technologies suggest they can forge an innovative form of therapy for hard to treat and potentially fatal forms of cancer, such as brain cancer. Live-cell encapsulation means that cannabis products can work in conjunction with other drugs to help optimize their anticancer traits and functions, while minimizing the adverse side effects that often go hand in hand with chemotherapy (Pharmacyte, 2017). For example, Pharmacyte, a company which is aggressively pursuing live-cell encapsulation, “…believes an understanding of the chemical and biochemical processes involved in the interaction of substances derived from Cannabis with live-cell encapsulation will provide the opportunity to develop targeted ‘green’ approaches to treating cancers, such as pancreatic, brain, breast and prostate, among others” (Pharmacyte, 2017). This form of cannabis delivery really does offer a host of promise for the future, as it opens the door to treating really difficult forms of disease.
Conclusion
Medical marijuana has made leaps and bounds in the last few decades in terms of the success of a range of delivery methods. Gone are the days when the only way to consume cannabis was through the dangerous smoking and inhalation methods of yesteryear. Edible cannabis products for paint relief are an option, but there are a host of products and delivery techniques that can ensure more accuracy in dosing, and an ability for the user to zero-in on the specific symptoms they want treated. Furthermore, science has discovered a host of methods to avoid the first pass degradation that the liver wages when it comes to edible marijuana products. The delivery of cannabis products now offer the user much discretion and an ability to select products that offer a more time-released dose—something that is no doubt appealing to those using cannabis to relieve pain. Without a doubt, we will continue to see more methods of cannabis delivery that offer greater specificity of dosing and of symptom treatment.

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