water soluble cbd oil for oxygenation

Water Soluble CBD Promises Effects in 30 Seconds

Customers used to waiting upwards of 30 minutes to feel the effects of CBD products may experience relief in less than a minute after consuming products engineered with the cannabis compound by Ojai Energetics, the company's CEO and founder said.

Ojai Energetics uses cutting-edge technology that encapsulates CBD in bubbles of water, which allows the compound to be absorbed almost instantly when consumed orally.

“The bio-availability is much higher,” Will Kleidon, the company's CEO and founder, told Cheddar in an interview Monday. “You can get a lot more usage for much less.”

The increased bio-available also makes the product far more efficient, Kleidon said. Ojai Energetics found that 90 percent of traditional CBD oil consumed is destroyed by liver enzymes and stomach acids.

“If you eat 20 milligrams, your body could only use two milligrams,” Kleidon explained.

Instead, Ojai Energetics’ CBD, which is sold as an elixir, bypasses the digestive system and is immediately absorbed into the bloodstream.

The water soluble nature of the CBD also stimulates cannabinoid receptors on the tongue, allowing users to dose the product by taste.

“You can pinpoint a perfect dose using the flavor change, which is unique to our technology,” Kleidon said. Users are advised to put small drops of the elixir under their tongue until the bitter taste becomes sweet and honey-like.

Ojai Energetics products, which also include CBD infused coconut oil and a therapeutic sports gel, are especially popular with athletes, Kleidon said.

“Athletes of all people are undergoing more oxidative stress,” he said. CBD helps “buffer oxidation and maintain balance.”

Why CBD Water Is Not Really A Thing And May Even Be Dangerous

Two identical drams of CBD from Avicanna’s laboratories demonstrate the lighter, pinkish one on the . [+] right was exposed to oxygen.

© Sara Brittany Somerset

CBD water is a perfect example of capitalism at its phoniest. While plenty of companies are looking to cash in by claiming their products contain beneficial CBD, CBD water is the easiest example of how a fool and his money are soon parted.

CBD or cannabidiol, the low THC product that everyone touts as being “the non-psychoactive form of cannabis,” (which in and of itself is slightly misleading, but that is for a different column) destabilizes when exposed to light or oxygen. Legitimate CBD products are sold in dark, opaque bottles with labels that warn the consumer to store the bottle away from light, in a cool, dark place.

Scientists are just beginning to understand how hemp-derived CBD is beneficial to the human body’s endocannabinoid system. Depending on the manufacturing process, the minuscule amount of CBD that CBD water contains is most likely rendered ineffective when it is exposed to light for an extended period of time, such as being stationary in a brightly-lit supermarket refrigerator or storage facility all day. CBD products should be kept out of direct light, in order for the CBD not to destabilize.

Some manufacturing processes may be able to keep the components stable while exposed to light in the short term, but it will not remain stable if the water is sitting on a shelf for months or even weeks.

That means CBD in a clear water bottle stored on a brightly-lit supermarket shelf is most likely completely useless and provides no other benefit than the regular hydrating effect of plain water.

Assuming some manufacturer takes the initiative to sell CBD in dark brown glass bottles, like Guinness, from the moment the cap is opened and oxygen hits the product, it begins to destabilize.

Therefore, putting a dropper full of CBD into a bottle of water and sipping it here and there is not advisable either. Opening and closing the bottle numerous times and allowing oxygen and light to penetrate the container weakens the CBD, rendering it all but ineffective, quite quickly. (Unless fitness buffs do this at Soul Cycle, where the room is pretty dark and cyclists tend to chug.)

“Cannabinoids are susceptible to degradation and specifically oxidization which is very concerning, as some of those degradants are toxic. Cannabinoids are most stable in their trichomes on the flower or even in the resin where the terpenes and other natural chemicals provide some protection and anti-oxidation properties. This is why purified or isolated CBD-THC are very unstable unless properly formulated,” said Aras Azadian, CEO of Avicanna, exclusively in an email.

Green Rush Daily published an article last year stating, “The World Health Organization (WHO) has done extensive research regarding CBD water. Unsurprisingly, their findings have shown that the water can provide a variety of health benefits.”

In fact, according to the spokesperson for the WHO, they have never heard of this mythical research. “The team has no idea where this journalist got his information. Perhaps ask him to send the report he mentions?” the spokesperson said via email from Geneva.

While the head of the WHO recommended on January 24, not to include CBD in the 1961 Single Convention on Narcotic Drugs, the world body is certainly not endorsing CBD water.

That aside, Love Hemp water, for example, is another company in a string of bandwagon jumpers that hopes to rope in unwitting consumers and cash in on the CBD craze. T here are only two milligrams of natural hemp extract in Love Hemp water, which is virtually useless. To provide a visual, two milligrams of powder would fit on the end of a toothpick or a toothbrush bristle.

Furthermore, a daily dose of at least 10-25mg is recommended to be beneficial to the human body’s endocannabinoid system, for non-medical reasons. At that rate, a person would have to drink five to thirteen bottles of Love Hemp water per day, provided it is stored in the dark, such as in a wine cellar, before purchase, then consumed all in one shot.

Additionally, when the body needs the benefits of CBD right away, the efficacy of a .2mg serving is non-existent. GW Pharmaceuticals doses at five to ten milligrams per kilogram of body weight. That means a person who weighs 120 lbs (54.431kg) would theoretically need approximately between 272 and 554 milligrams of CBD per day, for the dose to be efficacious, as opposed to two.

“Besides, one milligram typically gets stuck to the bottles,” adds Azadian.

Mr. Bunka’s company does medical cannabinoid research and holds four patents in the USA and Australia, and has 45 patents pending on the delivery of cannabinoids.

“Love Hemp water is not designed –I certainly hope– to treat any medical condition. I hope they are positioning themselves as more of a supplement company,” he added.

According to Pop Sugar, another brand, CBD Living Water, ” has 2.5 milligrams of CBD per bottle, but due to the nano application, you can get up to nine times the effect — 22.5 mg.”

“That is a terrifically sloppy way of insinuating they have super bioavailability; and, at such a high implied rate as to be nearly impossible. At worst, it showcases a terrific lack of knowledge and is simply not responsible,” debunks Bunka.

Take CBD water companies’ beneficial claims with a grain of salt, because that is about how much CBD their bottles contain.

To get the maximum health and wellness benefits out of CBD, consume it sublingually directly from the original, opaque medicinal or supplement bottle, and eschew gimmicky CBD water.

Towards Better Delivery of Cannabidiol (CBD)

Cannabidiol (CBD) has substantial therapeutic potential, but its development as an effective drug by the pharmaceutical industry is hindered by intrinsic characteristics such as low bioavailability, low water solubility, and variable pharmacokinetic profiles. Importantly, lack of patentability of the drug substance also limits the likelihood of an expensive, full development programme in anything other than orphan indications. Potential avenues to overcome these issues with CBD include self-emulsifying drug delivery systems, improved crystal formulations and other solid-state delivery formulations, which are mostly in the pre-clinical or early clinical stages of development. This review identifies issues compromising current delivery of solid-state CBD, and how advanced pharmaceutical development strategies can enable CBD to realise the full potential as a successful therapeutic agent.

1. Introduction

Cannabidiol (CBD) is a phytocannabinoid used globally for a variety of indications, but with few approved medicinal applications. Purified CBD is only licensed in treatment-resistant, rare paediatric forms of epilepsy [1,2,3,4,5]. Ongoing clinical trials are being conducted in potential indications such as anxiety, schizophrenia, addiction, post-traumatic stress disorder, graft-versus-host disease, cancer and inflammatory bowel disease. The United States (US) Food and Drug Administration and the European Medicine Agency approved drug formulations containing CBD include Epidiolex ® (a pure CBD oral solution) and Sativex ® (a CBD and Delta-9-tetrahydrocannabinol (THC, 1:1) oromucosal spray), both developed by GW pharmaceuticals.

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 [6], 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.

2. The Problems with CBD

2.1. Bioavailability and Pharmacokinetics

Successful drug delivery to the intended target sites of action is dependent on multiple factors including the individual’s physiology and the drug’s physicochemical properties (solubility, dissolution, stability, permeability and metabolism). Poor bioavailability, which is dependent on these factors, generally leads to insufficient therapeutic efficacy and is more likely to produce high inter-individual variability in pharmacokinetic (PK) parameters [7,8]. In this context, the bioavailability of CBD varies greatly with route and mode of administration [9,10]. The oil/water partition coefficient (Log P) describes a drug preference which exists either in the water or oil part of a solution; higher Log P values mean more of the drug will be distributed in the oil part of the solution. Due to the highly lipophilic nature of CBD (Log P 6.3) [11], it is most commonly supplied as an oil or alcoholic formulation either in soft-gel capsules, liquid solution, sublingual drops, or as an oromucosal spray [12]. Studies examining oral and oromucosal delivery of CBD and THC at equimolar concentrations in humans show high inter/intra-individual variability [13,14].

Highly lipophilic drugs delivered orally in solution can precipitate in the gastrointestinal (GI) tract, resulting in an absorption rate slower than elimination [8]. The oral bioavailability of CBD is estimated at 6%, although data in this area have been noted to be considerably lacking [15]. Time to peak plasma concentration following oral delivery is slow (1–4 h), the Cmax (maximum concentration) generated from 20 mg of orally delivered CBD/THC sprayed onto a gelatin capsule was 2.4 ng/mL of CBD, and the half-life of CBD was reported between 1.4 and 10.9 h after oromucosal spray [14,15]. Oil suspensions designed for oral and oromucosal routes of administration are currently favoured; Epidiolex ® is delivered orally in an oil solution, and Sativex as an oromucosal spray. The oromucosal route circumvents some of the problems associated with the oral route, and provides a more rapid onset of action. However, Itin and colleagues suggest that a substantial proportion of the oromucosal delivered dose may actually be absorbed through the GI tract [16]. Authors noted that the PK of Sativex is different when administered in a fasting state relative to a fed state (as is Epidiolex), but that this should not be the case as PK profiles should only be substantially influenced by a fed-state when consumed orally. Furthermore, in work published by Guy and colleagues, the PK parameters of Sativex were similar between oromucosal and oral routes of administration [14]. These observations are in agreement with further work by Itin and colleagues, demonstrating CBD’s lipophilic nature causes it to accumulate in the oral mucosal lining or enter the GI tract upon swallowing [17]. However, the authors suggest this route of administration remains viable, so long as exposure times to the oral mucosal lining are adequate, and a method of preventing washout of the drug by saliva is present.

A potential method to increase oral bioavailability is to administer CBD alongside a high-fat/high-calorie meal [16]. 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 [25]. 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 [26].

Smoking or vaporisation can overcome some of the problems of CBD delivery. The bioavailability of five individuals after smoking 20 mg of deuterium-labelled CBD was reported at 31 ± 13% (range 11–45%) [27]. Smoking allows for rapid delivery of CBD, and peak plasma levels occurred within 3 min following inhalation (110 ± 55 ng/mL). A more recent study assessing the pharmacokinetics of vaporised CBD (100 mg) in healthy men (n = 6) and women (n = 6) showed a mean Cmax of 125.4 ng/mL ± 95.2 in men and 83.7 ng/mL ± 8.8 in women [28]. This study also compared vaporised CBD to orally delivered CBD at the same dose, and found vaporisation produced around a ten-fold increase in Cmax. Whilst vaporisation increases the bioavailability of CBD, large standard deviations indicate there is still substantial variability in inter-subject pharmacokinetics. Furthermore, the use of solubilisers required to create a vaporisable solution can result in irritation of the airways and may not be suitable for all patients. Smoking a cannabis-based medicinal product is also not currently allowed under legislation in the UK.

A number of alternative delivery methods by-passing the digestive tract and first pass metabolism are currently under investigation including transdermal and nasal routes, and eye drops, which have been reviewed elsewhere [29].

2.2. Stability

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 [30]. 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 [31]. Whether the stability of CBD products is altered by different formulations is not known [32]. 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 [33]. 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/)).

2.3. Dosing and Side Effects

In our systematic review, within randomised controlled trials administering CBD (by oral solution, capsules, or oromucosal spray), an average dose of 14 mg/Kg/day was reported in positive outcome trials, compared to 5 mg/Kg/day average dose reported in trials in which CBD did not demonstrate efficacy [34]. The high oral doses that are required for efficacy may impact the occurrence of adverse events (AEs), as well as increasing drug costs to the healthcare provider or patient.

CBD is generally described as well tolerated, with a favourable safety profile, and does not demonstrate any evidence of abuse potential [35,36]. CBD has been most extensively studied in the clinical setting of patients with epilepsy. Within these trials, the most common side effects observed have been somnolence/sedation, diarrhoea, loss of appetite, fatigue, and sleep disturbances [37]. Concomitant increases in anti-epileptic drug metabolites because of drug–drug interactions (DDIs) with CBD may contribute to particular side effects observed such as somnolence [2,38]. A recent review which analysed prescribing information and new drug applications from federal agency websites (U.S. FDA, Health Canada, and others) reported that nearly one half of CBD users experienced an AE, which generally followed a dose-dependent relationship [39]. In one randomised controlled trial in treatment resistant epilepsy, AEs were reported in 93% of patients taking CBD and included vomiting and diarrhoea, while 86% of patients in another trial reported similar AEs [4,40]. A recent systematic review and meta-analysis on the clinical benefits of CBD found mild side effects to be present in 76% of patients taking purified CBD (such as Epidiolex ® ) and 33% in those taking CBD-rich extracts, and this was statistically different from placebo [41]. It was also noted that those receiving pure CBD reported administering higher doses compared to those taking CBD-rich extracts (25 mg/Kg/day vs. 6 mg/Kg/day), without differences in efficacy. It is unclear whether CBD-rich extracts demonstrate a more favourable side effect profile due to the presence of non-standardised herbal compositions, improved absorption of the CBD in the more complex mixture of compounds or whether it is due to the lower doses of individual cannabinoids reportedly consumed. It is also noteworthy that all CBD-rich extract studies were retrospective records or online surveys, while pure CBD trials were prospective, randomised controlled trials [41]. Thus, it is not clear whether various CBD formulations have different side effect profiles.

2.4. Drug–Drug Interactions

Drug–drug interactions (DDIs) with CBD are a high risk as it is metabolised by, and a competitive inhibitor of, CYP450 enzymes (specifically CYP3A4 and CYP2C19) [39,42]. A case report of a 32-year-old woman with refractory epilepsy receiving tacrolimus (5 mg/day) and CBD (2000–2900 mg/day) reported that after two weeks of co-administration there was a threefold increase in dose-normalised tacrolimus concentrations [43]. A case report of a 37-year-old male similarly suggested CBD can increase warfarin concentrations [44]. More robust evidence of DDIs comes from a meta-analysis assessing four randomised, double-blind, placebo-controlled trials in Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) (n = 396 LGS, 318 DS) [45]. Authors noted incidences of serious AEs were 8% higher in CBD groups relative to placebo, and in patients taking clobazam alongside CBD, AEs were 14% more common than CBD alone. Blood plasma levels of the pharmacological active metabolite of clobazam, N-desmethylclobazam, were three times higher when administered alongside CBD. Likewise, increases in the CBD metabolite, 7-OH-CBD, are also seen when these drugs are co-administered [46]. Valprorate, another common anti-epileptic drug, is strongly associated with increased liver transaminases levels with CBD use. An FDA report describing clinical data for Epidiolex ® in the treatment of LGS or Dravet syndrome highlighted alanine aminotransferase (ALT) levels were three times the normal limit in 13% of Epidiolex ® treated patients. This AE was also true for patients taking clobazam, but was more common in valproate treated patients. Another study investigating the potential for DDIs with cannabis-based medications using the FDA drug interaction database identified three of the main cytochrome enzymes (CYP3A4, CYP2C9 and CYP2C19) responsible for 20–70% of total cytochrome p450 activity were inhibited by CBD [47]. Furthermore, following oxidative reactions at phase 1 metabolism, CBD is then subject to phase II glucuronidation reactions by the enzymes UGT1A9 UGT2B7 and UGT1A7. Competitive binding for these enzymes between drugs also presents another point at which drug metabolite levels could be altered [47]. These observations indicate the potential for DDIs with CBD in a variety of conditions are likely, and needs to be investigated using large patient studies.

2.5. Polymorphisms

In material science, a polymorphism refers to the occurrence of differing crystalline structures of the same chemical compound which can be due to the crystallisation conditions (such as the rate of crystallisation) leading to different molecular conformations [48]. Polymorphic substances have identical chemical composition, thus will demonstrate the same chemical behaviour once in solution. Polymorphism screening is a vital component of pharmaceutical drug development as the existence of polymorphisms can affect drug performance and characteristics; for example, a fourfold difference in solubility can occur between different forms due to differences in dissolution rates [49]. An active pharmaceutical ingredient (API) based on a single polymorphism is likely to have an improved and consistent safety and efficacy profile. These properties may include thermodynamic, kinetic, surface, and mechanical properties, amongst others [48]. Polymorphism is acknowledged as an issue in drug development by key regulatory agencies who have issued guidance on approaches used to control for and to justify using polymorphic forms in drug substances. As stated by the FDA’s guidance document “polymorphism can affect the quality, safety, and efficacy of the drug product”; so controlling polymorphism from the drug substance can provide an easier development with regards to regulatory approval [50]. CBD has been shown to be present as two or more inherent crystalline forms which have potential effects on drug absorption and bioavailability due to different physicochemical properties [6]. To date, no studies have assessed how different crystalline forms may impact the pharmacokinetic profile of CBD, which may have implications for CBD being developed as solid-state forms.

3. Novel CBD Medical Products in Development

Due to the challenges with CBD, many companies are trying to develop CBD medicines with better PK profiles. These strategies include self-emulsifying drug delivery systems, improved single crystal structures, and CBD cocrystals. Table 1 summarises some of the different CBD formulations under development by commercial companies with information in the public domain.

Table 1

Cannabidiol (CBD) formulations under development by commercial companies (presented in alphabetical order) with information in the public domain. Abbreviations: CBD, cannabidiol; i.v., intravenous; N/A, not available; NHIE, Neonatal Hypoxic-Ischemic Encephalopathy; TMP, tetramethylpyrazine; PPARγ, peroxisome proliferator-activated receptor gamma; CB2, cannabinoid type 2 receptor; US, ultrasound; BBB, blood–brain barrier.

Company Name Formulation (If Available) Delivery PK Data/Other Clinical Development References
Ananda Scientific Enhanced CBD ANANDA’s Liquid Structure™ Enhanced CBD N/A (presumed oral) Reported as: fully water soluble (100%); high bioavailability (20× more than other CBD oils at 30 min); no degradation in stomach; stable—storable at room temperature for at least 2 years; consistent dosing—reliable results with use Phase 1 studies underway for indications: neuropathic pain and opioid replacement and withdrawal [57]
Aphios APH-1501 Nanoencapsulated Cannabidiol Time Released Capsules; CBD encapsulated in biodegradable polymer nanospheres as a lyophilised powder Oral capsule N/A Phase 2 trial planned for the treatment of opioid addiction [58]
Artelo Biosciences ART12.11 Co-crystal solid state formulation with TMP Oral N/A Pre-clinical development for PTSD, IBD, Stroke and Rare Diseases [59]
Botanix Pharmaceuticals BTX1503 Gel Transdermal N/A Phase 1b study completed, phase 2 study underway in moderate to severe acne [60]
BTX1308 Gel Transdermal N/A Phase 1b study planned in Plaque psoriasis [61]
BTX1204 Gel Transdermal N/A Phase 1b study—unknown status. Phase 2 study recruiting. Indication: atopic dermatitis [62]
BTX 1701 Facial cleanser utilising Permetrex™ skin delivery technology in conjunction with a novel oil clearing agent Facial cleanser N/A Small clinical study performed in mild acne [61]
Columbia Care BeneCeed 200 mg CBD tablet Oral N/A N/A [63]
Diverse Biotech Inc. BRCX014 Sublingual formulation Sublingual N/A Two registered phase 1/2 trials in Cancer [64]
Echo Pharmaceuticals Arvisol Lipophilic compound delivery technology Alitra ® Oral Claims to improve bioavailability and steadier temporal profile Preclinical – indicated for Rett Syndrome—Epilepsy, and Schziophrenia [65]
Emerald Health Pharmaceuticals EHP-101 Synthetic CBD designed to enhance the therapeutic benefits of CBD by being a dual PPARγ and CB2 agonist Oral liquid N/A Phase 1 trial completed in healthy volunteers but no results published yet. Phase 2a trial registered but not yet recruiting for Diffuse Cutaneous Systemic Sclerosis [66]
GW Pharmaceuticals GWP42003 NA i.v. N/A Phase 1 trial completed in NHIE [67]
Kalytera K-1052 CBD +(S)-2-amino-(1-iminoethylamino)-5-thioheptanoic acid (iNOS inhibitor) coupled pro-drug molecule i.v. N/A In vivo efficacy studies in rodents completed in Sepsis-induced Acute Renal Failure and Traumatic Brain Injury [68]
KAL-1816 CBD conjugated with naproxen Oral and i.v. N/A Patents filed in acute and chronic pain [68]
K-1022 Bi-sulphate derivative of CBD Oral Water soluble In vivo efficacy studies performed in Ulcerative Colitis; currently ADME/PK analysis in rats, as well as non-clinical safety assessment of K-1022 in rats and dogs [68]
K-1012 Bi-phosphate derivative of CBD; novel aerosolised formulation Intra-tracheally Soluble in aqueous solution; expected to increase the bioavailability In vivo efficacy studies carried out in rodents in Adult Respiratory Distress Syndrome [68]
K-1032 L-valine-ester derivative of CBD Topical delivery N/A In vivo efficacy models in rodents conducted in chronic inflammatory skin diseases [68]
Lexaria Bioscience Corp TurboCBD Capsules also containing American ginseng, ginkgo biloba, and organic hemp oil using DehydraTECH™ delivery technology Oral Increased circulating CBD levels compared to control CBD (+86% at 90 min) On the market (over the counter) [69,70]
Medexus Pharmaceuticals CA2476833C Complex of RM-β-, DM-β and TM-β cyclodextrin with CBD N/A Improve aqueous solubility, dissolution rate, absorption and bioavailability N/A [71]
Preveceutical Sol-Gel CBD gel Intranasal Expected to increase bioavailability Pre-clinical evidence to suggest better distribution along the olfactory epithelia [72]
PureForm Global PureForm CBD Molecularly identical, non-hemp-based CBD, developed using InterMolecular Stacking Technology Liquid and powder Expected to improve solubility and stability N/A [73]
Satipharm Gelpell (PLT-101) CBD in gelatine beads encapsulated in gastro-resistant capsules Oral 30% higher bioavailability compared to oromucosal spray. Phase 1 and phase 2 (efficacy in paediatric epilepsy) trials completed [1,52]
Vireo Health LLC US2019030170 CBD and a sulfoalkyl ether cyclodextrin N/A Increase water solubility N/A [74]
Zynerba Pharmaceuticals Zygel TM ZYN002 Permeation-enhanced gel Transdermal N/A Pre-clinical, phase 1 and phase 2 trials all underway in Fragile X syndrome and other rare neuro-psychiatric conditions [75]

3.1. Self-Emulsifying Drug Delivery Systems

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 [51]. 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 [1]. 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 [51]. 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 [55]. 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 [56]. 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 ).

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.

3.2. Solid-State Delivery Formulations

Solid-state oral delivery allows for 100% of the drug to reach the GI tract and has the potential to improve PK characterisation [76,77]. CBD delivered via this route would also further avoid local side effects associated with use of Sativex oromucosal spray (1:1 CBD:THC) or GI discomfort or pain associated with the vehicle itself in oral liquid formulations [78]. Current investigated solid-dose oral formulations of CBD include a 200 mg CBD tablet by Columbia Care called BeneCeed™, which will be used in a UK clinical trial. Elsewhere, a patent by GW pharmaceuticals lists a solid-state CBD as a potential clinical consideration in the treatment of inflammatory bowel disease [79]. Whilst dosing in this fashion ensures a consistent dose, formulations of this nature do not necessarily address problems associated with poor bioavailability.

3.3. Improved Single Crystal Structures

Some researchers claim to have improved the single crystal form of CBD. For example, one patent listed describes a crystalline CBD of a novel form, including (R,R)-(−)-crystalline cannabidiol [80]. This crystalline form was shown to possess a melting point of 37–50 °C, compared with a melting point of 66–67 °C for CBD. Intramolecular crystal lattice binding between ions within a crystal affects its melting point and reductions in lattice energies may increase aqueous solubility [8]. PureForm CBD™ is described as a molecularly identical, non-hemp-based CBD that has been developed using their Inter-Molecular Stacking Technology to improve solubility and stability [81]. There is no further publicly available information on these products.

3.4. Cocrystal Engineering as a Potential Solution for CBD Oral Delivery

Interest and progress in the concept of cocrystallisation have expanded over recent years and is becoming a well-established process in drug development. Cocrystals consist of the API and one or more unique crystalline co-formers which modify the material properties whilst retaining the intrinsic pharmacological drug activity. Cocrystallisation is a useful method for overcoming problematic properties of drugs by increasing the bioavailability, solubility, dissolution rate, physical form, melting point, tableting, stability, or permeability of drug substances [82,83,84]. Further advantages of crystal preparations include the potential for numerous co-molecules including preservatives, other APIs, and pharmaceutical excipients, as well as providing the opportunity to address intellectual property issues by extending API life cycles and fulfilling patent eligibility criteria [85].

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 [86]. 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 [87].

Artelo Biosciences have developed a cocrystal with CBD that was designed to take advantage of cocrystal properties and help alleviate some of the problems with CBD delivery. This cocrystal uses the co-former tetramethylpyrazine (TMP; also called ligustrazine), a plant-derived compound from the Ligusticum species that is widely used in Chinese medicine. TMP may offer increased efficacy and bioavailability, by acting synergistically and changing the physiochemical properties that are associated with ineffective absorption. ART12.11 (CBD:TMP cocrystal) is currently in the nonclinical phase of pharmaceutical development targeted towards post-traumatic stress disorder (PTSD), inflammatory bowel disease (IBD), stroke and rare diseases, and has been recently granted a composition of matter patent in the US.

3.5. Other Delivery Systems and Formulation 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 [69].

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 [75]. 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.

Kalytera are also exploring inflammatory skin conditions using an L-valine-ester derivative of CBD for topical delivery, which is in pre-clinical stages. Kalytera are also developing a bi-sulphate derivative of CBD for oral delivery which claims to be water soluble, a bi-phosphate CBD derivative aimed for intra-tracheal delivery via a novel aerosolised formulation, and an intravenous (IV) formulation (see Table 1 ). GW Pharmaceuticals list an IV formulation in phase 1 trial for neonatal hypoxic-ischemic encephalopathy (NHIE).

A sublingual formulation by Diverse Biotech Inc., and an oral liquid by Emerald Health Pharmaceuticals containing a pure synthetic CBD are both in early clinical phases (see Table 1 ).

Complexation of CBD with cyclodextrins (CD) has also been investigated as a potential method to increase the water solubility and subsequently improve the bioavailability of sublingually delivered CBD. Mannila and colleagues demonstrated precipitation complexation of CBD and β-CD at a 1:2 ratio could increase the water solubility of CBD and increase the dissolution rate [88]. The authors noted sublingual delivery of the CBD/β-CD complex produced superior bioavailability compared to oral dosage forms of CBD in rabbits. However, in this study, CBD delivered in an ethanol solution sublingually was comparable to sublingual delivery of the CBD/β-CD complex. Two formulations of CBD and CDs are currently in development by Medexus pharmaceuticals and Vireo health LLC. These companies propose complexes of CBD and CDs will increase the aqueous solubility and subsequently improve bioavailability. However no clinical studies have been performed using these exact formulations to date.

4. Conclusions

Intrinsic problematic issues, such as polymorphism, low aqueous solubility and poor bioavailability, hinder the effective clinical development of CBD as an oral drug in the solid-state. SEDDS offer a way to increase bioavailability by increasing the solubilisation of CBD in the aqueous environment of the GI tract, allowing more CBD to cross the unstirred water layer of the GI tract and move into lymphatic or blood circulation [51]. However, SEDDS can cause chemical instabilities of drugs and high surfactant concentrations have the potential to irritate the GI tract. Furthermore, some of hydrophilic components can diffuse into the shells of gelatine capsules causing precipitation and poor dissolution rates of the drug in the GI tract [89]. While SEDDS formulations may have merit, these approaches suffer from using a lipophilic molecule which is not optimised for absorption within the gut, and intellectual property protecting these innovations can often be circumnavigated by experienced scientists. A cocrystal modification has the potential to overcome numerous physiochemical issues, allowing improved stability and bioavailability. Cocrystals can be “fine-tuned” using various inert or pharmacologically active co-formers, which may provide a more predictable pharmacokinetic profile and subsequently reduce side effects associated with high intra- and inter-personal variability. Importantly, because co-crystal formulations offer a unique and defined composition of matter, patentability ensures financial investment is available to push CBD from bench to bedside. What is clear is that the field of cannabinoid-based medicines, with CBD as a leading example, has a rich and diverse future ahead with continued preclinical research and a strong clinical pipeline. If companies are able to overcome the challenges facing the druggability of CBD, or indeed other cannabinoids or phytochemicals, in the oral solid dosage form, and protect their investment through strong intellectual property, it will undoubtedly lead to the best chance of wide therapeutic applications, offering solutions to many more patients.