Writing in three separate international patents (I, II & III), Colgate-Palmolive said it had created different oral care compositions comprising a cannabinoid, in particular CBD, integrated with an orally acceptable carrier. These blends, it said, could be used to make a range of oral care products, including toothpaste, mouthwash, oral gels, chewing gum and mouth spray, among others.
Cannabinoid oral care – CBD has ‘antibacterial and anti-inflammatory properties’
“Accordingly, there is a need for oral care compositions with antibacterial efficacy, but which are also palatable and desirable for the user,” Colgate-Palmolive wrote in its patent filings.
Colgate-Palmolive said “unchecked bacterial growth” in the oral cavity could lead to “a number of adverse conditions”, including gingivitis – an inflammation of the gums and one of the most common disorders – as well as abscesses and cold sores which also involved inflammation.
Entresto™ is an example of a drug–drug cocrystal containing monosodium sacubitril and disodium valsartan used to treat chronic heart failure that has obtained FDA approval. PK studies demonstrated a mean relative bioavailability of 161% in the cocrystal form of valsartan compared to reference valsartan tablets . The cocrystal demonstrates high solubility and medium permeability. Suglat ® is another marketed cocrystal, comprised of the sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin and L-proline, approved in Japan for the treatment of diabetes mellitus. The third cocrystal currently on the market is Depakote ® , an anti-convulsant drug, which is comprised of valproate sodium with valproic acid .
Methods to increase oral CBD bioavailability have included self-emulsifying drug delivery systems (SEDDS). These involve mixtures of oils, surfactants, and solvents that produce nano or micro sized droplets when they come into contact with an aqueous solution such as in the gut . The small nature of the droplets increases the surface area available for drugs to be dissolved and absorbed. For example, soft gelatin capsules containing CBD developed by Satipharm, based on an advanced self-nanoemulsifying technology, have demonstrated greater bioavailability (about 31–34% higher compared to a reference oromucosal spray), solubility, and faster time to peak plasma concentrations in humans [52,53,54]. However, inter-individual variations were still high. This formulation has been proven safe and effective in a paediatric population with treatment-resistant epilepsy . Another group recently reported a 4.4-fold increase in Cmax, enhanced bioavailability, and shorter Tmax with a SEDDS-CBD formulation based on VESIsorb ® technology compared to a control CBD oil . VESIsorb ® is a novel lipid-based delivery system which self-assembles on contact with an aqueous phase into a colloidal delivery system, which solubilises the drug and improves diffusion and absorption and thus bioavailability . In rats, another approach of a nano-emulsion (NE) formulation has been tested. CBD-NE oil drops increased absorption and bioavailability (21% higher) compared to a control CBD oil . However, there may be practical (stability, complex formulations, safety of excipients, scalability) and economic (cost of formulation, patentability) issues with this method of increasing oral CBD bioavailability.
Although the methodology is not clear from publicly available information, Echo Pharmaceuticals and Ananda Scientific are also investigating formulations which claim to enhance bioavailability and consistency in PK profiles by increasing CBD’s water solubility; Ananda’s Liquid Structure™ Enhanced CBD and Echo Pharmaceutical’s Arvisol, using their lipophilic compound delivery technology Alitra ® . Both compounds are in preclinical or early clinical phase 1 development (see Table 1 ).
In order to be successfully utilised as a medicine, it is paramount to identify and overcome the inherent challenges that face CBD’s effective delivery, particularly through the oral route, which is the most preferred route for drug delivery by patients and drug developers. Some of the most significant issues with oral CBD include poor bioavailability, variable pharmacokinetics profiles, and possible polymorphisms , which may have unintended consequences of less predictable efficacy, increased side effects and drug–drug interactions with higher doses. This review will outline some of the current issues with CBD pharmaceutics, the novel CBD formulations under development and under clinical investigation, and the strategies to improve CBD delivery and efficacy.
3.2. Solid-State Delivery Formulations
CBD can be degraded depending on temperature, light and auto-oxidation. Mazzetti and colleagues examined nine commercially available CBD E-liquids and found an average degradation by 13% in 30 days when exposed to light and room temperature. However, samples stored in the dark at room temperature only suffered 4% degradation, suggesting light is a significant contributing factor in degradation at room temperature . Another recent analysis found that CBD samples stored in the dark at room temperature for three months showed the presence of Δ 9 -THC and Δ 8 -THC impurities . Whether the stability of CBD products is altered by different formulations is not known . However, one study demonstrated that CBD dissolved in medium-chain triglycerides (MCT) oil is completely devoid of any lipid oxidation products, indicating MCT oil matrices are less susceptible to oxidative degradation than olive oil or hemp seed oil. Oxidative processes are associated with rancidity and deterioration of fats, as well as decreased concentrations of cannabinoids and terpenes . Epidiolex ® (suspended in sesame seed oil and ethanol) and Sativex (suspended in ethanol anhydrous, propylene glycol and peppermint oil) are said to be stable 56 and 48 days after opening the container, respectively (see prescribing information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf) and online website (http://sativex.co.uk/ms-nurses/frequently-asked-questions/)).
Another encapsulated form of CBD is APH-1501 (produced by Aphios), which are time-released capsules in which CBD is encapsulated in biodegradable polymer nanospheres as a lyophilised powder. This CBD is awaiting phase 2 testing in opioid addiction.
A potential method to increase oral bioavailability is to administer CBD alongside a high-fat/high-calorie meal . This has been demonstrated in healthy subjects with about four-fold increases in bioavailability compared to fasted, and in adult patients with refractory epilepsy with four- and fourteen-fold increases in area under the curve (AUC) and Cmax, respectively, in the fed state compared to fasted [18,19,20]. This is likely due to increased micelle and chylomicron formation making more drugs available for lymphatic transport [21,22]. High fat meals also potentially inhibit the activity of drug efflux transporters present on the apical membrane of enterocytes, and stimulate the release of biliary secretion, which further inhibits efflux transporter activity [23,24]. Although lymphatic transport bypasses the liver into systemic circulation, CBD delivered orally is still subject to first pass metabolism. One study showed the AUC of 7-hydroxy-cannabidiol (7-OH-CBD) is about 40% the level of orally delivered CBD, however participants were also receiving concomitant treatment Clobazam, Valproate or Stripentol . Indeed, impaired hepatic metabolism has been shown to cause an increase in the bioavailability of CBD, and indicates first pass metabolism represents a significant barrier in increasing the bioavailability of CBD .
3. Novel CBD Medical Products in Development
An oral capsule developed by Lexaria Bioscience Corp called “TurboCBD” claims to result in increased circulating CBD levels compared to control CBD, and contains American ginseng, ginkgo biloba, and organic hemp oil, produced using DehydraTECH™ delivery technology .
Preveceutical’s “Sol-Gel” is exploring an intranasal CBD formulation to increase bioavailability and is currently in the pre-clinical stage (see Table 1 ). Zynerba Pharmaceuticals have progressed a permeation-enhanced CBD gel “Zygel” for transdermal application to phase 2 trials . Botanix pharmaceuticals are exploring a number of gel formulations for transdermal application in indications such as acne, psoriasis and dermatitis that are in early clinical development.
What’s more, CBD can have serious interactions with certain medications. In evaluating available information on five prescription CBD-based medications, researchers found 139 medications could have a potential drug-drug interaction with CBD  Kocis PT, Vrana KE. Delta-9-Tetrahydrocannabinol and Cannabidiol Drug-Drug Interactions. Medical Cannabis and Cannabinoids. 2020;3:61–73. . People who take certain blood thinners, heart rhythm medications, thyroid medications and seizure medications need to be particularly careful.
Some CBD products do some of this math for you and illustrate how many milligrams are in a milliliter, some even marking these points on the dropper so you know exactly what you’re taking.
$45 per container
In many medical studies on CBD, you see administered doses reach hundreds of milligrams a day, which sounds severe compared to our starting dosage example of 25 milligrams. However, Steven Phan, founder of Come Back Daily, a CBD dispensary in New York, points out that patients in these studies are often dealing with serious flare-ups and pain-inducing conditions compared to everyday dispensary customers.
Can You Take Too Much CBD?
With the exception of one CBD product, a prescription drug used to treat seizures associated with particular syndromes, the Food and Drug Administration (FDA) doesn’t regulate the use of CBD. (In fact, it’s illegal to market CBD as a supplement or add it to food.) Therefore, it’s best to consult a doctor with experience in CBD administration to determine your ideal dosage.
With this CBD oil dosage calculator as your guide, you would find that you needed to consume 10 drops, or 0.5 milliliters, to reach 25 milligrams. And if you intend to consume 25 milligrams daily, you can expect this particular bottle to serve as a 60-day supply.
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Determining the Best CBD Dosage for You
Expressed in milligrams (mg), CBD dosage largely depends on the conditions and symptoms you’re trying to treat and your unique endocannabinoid system, which is associated with motor control, behavior, emotions, the nervous system and homeostasis. CBD dosage remains an area of active research—more large, high-quality studies are needed in different populations to determine appropriate dosing, efficacy and safety guidelines.
Without FDA approval, there is little guidance in the U.S. on how much CBD a person should consume for various conditions.