Sodium alginate microencapsulation improves the short-term oral bioavailability of cannabidiol when administered with deoxycholic acid

Background Cannabidiol (CBD) confers therapeutic effects in some neurological disorders via modulation of inflammatory, oxidative and cell-signalling pathways. However, CBD is lipophilic and highly photooxidative with low oral bioavailability in plasma and brain. In this study, we aimed to design and test a CBD microencapsulation method as a drug delivery strategy to improve the absorption of CBD. Additionally, we evaluated the brain uptake of CBD capsules when administered alongside capsules containing a permeation-modifying bile acid, deoxycholic acid (DCA). 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.

[1]  H. Al‐Salami,et al.  Pharmacological and Advanced Cell Respiration Effects, Enhanced by Toxic Human-Bile Nano-Pharmaceuticals of Probucol Cell-Targeting Formulations , 2020, Pharmaceutics.

[2]  H. Al‐Salami,et al.  Alginate-based drug oral targeting using bio-micro/nano encapsulation technologies , 2020, Expert opinion on drug delivery.

[3]  H. Al‐Salami,et al.  Micro-Nano formulation of bile-gut delivery: rheological, stability and cell survival, basal and maximum respiration studies , 2020, Scientific Reports.

[4]  Hesham S. Al-Sallami,et al.  Bile acid bio-nanoencapsulation improved drug targeted-delivery and pharmacological effects via cellular flux: 6-months diabetes preclinical study , 2020, Scientific Reports.

[5]  I. McGregor,et al.  Pharmacokinetics of Phytocannabinoid Acids and Anticonvulsant Effect of Cannabidiolic Acid in a Mouse Model of Dravet Syndrome. , 2019, Journal of natural products.

[6]  Hesham S. Al-Sallami,et al.  Probucol-poly(meth)acrylate-bile acid nanoparticles increase IL-10, and primary bile acids in prediabetic mice. , 2019, Therapeutic delivery.

[7]  Xiangdong Li,et al.  Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model. , 2019, Environmental toxicology and pharmacology.

[8]  S. O'Sullivan,et al.  A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans , 2018, Front. Pharmacol..

[9]  N. Pavlović,et al.  Bile Acids and Their Derivatives as Potential Modifiers of Drug Release and Pharmacokinetic Profiles , 2018, Front. Pharmacol..

[10]  H. Al‐Salami,et al.  Sodium alginate capsulation increased brain delivery of probucol and suppressed neuroinflammation and neurodegeneration. , 2018, Therapeutic delivery.

[11]  S. Oliaro-Bosso,et al.  Cannabinoid Delivery Systems for Pain and Inflammation Treatment , 2018, Molecules.

[12]  M. Kaur,et al.  Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies , 2018, Cardiovascular Diabetology.

[13]  Sangeeta Rao,et al.  Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. , 2018, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[14]  F. Grotenhermen,et al.  An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies , 2017, Cannabis and cannabinoid research.

[15]  Michael Bazelot,et al.  Molecular Targets of Cannabidiol in Neurological Disorders , 2015, Neurotherapeutics.

[16]  P. Rakesh,et al.  Alginate Beads Prepared by Ionotropic Gelation Technique: Formulation Design , 2015 .

[17]  Hesham S. Al-Sallami,et al.  Novel artificial cell microencapsulation of a complex gliclazide-deoxycholic bile acid formulation: a characterization study , 2014, Drug design, development and therapy.

[18]  G. Cabral,et al.  Marijuana use and brain immune mechanisms. , 2014, International review of neurobiology.

[19]  J. Chiang Bile acid metabolism and signaling. , 2013, Comprehensive Physiology.

[20]  I. McGregor,et al.  Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice , 2012, PloS one.

[21]  P. Pacher,et al.  The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications. , 2012, The American journal of pathology.

[22]  B. Platt,et al.  Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive–compulsive behaviour , 2011, Psychopharmacology.

[23]  A. M. Martín-Moreno,et al.  Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer's Disease , 2011, Molecular Pharmacology.

[24]  J. Martínez-Orgado,et al.  Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study , 2011, Journal of Neuroinflammation.

[25]  Yong Zhang,et al.  PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel , 2010, Comput. Methods Programs Biomed..

[26]  L. Liaudet,et al.  Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. , 2007, American journal of physiology. Heart and circulatory physiology.

[27]  L. Chan,et al.  Microencapsulation of oils using sodium alginate. , 2000, Journal of microencapsulation.

[28]  M. Feldmann,et al.  The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.