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Interest in natural phytochemicals or synthetic derivatives of cannabinoids has risen.
As understanding of the endocannabinoid system increases, interest in developing drug candidates that are either natural phytochemicals or synthetic derivatives of cannabinoids has risen. The endocannabinoid system consists primarily of two G-protein-coupled receptors known as cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) and their natural ligands anandamide and 2-arachidonoylglycerol. It also includes, however, numerous other components, many of which are present in most types of cells in the human body.
In fact, approximately 600 Cannabis metabolites have been isolated, with more than 100 of them classified as cannabinoids and seven specifically as cannabidiol (CBD)-type compounds (1). CBD has been shown to have antioxidant, anti-inflammatory, and analgesic properties. Other cannabinoids aside from CBD and Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive ingredient in marijuana, include cannabichromene (CBC), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabinol (CBN), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA), cannabicyclol (CBL), Δ8-THC, tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivarin (THCV).
FDA has, to date, approved one cannabis-derived drug product, Epidiolex (GW/Jazz Pharmaceuticals, cannabidiol) for the treatment of certain types of seizures, and three synthetic cannabis-related drug products, Marinol (dronabinol), Syndros (dronabinol), and Cesamet (nabilone), all for the treatment of nausea associated with cancer chemotherapy and anorexia associated with weight loss in AIDS patients.
Sativex (nabiximols, GW/Jazz Pharmaceuticals), a formulated cannabis extract that contains the principal cannabinoids Δ9-THC and CBD, as well as other minor cannabinoids and terpenes, is now approved in more than 25 countries around the world for the treatment of spasticity due to multiple sclerosis.
Several small biopharmaceutical companies, along with Jazz Pharmaceuticals, are developing additional phytochemicals and novel synthetic derivatives as potential cannabinoid-based drug candidates.There are advantages and disadvantages to both approaches.
Regardless of whether cannabis-based medicines are extracted from plants or produced using chemical synthesis techniques, the goal is to develop treatments that are safe and efficacious. “At GW, which is now part of Jazz Pharmaceuticals, we have a passionate belief in the potential therapeutic benefits of the cannabis plant and the possibility of creating tried and tested, regulatory approved, and modern cannabis-based medicines,” says Chris Tovey, the company’s chief operating officer.
“Whether plant-derived or synthetics, we believe patients and their clinicians deserve access to effective and well-evidenced cannabis-based medicines with an acceptable safety profile.This can only be achieved if a cannabis product, synthetic or otherwise, is subject to rigorous high-quality clinical trials and approval by medicines regulators, in the same way that all other medicines are,” Tovey stresses.
The preference for chemical synthesis or extraction of phytochemicals depends largely on the strategy of the drug developer. For a company such as Corbus Pharmaceuticals, which is focused on novel compounds that target the endocannabinoid receptors, synthesis is the only option because these compounds do not exist in nature, explains the company’s CEO Yuval Cohen. “For us, chemical synthesis offers the same advantage that it offers all pharmaceutical products: high purity, high yield, and the potential to manufacture at a large scale,” he adds.
Some cannabinoids, notes Tovey, exist as two or more stereoisomers. Although these compounds have the same formula, the atoms are in a slightly different arrangement and thus the molecules can have different pharmacological effects. The stereochemistry of the phytochemicals is determined by the enzymes, or synthases, in the Cannabis plant, according to John A. MacKay, founder and CEO, Synergistic Technologies Associates. “It can be difficult to synthesize specific stereoisomers with high stereoselectivity,” he says. The earliest synthesis of stereospecific isomers was achieved in the early 1940s by Roger Adams at the University of Illinois in cooperation with the Treasury Department Narcotics Laboratory (2,3).
As a result, due to the differences in the stereochemistry of plant-derived and synthetic versions of the same target cannabinoids, the extracted and synthesized products can have different chemical profiles (4,5). The approach to manufacturing candidates may therefore be dictated by the desired properties of the product.
“While we have, to date, chosen to focus on plant-derived cannabinoids and cannabis-based medicines, we cannot say whether there are particular advantages or disadvantages to a plant-derived or synthetic medicine, except that the chemical profiles of these cannabinoids are almost certain to be different, coming from different manufacturing processes,” concludes Tovey.
In certain cases, the composition of the plant and, therefore, the plant-derived medicine may be advantageous in treating a specific patient population. However, Tovey points out that further clarity on this hypothesis is needed and can only be gained through the high-quality research GW and other responsible organizations are conducting in both plant-derived and synthetic forms of cannabis-based medicines.
The biggest challenge with isolation of phytochemicals is the number of diverse compounds in the natural plant, MacKay observes. Techniques for extraction of natural cannabinoids have improved during the past decade, with advances occurring at an accelerated rate outside of the United States where research on these compounds can be pursued with fewer restrictions, he comments. A review of recent developments can be found in reference (6). “One of the critical factors of this increased success has been adherence to scientific principles and access to modern tools,” he adds.
For those cannabinoids that are produced via chemical synthesis, Cohen emphasizes that there are no unusual challenges to synthesizing novel compounds targeting the endocannabinoid system that are not faced during chemical synthesis of other complex small-molecule drug substances. As a rule of thumb, he mentions that this class of compounds tends to have solubility issues, but they are addressed with formulation and are generally manageable.
Cohen goes on to remark that, “Corbus’ hypothesis is that for the purposes of cannabinoid-related medical therapeutics (in contrast to the ‘wellness’ sector), it is imperative to have intellectual property protection and potency that is high and targeted. We believe that only rationally designed, synthetic, novel small molecules can achieve that.”
Managing the complexity of natural compounds and the concentration levels of each that exist in Cannabis plants is an important factor in developing potential drug products based on hundreds of metabolites that are present.
GW, according to Tovey, has designed its growing protocols and manufacturing facilities to ensure the highest quality of medicines with the goal of achieving consistent, standardized processes and products that comply with required regulations.
As an example, GW has invested in state-of-the-art facilities that include high-tech glasshouses that allow the company to control the entire growing environment for its plants, including the temperature, light, air quality, and moisture levels. Using lights and blinds in the glasshouses, it is possible to artificially adjust light exposure to ensure that plants rapidly reach an optimal size and control their flowering time, Tovey explains.
Whether cannabinoids are isolated from plants or produced chemically, careful analysis is required to ensure that the right molecules are included in the final product. With such complex matrices coming from the Cannabis plant and the potential to produce complex mixtures of various structural and stereoisomers during chemical synthesis, it is essential to use an array of complementary, advanced bioanalytical tools to ensure full characterization as well as to gain insights into their bioactivities and medicinal properties and conduct risk assessments (1).
Nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) methods have become increasingly useful in metabolomics analyses of cannabis-derived matrices (1,7). In addition, for phytochemicals, the modern analytical and concentration instruments used for natural product processing have application in natural cannabinoid product development, according to MacKay.
Supercritical fluid chromatography is, MacKay says, also well-suited to the challenge. “This technique allows high resolution of different compounds based on minor chemical properties differences. It is also used for the separation of enantiomers and diastereomers and is an essential medicinal tool for understanding enantiomeric excess.” He points to two papers as good examples of work done in this area (8,9).
Advanced analytics also facilitate structure-property relationship studies during development of cannabinoids with increased bioactivity and bioavailability. “Minor changes in the length of a carbon chain substituent or the addition of a hydroxyl group or hydrogenation of an unsaturated functionality can have different effects on the metabolism of cannabinoids. Analytical tools that can detect minor differences in chemical structures and different responses in the body are needed to perform these evaluations—a challenge that exists in drug development across all classes of compounds,” MacKay observes.
As previously alluded to, in the US, compounds that target the endocannabinoid system often fall under the auspices of the Controlled Substances Act (CSA). This issue is the biggest challenge to developing rationally designed cannabinoid derivatives, Cohen contends. “For compounds covered by the CSA, there are limited choices with respect to US-based contract research organizations (CROs) and contract development and manufacturing organizations (CDMOs) that have the permits necessary to handle and synthesize Schedule 1 compounds,” he explains. One way to avoid this problem is to use non-US-based service providers, because they typically do not have these issues.
It is important to remember that the cannabinoids being developed as therapeutic drug candidates are not the same as products developed for direct sale to consumers, whether those are CBD-based gummies or brownies containing Δ9-THC that are sold for medicinal use. The former must undergo the same rigorous development and approval process—whether plant-derived or synthetic—that is required for all regulated drug products.
“We believe that it is important to stress the difference between regulatory-approved cannabis-based medicines and other products that have not been through regulatory approvals, as non-regulatory approved cannabis-based products lack all or many of the important characteristics of a modern medicine since they are not rigorously tested and have not been scrutinised by regulators—we do not know their effect, side effects, correct dose, potential harm, and toxicology, amongst many other things,” Tovey notes.
Cannabinoids have been shown to have a wide range of pharmacological effects, including psychotropic, analgesic, anticancer, anti-inflammatory, antioxidant, antidiabetic, anticonvulsive, anti-glutamatergic, antibacterial and antifungal, and so on.
Consequently, the range of diseases for which cannabinoid-based drugs in development are targeting is expansive, and includes multiple sclerosis, scleroderma, Parkinson’s Disease, Huntington’s disease, cystic fibrosis, dermatomyositis, and systemic lupus erythematosus, and glaucoma, among others (10).
In addition to the few cannabinoids approved by FDA, there are several others progressing through the clinic. Corbus is developing synthetic candidates that target chronic inflammatory diseases that involve dysregulation of the immune system. Its lead candidate is lenabasum, which by binding to and activating the CB2 receptors on immune cells down-regulates the immune response and upregulates anti-inflammatory activity. This candidate is currently in a Phase III clinical trial in cystic fibrosis and Phase II study for systemic lupus erythematosus.
Emerald Health Pharmaceutical’s candidate EHP-101 for the treatment of systemic sclerosis completed a Phase I study in September 2019 and entered a Phase IIa study (delayed by COVID-19) in 2020. The company is also initiating a Phase II study in multiple sclerosis. The compound, an aminoquinone derivative of CBD, interacts with CB2 receptors and peroxisome proliferator-activated receptor γ (PPARγ), which is associated with neuroprotective effects (11). Emerald is also in preclinical development of a CBG derivative (EHP-102) for the treatment of brain disorders that affects pathways other than those that involve CB2 receptors.
Other cannabinoid derivatives in early development (preclinical or earlier) as potential therapeutics include SBI-100, previously THC-Val-HS (THCVHS, THC-valine hemisuccinate) and CBD-Val-HS (CBDVHS) from Skye Bioscience for glaucoma and possibly ocular, analgesic, neurologic, and anti-infective applications, respectively. SBI-100 is a Schedule 1 controlled substance, while CBDVHS is not. The addition of the valine hemisuccinate moiety helps improve the water solubility of THC and reduces the euphoria and intoxication associated with this psychoactive substance, according to a company spokesperson. The company is exploring the use of SBI-100 in eye drop formulations for the treatment of glaucoma and expects to complete its Phase I clinical trial evaluating the safety and tolerability of this candidate by mid-year. A Phase II clinical trial is anticipated to initiate there shortly after.
KLS-13019 from Neuropathix (previously Kannalife Sciences), a derivative of CBD designed to be more water soluble and thus more orally bioavailable, is intended for the treatment of certain types of pain and possibly chronic neurodegenerative diseases. In September 2021, Neuropathix received a $2.97 million Phase 2 STTR Study Grant from the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) to support the further development of KLS-13019 for chronic and neuropathic pain, specifically chemotherapy-induced peripheral neuropathy (12).
Volume 46, Number 2
When referring to this article, please cite it as C. Challener, “Synthesis, Extraction, and Purification of Cannabinoids,” Pharmaceutical Technology 46 (2) 2022.