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October 26, 2022 - 3 min read
Cannabinoid-based medicines like CBD have a rich future, with much preclinical research underway, and a full pipeline of valuable pharmaceutical drugs. Companies will need to overcome some remaining challenges in drug deliverability, however, particularly in the oral solid form, the manner of consumption familiar and convenient to most patients.
CBD is a tricky drug to optimize for delivery. It is unstable, for one thing. It degrades with temperature, light, and auto-oxidation. This last does not occur in oil preparations, which is why drugs like Epidiolex® and Sativex are suspended in sesame seed oil and ethanol, or ethanol anhydrous, propylene glycol and peppermint oil. Successful delivery of any drug also depends on its inherent solubility, dissolution capability, and permeability. Bioavailability varies greatly with route and mode of administration.
CBD, being highly lipophilic, can precipitate in the gastrointestinal tract if delivered in solution, resulting in an absorption rate slower than elimination. The same may be true even if, instead of being swallowed, the drug is administered by oromucosal spray. There is evidence that it precipitates there too, and in the end still absorbs (slowly) in the GI tract. One way around this is to take CBD with a high-fat meal. This has been tested, and appears to work, probably because of increased micelle and chylomicron formation, which could make more drug available for lymphatic transport. High fat meals may also inhibit drug efflux transporters on the apical membrane of enterocytes. Another way is to smoke or vaporize the drug. This too has been demonstrated, with deuterium-labelled CBD. Delivery this way is rapid, and very large. The general disadvantage is that smoke and vapor irritate airways. Other delivery modes are under investigation, including transdermal and eye-drop preparations.
A more basic problem exists, and it is a commonplace in translational medicine. That is the likely occurrence of differing crystalline structures of the same chemical compound due to crystallisation conditions. This variability in molecular conformation is spoken of as ‘polymorphism’. Polymorphic iterations of a drug have identical chemical composition, and will demonstrate the same chemical behavior once in solution, but will perform differently in clinical use. It is an acknowledged issue in drug development, and regulatory agencies have issued guidance on how to control for it, or how to justify using polymorphic forms in drug products. CBD has been shown to exist in at least two inherent crystalline forms, with different profiles for absorption and bioavailability. To date, there have been no studies assessing possible implications for CBD development in solid-state form with polymorphisms in mind.
Altogether new strategies for CBD medicines with better pharmacokinetic profiles are needed. Broadly speaking, the ones in development are self-emulsifying drug delivery systems, improved single crystal structures, and CBD co-crystals.
Self-emulsifying drugs increase bioavailability by increasing solubility. The idea is to allow more CBD to cross the water layer in the GI tract and move into lymphatic or blood circulation. These involve cocktails of oils, surfactants, and solvents that produce nano or micro sized droplets, whose small size increase the surface area available for drug dissolution and absorption. There can be chemical instabilities with this method, though, and preparations with high surfactant concentrations can irritate the GI tract. Some hydrophilic components can also diffuse into the shells of gelatine capsules, again causing precipitation in the gut. Lipophilic molecules like CBD do not lend themselves well to this delivery mode.
Improvements to the single crystal form of CBD are a better tack. Modifying intramolecular crystal lattice binding between ions within a crystal lowers the crystal’s melting point. Reducing lattice energy like this can increase aqueous solubility. PureForm CBD™ is produced with this approach, a molecularly identical, non-hemp-derived CBD developed with a proprietary Inter-Molecular Stacking Technology, for improved solubility and stability.
Co-crystallization, the third novel development strategy, is becoming well established. Here, the active pharmaceutical ingredient partners with one or more crystalline co-formers that modify the material properties while retaining the intrinsic pharmacological activity. This can change a drug’s bioavailability, solubility, dissolution rate, physical form, melting point, stability, or permeability. It can make drug preparations easier to render into tablet form. It’s also a way of bundling preservatives, other drugs, or pharmaceutical excipients.
DiolPure products contain PureForm CBD™ transformed from aromatic terpenes for pharmaceutical-grade purity. PureForm CBD™ is bioidentical to CBD extracted from hemp and cannabis, but free of any residual cannabinoids like THC or impurities or chemicals that can associate with traditional plant-derived production processes.
The foregoing is a report on trends and developments in cannabinoid industry research. No product description herein is intended as a recommendation for diagnosis, treatment, cure or prevention of any disease or syndrome.
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