Australian scientists have found a potential new way to improve the absorption rate of CBD when taken orally. A combination of sodium alginate microencapsulation method and deoxycholic acid (DCA) improved CBD brain delivery in mice by 40 times. In the future, the novel delivery method could be used to treat multiple sclerosis, Alzheimer’s disease, and other neurological disorders, as well as traumatic brain injuries.
According to the Atlas on Multiple Sclerosis published by the World Health Organization (WHO) in 2008, approximately 1.3 million people worldwide are diagnosed with MS. The countries reporting the highest estimated prevalence of MS are Hungary (176 per 100.000), Slovenia (150), Germany (149), United States of America (135), Canada (132.5), Czech Republic (130), Norway (125), Denmark (122), Poland (120), and Cyprus (110). This data doesn’t include information from Russia, so the actual total number of patients might be much higher.
The disease is more common among women than men. The onset of symptoms starts between 15 and 50 years of age, and the average age of diagnosis is 30. Multiple sclerosis is a disease of the immune system that targets the central nervous system (the brain and spinal cord) and the optic nerves. A fatty material that insulates nerves, called myelin, normally helps nerves transmit impulses rapidly and without conscious effort. In multiple sclerosis, there is a loss of myelin that appears in multiple places, which causes hardened sclerotic (scarred) areas. Also, the nerve fiber itself is affected and can degenerate.
The multiple sclerosis symptoms vary from patient to patient because they depend on the location of the lesions in the central nervous system. However, in 90% of the MS cases, at some point of the disease development, the patients experience spasticity. It can be as mild as the feeling of tightness of muscles or so severe as to produce painful, uncontrollable spasms of extremities, usually of the legs. It can also produce feelings of pain or tightness in and around joints and cause low back pain.
Cannabis-based MS drugs
The symptom of spasticity is the main MS symptom targeted by cannabis-based drugs. So far, the drug approved for the treatment of symptoms in patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti-spasticity medication is GW Pharmaceuticals’ nasal spray Sativex®. In this drug, each single 100 microlitre spray contains 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD) from Cannabis sativa L.
In June 2010, the UK Medicines and Healthcare products Regulatory Agency licensed Sativex® as a prescription-only drug for the treatment of spasticity due to multiple sclerosis. This authorization represented the world’s first full regulatory approval for this medicine. Since then, it was approved in several European countries, and in total in 25 countries in the world, including Australia and Canada.
However, Nabiximols, as this drug is called in the US, is still not approved in the States. After three positive phase 3 trials completed elsewhere, GW Pharmaceuticals has announced five new MS spasticity phase 3 trials in the US. The company said it was advancing multiple late-stage clinical programs in order to seek FDA approval for Nabiximols that would result in a clear path to the New Drug Application (NDA) submission. Apart from the drug for the treatment of spasticity associated with multiple sclerosis and spinal cord injury, the company has announced additional cannabinoid product candidates in clinical trials for autism and schizophrenia.
CBD for MS: Bioavailability is the key
CBD bioavailability is a measure of the rate and fraction of the initial CBD dose that successfully reaches either; the site of action or the bodily fluid from which the drug’s targets have access. In other words, CBD bioavailability is the proportion of CBD that enters the organ or the circulation when introduced into the body and the only proportion that has an active effect. The oral bioavailability of CBD in humans is very low (13–19%) as it undergoes extensive first-pass metabolism, and its metabolites are mostly excreted through the kidneys. In comparison, the CBD bioavailability in humans following smoking is 31%.
The bioavailability with nasal application is significantly higher than when CBD is taken orally. Research on guinea pigs and rats shows that the CBD intranasal absorption takes place within 10 minutes with a bioavailability of 34-46%. On the other side, transdermal application is also intriguing, with the proven 3.7-fold increasement in steady-state plasma concentration of CBD in the presence of an enhancer. The reaction to the enhancers is different between nasal and transdermal applications since bioavailability in the nasal application does not improve with the enhancers.
Obviously, there is a need for further research on the possibilities of using different ingredients in oral CBD formulations as enhancers that would enable a rise in their bioavailability.
Deoxycholic acid as a promising new enhancer
A new study published on the 17th of June in the journal PLOS ONE found that one of these enhancers is deoxycholic acid (DCA), a metabolite of chenodeoxycholic acid, a primary bile acid made from cholesterol in the human liver. The study found that DCA shows an increasing trend in uptake of CBD by up to 40 times within the brain, and can promote the neuroprotective efficacy of orally administered CBD, particularly for the treatment of neurodegenerative disorders.
This is the first study to show that the naturally occurring bile acid increases the uptake and retention of CBD within the brain, and could be used to enhance the delivery of CBD when taken orally, particularly when treating neurological disorders.
New drug delivery method
In the study, DCA was used in combination with a novel encapsulation method. Scientists from the Curtin University in Australia used sodium alginate, an extract from brown algae that is biocompatible, hydrophilic, non-toxic, and readily available for human use. As it is explained in the published study, these kinds of microcapsules provide a ‘physical’ barrier for volatile drugs such as CBD against exposure to light and air. Also, the previous studies have demonstrated that the sodium alginate microcapsules significantly increase the brain uptake and associated neuroprotective effects of highly lipophilic drugs, such as CBD. Furthermore, microencapsulation improves the therapeutic efficiency of lipophilic drugs by protecting against degradation due to low stomach pH and possible resistance due to efflux protein activity.
“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.”, said lead researcher, Associate Professor Ryu Takechi from the Curtin Health Innovation Research Institute (CHIRI) and the School of Population Health at Curtin University in Austalia in a press release.
Formulations and dosage
CBD used in this study was a 14.5% solubilized extract in MCT oil provided by the Australian company Zelira Therapeutics. Medium Viscosity Sodium Alginate (MVSA) (≥2,000 cP, 2% (25°C)), deoxycholic acid (DCA), and Calcium Chloride anhydrous (98%) were purchased from Sigma-Aldrich, (St Louis, MO, USA). Formulations were made up in HPLC-grade deionized water. Solutions containing 1.5% MVSA in 80 mL of HPLC-grade deionized water were mixed overnight. The CBD formulation was made by adding 800 μL of Miglyol 812N containing 109.24 mg CBD to the MVSA solution while protected from air and light and mixed for 3 days. The DCA formulation was made by adding 10 mg of DCA to a separate MVSA solution and mixed overnight. The MVSA solution and drug formulations were mixed at the same speed at room temperature.
The CBD and DCA formulations were encapsulated immediately after emulsification using the gelation technique with the vibrating Encapsulator B-390 by BUCHI Labortechnik, Switzerland. The microencapsulation technology utilized in this study was pioneered by Curtin University laboratory and has been adopted for enhanced lipophilic drug delivery in varied preclinical models of metabolic disorders.
Prepared formulations were projected into the 100 mM CaCl2 hardening bath, which stirred with a mild vortex, at a flow rate of 5 mL/minute and formed spherical microcapsule beads. After 10 minutes in CaCl2, microcapsules were sieved, rinsed with deionized water, and dried with a paper towel patted under the strainer. They were placed on a petri dish, covered, and dried completely at 37°C for 2.5 days. Microcapsules were analyzed and used for experimentation within 48 hours of drying.
The formulation that generated the most optimal, reproducible microcapsules was at 1.5% MVSA and 1% CBD. The microcapsules were spherical, and their size was 400±50 μm immediately post drying. The CBD capsules were white and their appearance remained consistent for 30 days at room temperature; followed by gradual discoloration with the capsules appearing brown, rough and shrived. Following the desiccation process, over 98% of capsulated CBD remained intact after exposure to the ambient air and light for 72 hours, indicating marked protection of CBD by the MVSA encapsulation.
Mice used in this study were healthy wild-type mice. They were orally administered 5 mg/kg weight CBD in oil by itself (naked CBD oil), in capsulation (CBD capsule), or capsulation with additional 4 mg/kg weight DCA capsules (CBD capsule + DCA capsule). CBD capsules were combined with DCA capsules at the time of administration. For better taste, the drugs were mixed in raspberry jam. The dosage of 5mg/kg used in this study is lower than the typically administered dosage of 20 mg/kg in previous studies.
The outcomes of this study indicate that MVSA encapsulation may protect CBD from oxidation, degradation by light, and acidic digestion within the stomach, enhancing the absorption through the GI tract and cumulative plasma bioavailability.
The study was funded by Zelira Therapeutics, an Australian pharmaceutical company focused on the development of cannabis-based products for a variety of medical conditions.