A team of researchers led by Curtin University has discovered a new way to improve the absorption rate of medicinal cannabis when taken orally, which could potentially be used to treat neurological disorders such as Alzheimer’s disease, multiple sclerosis and traumatic brain injuries in the future.
Published in the journal PLOS ONE and funded by industry partner Zelira Therapeutics, the researchers were able to create tiny capsules containing cannabinoids which, when taken orally, were absorbed by the body faster and penetrated the brain quicker in mice models with neurological diseases, than when it was delivered in liquid form.
Lead researcher, Associate Professor Ryu Takechi from the Curtin Health Innovation Research Institute (CHIRI) and the School of Population Health at Curtin University, said there has been a growing interest in the use of cannabidiol to treat various neurological diseases, but there are limitations due its poor absorption and sensitivity to light and stomach acid when consumed orally.
“Cannabidiol is found in medicinal cannabis and is a popular natural remedy for people living with neurological and metabolic diseases. Due to limitations in absorption, we aimed to design and test a new drug delivery method,” Associate Professor Takechi said.
“Our team was able to significantly improve the absorption and brain delivery of cannabidiol by administering it in a novel microcapsule form, in combination with a naturally occurring bile acid.
“With this new capsulated form, we were able to improve the brain delivery of cannabidiol remarkably by 40 times in animal models and we were also able to protect the drug from oxidation and degradation by light, which helps extend product shelf-life.”
Associate Professor Takechi said the findings may be helpful in supporting the clinical use of medicinal cannabis in the treatment of neurological disorders.
“In this study, we were able to show for the first time that a bile acid actually increased the uptake and retention of cannabidiol within the brain. This shows that bile acids, could be used to enhance the delivery of cannabidiol when taken orally, particularly when treating neurological disorders,” Associate Professor Takechi said.
“Further research is needed to test whether this type of drug delivery method could be successful in human studies, but our findings are very promising.”
Zelira CEO Dr Oludare Odumosu said he was delighted with the outcome of the collaboration with Associate Professor Takechi and his team.
“The new encapsulation technology appears to significantly improve the efficiency with which cannabinoid-based drugs can be delivered into the brain. This could lead to improvements in the effectiveness of cannabinoid therapies to treat neurological disorders while reducing cost and enhancing safety,” Dr Oludare Odumosu said.
This research was a collaborative effort involving researchers from CHIRI, the Curtin Medical School and the School of Population Health at Curtin University, the University Newcastle and the University of Otago.
Methods
Microcapsules containing either CBD or DCA were formed using the ionic gelation method with 1.5% sodium alginate formulations and 100 mM calcium chloride. C57BL/6J wild type mice randomly assigned to three treatment groups (3–4 mice per group) were administered CBD in the following preparations: 1) CBD capsules, 2) CBD capsules + DCA capsules and 3) naked CBD oil (control). To assess the short-term bioavailability of CBD, plasma and brain samples were collected at 0.3, 1 and 3 hours post administration and CBD levels were analysed with liquid chromatography mass spectrometer.
Results
We produced spherical capsules at 400 ± 50 μm in size. The CBD capsules were calculated to have a drug loading of 2% and an encapsulation efficiency of 23%. Mice that received CBD capsules + DCA capsules showed a 40% and 47% increase in CBD plasma concentration compared to mice on CBD capsules and naked CBD oil, respectively. Furthermore, the CBD capsules + DCA capsules group showed a 48% and 25% increase in CBD brain concentration compared to mice on CBD capsules and naked CBD oil, respectively.
In mice treated with CBD capsules + DCA capsules, the brain CBD concentration peaked at 0.3 hours with a 300% increased availability compared to CBD capsules and naked CBD oil groups, which peaked at 1 hour after administration.
Conclusions
The microencapsulation method combined with a permeation enhancer, DCA increased the short-term bioavailability of CBD in plasma and brain.
Cannabidiol (CBD) is a potent non-psychoactive constituent in marijuana (Cannabis sativa) with no reported intoxicating effects unlike tetrahydrocannabinol (THC) [1]. CBD binds to receptors CB1, CB2 and 5HT1A to modulate cellular activity and inhibit excitotoxicity [2].
The anti-inflammatory and antioxidant properties of CBD have been reported across numerous pathologies, including neurodegenerative and metabolic diseases. Studies show that repeated administration of CBD may be neuroprotective in animal models of Alzheimer’s disease via decreasing microglial activation and attenuation of memory deficits [3].
Furthermore, activation of the endocannabinoid system has been shown to preserve the cerebral capillary endothelium that forms the blood brain barrier (BBB) [4, 5] and exert therapeutic effects in animal models of diabetes [6].
CBD is highly lipophilic, sensitive to light and largely broken down in the duodenum resulting in extremely low oral bioavailability in plasma and tissues (approximately 6% and 1%, respectively) [7]. Whilst chronic usage of CBD is clinically well tolerated, its lability poses limitations for use in research and adaptation as a pharmacotherapy [8]. Therefore, emerging studies have focused on encapsulation techniques that function as a vehicle for CBD [9].
Sodium alginate is an extract from brown algae that is biocompatible, hydrophilic, non-toxic and readily available for human use. The alginate cross-links with multivalent ions like Ca2+ to form stable hydrogel polymers under mild aqueous conditions [10]. Thus, calcium alginate microcapsules provide a ‘physical’ barrier for volatile drugs such as CBD against exposure to light and air in pharmacological protocols.
Previously, our studies have demonstrated that sodium alginate microcapsules significantly increase the brain uptake and associated neuroprotective effects of probucol—the highly lipophilic, antilipidemic drug [11]. Subsequent studies of ours confirmed that microencapsulation improves therapeutic efficiency of lipophilic drugs by protecting against degradation due to low stomach pH and efflux protein activity in the intestinal epithelium [12, 13].
The use of absorption enhancers is yet another method of improving bioavailability in drug delivery research. Deoxycholic acid (DCA) is a metabolite of chenodeoxycholic acid, a primary bile acid made from cholesterol in the liver in humans [14]. Bile acids have amphiphilic properties and primarily function as surfactants in the body. DCA is among several secondary bile acids to be utilised in pharmacokinetic research as a permeation-modifying biomolecule [15].
Specifically, lipophilic drugs with low intestinal dissolution rates have shown improved absorption when administered with DCA [16]. Bile acids promote aqueous solubility and increase fluidity of phospholipid membranes, making them ideal candidates for BBB permeability experiments [16].
A report from our lab showed that co-encapsulation with a DCA variant improved the targeted-delivery effects of probucol [12]. However, there is a relative paucity of studies focusing on the permeation effects of DCA on CBD absorption. The fundamental challenges of administering DCA alongside a labile drug such as CBD with minimal exposure to the environment and impost on experimental animals have yet to be resolved.
In this study, we utilised the established sodium alginate microencapsulation method to develop CBD capsules and assess the abundance of CBD in plasma and brain samples of wild-type mice. Furthermore, we administered CBD capsules alongside DCA capsules to examine the blood-to-brain kinetics of CBD in conjunction with a permeation enhancer.
The study captured CBD absorption at three time points leading up to- and immediately post its peak concentration to elucidate the short-term effects of our drug excipients. The findings of this study may provide a potential avenue for improving the penetrance of CBD in models of neurodegeneration.
Original Research: Open access.
“Sodium alginate microencapsulation improves the short-term oral bioavailability of cannabidiol when administered with deoxycholic acid” by Ryu Takechi et al. PLOS One
