Cannabidiol Bioavailability Research Articles

Rapeseed oleosomes facilitate intestinal lymphatic delivery and oral bioavailability of cannabidiol.

Due to high lipophilicity and extensive first-pass metabolic loss, cannabidiol (CBD) has low oral bioavailability. Co-administration of CBD and long-chain lipids facilitates the intestinal lymphatic delivery, resulting in higher systemic bioavailability, as well as high levels of the drug within the intestinal lymphatic system. However, despite previous attempts with various lipid-based formulations, the oral bioavailability of CBD is still limited. In this work, we have developed a novel formulation of CBD based on natural rapeseed oleosomes. In vivo studies in rats demonstrated that oral administration of CBD-loaded rapeseed oleosomes leads to substantially higher oral bioavailability and intestinal lymphatic targeting of CBD in comparison with rapeseed oil or artificial emulsion made of rapeseed oil and lecithin. In vitro mechanistic assessments, including in vitro lipolysis and peroxide value determination suggest that the lower oxidative state of the oil in oleosomes in comparison to crude oil or artificial emulsion is likely to be the main factor responsible for the superior performance of the CBD-loaded rapeseed oleosomes in vivo. Although further investigation will be needed, the data suggest that natural seeds-derived oleosomes can be used as a promising lipid-based drug delivery platform promoting the bioavailability and lymphatic delivery of lipophilic drugs.

Quantitative summary on the human pharmacokinetic properties of cannabidiol to accelerate scientific clinical application of cannabis.

Cannabidiol (CBD) is a non-psychoactive substance that exerts numerous pharmacological benefits, including anti-inflammatory and antioxidant properties. It has received attention as a useful substance for the treatment of intractable pain, seizures, and anxiety, and related clinical trials have continued. However, the CBD pharmacokinetic results between reports are highly variable, making it difficult to clearly identify the pharmacokinetic properties of CBD. The main purpose of this study was to identify CBD clinical pharmacokinetic properties through meta-analysis. In particular, we sought to derive valid, interpretable independent variables and interpret their pharmacokinetic parameter correlations in relation to the large inter-individual and inter-study variability in CBD pharmacokinetics. For this study, CBD-related clinical trial reports were extensively screened and intercomparisons were performed between internal data sets through systematic classification and extraction of pharmacokinetic parameter values. The candidate independent variables associated with interpretation of CBD pharmacokinetic diversity established and explored in this study were as follows: diet, tetrahydrocannabinol (THC) combination, sample matrix type, liver and renal function, exposure route, dosage form, CBD exposure dose, cannabis smoking frequency, multiple exposure. The results of this study showed that CBD pharmacokinetics were influenced (increased plasma exposure by approximately 2-5 times) by diet immediately before or during CBD exposure, and that THC was not expected to have an antagonistic effect on the CBD absorption. The influence of changes in liver function would be significant in CBD pharmacokinetic diversity. Due to decreased liver function, the plasma exposure of CBD increased 2.57-5.15 times compared to healthy adults, and the half-life and clearance showed a 2.58-fold increase and a 5.15-fold decrease, respectively. CBD can be rapidly absorbed into the body (time to reach maximum concentration within 3.18h) by oral, transdermal, and inhalation exposures, and lipid emulsification and nanoformulation of CBD will greatly improve CBD bioavailability (up to approximately 2 times). The pharmacokinetics of CBD generally follow linear kinetic characteristics. The importance of this study is that it suggests key factors that should be considered in terms of pharmacokinetics in further clinical trials and formulations of CBD in the future.

Enhanced oral bioavailability of cannabidiol by flexible zein nanoparticles: in vitro and pharmacokinetic studies.

Cannabidiol (CBD) has a variety of pharmacological effects including antiepileptic, antispasmodic, anxiolytic and anti-inflammatory among other pharmacological effects. However, since CBD is a terpene-phenolic compound, its clinical application is limited by its poor water solubility, low stability, and low bioavailability. In this study, we used several strategies to address the above problems. Hydrochloric acid was used to modify zein to improve the molecular flexibility. Flexible zein nanoparticles (FZP-CBD) loaded with CBD was prepared to improve the stability and bioavailability of CBD. The parameters were evaluated in terms of morphology, particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), loading capacity (LC%), and storage stability. Simulated gastrointestinal fluid release experiment and bioavailability assay were applied in the evaluation. The simulated gastrointestinal fluid experiment showed that the release rates of FZP-CBD and natural zein nanoparticles (NZP-CBD) loaded with CBD were 3.57% and 89.88%, respectively, after digestion with gastric fluid for 2 h, 92.12% and 92.56%, respectively, after intestinal fluid digestion for 2 h. Compared with NZP-CBD, the C max of FZP-CBD at 3 different doses of CBD was increased by 1.7, 1.3 and 1.5 times respectively, and AUC0-t was increased by 1.4, 1.1 and 1.7 times respectively, bioavailability (F) was increased by 135.9%, 114.9%, 169.6% respectively. The experimental results showed that FZP-CBD could protect most of the CBD from being released in the stomach, and then control its release in the intestines, promote the absorption of CBD in the small intestine, and increase the bioavailability of CBD. Therefore, FZP-CBD could improve the utilization value of CBD and provide a new idea for the application of CBD in medicine and pharmacy.

Enhanced oral bioavailability and in vitro evaluation of cannabidiol camel milk-derived exosome formulation in resistant MDA-MB-231 and MDA-MB-468 breast cancer cells

The potential of camel milk-derived exosomes (CMDE) to enhance the bioavailability of Cannabidiol (CBD) was investigated. CBD-CMDE formulation was prepared using an established procedure and its particle size was 138.4 ± 4.37 nm, and CBD entrapment efficiency of 56.56 ± 4.26 %. In-vitro release studies showed release of 78.27 ± 5.37 % and 46.42 ± 4.75 % CBD from CMDE and control CBD formulation respectively in pH 6.8 at 24 hr. The apparent permeability (Papp) of CBD-CMDE was found to be enhanced by 3.95-fold with Papp of 22.9*10-6 ± 0.34 cm/sec as compared to control CBD formulation with Papp of 5.8*10-6 ± 0.65 cm/sec in MDCK cells. CBD-CMDE was found to be more potent than CBD in 2D cytotoxicity assay with IC50 values of 3.6 ± 0.54 µM, 3.88 ± 0.54 µM and 7.53 ± 0.59 µM, 7.53 ± 0.59 µM against Doxorubicin (DOX) resistant MDA-MB-231 and Rapamycin (RM) resistant MDA-MB-468 breast cancer cells respectively. Moreover, 3D spheroids assay results demonstrated CBD-CMDE with IC50 values of 14 ± 0.85 µM, 15 ± 0.07 µM as compared to CBD alone with IC50 values of 25 ± 0.93 µM, 34.7 ± 0.08 µM in MDA-MB-231 DOX RT cells and MDA-MB-468 RM RT cells respectively. In-vivo PK studies showed enhanced bioavailability of CBD from CBD-exosomes with AUC(0-24h) of 1350.56 ± 187.50 h.ng/mL as compared to CBD control formulation with AUC(0-24h) of 351.95 ± 39.10 h.ng/mL with a single oral dose of 12 mg/kg. The data indicate that CMDE significantly improved the oral bioavailability of CBD. Overall, CMDE can be used to enhance the oral absorption of poorly bioavailable APIs.

Infant formula as a solid lipid dose form for enhancement of the oral bioavailability of cannabidiol for paediatric patients

Cannabinoids can save paediatric patients from harmful psychological conditions caused by epilepsy. However, the limited aqueous solubility of the drug presents a limitation to oral absorption and bioavailability. Previous studies have shown the enhancement of oral bioavailability for poorly water-soluble drugs using milk or milk-based products like infant formula as a novel lipid-based formulation, due to digestion of the lipids to enhance drug solubility that is particularly well suited to infants and in low economy settings. Therefore, this study has investigated the in vitro solubilisation enhancement of cannabidiol (CBD) in milk-based products during digestion using synchrotron small angle X-ray scattering, followed by pharmacokinetic studies to determine the relative oral bioavailability. The in vitro results, coupled with in vivo data, demonstrate a two-fold increase in the oral bioavailability of CBD in bovine milk as well as infant formula. The results of this study indicate the potential for infant formula to be considered as a novel formulation approach for CBD. Further study is encouraged for more drugs with infant formula to strengthen the correlation between the solubilisation of drug and their oral bioavailability.

Key Transdermal Patch Using Cannabidiol-Loaded Nanocarriers with Better Pharmacokinetics in vivo.

Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor solubility in water and low oral bioavailability. To harness the potential of CBD by combining it with a transdermal drug delivery system (TDDS). This innovative approach sought to develop a transdermal patch dosage form with micellar vesicular nanocarriers to enhance the bioavailability of CBD, leading to improved therapeutic outcomes. A skin-penetrating micellar vesicular nanocarriers, prepared using nano emulsion method, cannabidiol loaded transdermal nanocarriers-12 (CTD-12) was presented with a small particle size, high encapsulation efficiency, and a drug-loaded ratio for CBD. The skin permeation ability used Strat-M™ membrane with a transdermal diffusion system to evaluate the CTD and patch of CTD-12 (PCTD-12) within 24 hrs. PCTD-12 was used in a preliminary pharmacokinetic study in rats to demonstrate the potential of the developed transdermal nanocarrier drug patch for future applications. In the transdermal application of CTD-12, the relative bioavailability of the formulation was 3.68 ± 0.17-fold greater than in the free CBD application. Moreover, PCTD-12 indicated 2.46 ± 0.18-fold higher relative bioavailability comparing with free CBD patch in the ex vivo evaluation. Most importantly, in the pharmacokinetics of PCTD-12, the relative bioavailability of PCTD-12 was 9.47 ± 0.88-fold higher than in the oral application. CTD-12, a transdermal nanocarrier, represents a promising approach for CBD delivery, suggesting its potential as an effective transdermal dosage form.

Cannabidiol Bioavailability Is Nonmonotonic with a Long Terminal Elimination Half-Life: A Pharmacokinetic Modeling-Based Analysis.

Background: Oral and inhalation-based cannabidiol (CBD) administration has been clinically evaluated for various therapeutic indications, alongside widespread off-label use. However, the long-term exposure kinetics and varied bioavailability have not been fully characterized. Methods: Human CBD plasma concentration-time profiles from six studies evaluating the oral administration of Epidiolex® and three studies evaluating inhalation-based delivery were obtained. A four-compartment pharmacokinetic (PK) model with Weibull-based oral absorption kinetics was employed to describe the long-term PKs of CBD. Furthermore, a Cedergreen-Ritz-Streibig model was applied to evaluate nonmonotonic oral bioavailability. Results: CBD was extensively distributed into tissue compartments with varied kinetics resulting in a long plasma terminal elimination half-life of >134 h in humans. For once-a-day oral dosing, the plasma trough concentrations require >70 days to reach a steady state. The oral bioavailability of CBD for different doses administered in fasted state follows a nonmonotonic pattern with an inverted U-shaped profile. Oral administration of CBD under fed state or subjects with hepatic impairment yields higher oral bioavailability with varied exposure. In contrast, inhalation-based delivery of CBD, while delivering a similar systemic delivered dose compared with oral dosing due to high device losses, bypasses first-pass metabolism and can be efficient. Conclusion: CBD PKs vary across different doses due to nonmonotonic oral bioavailability, and inhalation-based delivery could minimize such variability in humans. The delayed attainment of steady state and prolonged terminal half-life, resulting from differential but extensive tissue distribution, needs to be considered when dosing CBD in the long term. These fundamental findings are critical for establishing dose-exposure relationship for further clinical evaluation of novel CBD-based therapies.

Enhancing transmucosal delivery of CBD through nanoemulsion: in vitro and in vivo studies.

Cannabidiol (CBD) has gained significant attention as a complementary and alternative medicine due to its promising therapeutic properties. However, CBD faces obstacles when administered orally due to its poor solubility in water, leading to limited absorption into the bloodstream and low and variable bioavailability. Therefore, the development of innovative delivery approaches that can enhance CBD's bioavailability, facilitate administration, and promote patient adherence is crucial. We propose a new approach for buccal delivery of CBD based on a self-assembling nanoemulsion (NE) made of a mixture of surfactants (Tween 80 and Labrasol) and medium chain triglycerides (MCTs). The NE formulation showed properties suitable for buccal administration, including appropriate size, CBD content, and surface properties, and, if compared to a CBD-MCT solution, it exhibited better control of administered doses, faster dissolution in buccal medium, and enhanced stability. The CBD-NE effectively released its active load within 5h, remained stable even when diluted in simulated buccal fluids, and could be easily administered through a commercially available spray, providing consistent and reproducible doses of NE with optimized properties. In vitro permeation studies demonstrated that the CBD-NE facilitated swift and consistent permeation through the buccal mucosa, resulting in a higher concentration in the acceptor compartment compared to CBD-MCT. Furthermore, the in vivo study in mice showed that a single buccal administration of CBD-NE led to a quicker onset of action than a CBD solution in MCT, while maintaining the same plasma levels over time and leading to typically higher plasma concentrations compared to those usually achieved through oral administration. In conclusion, our CBD-NE represents a promising alternative formulation strategy for buccal CBD administration, overcoming the challenges associated with conventional formulations such as variable bioavailability and low control of administered doses.

Absorption and Bioavailability of Novel UltraShear Nanoemulsion of Cannabidiol in Rats

Introduction: Cannabidiol (CBD) has several potential benefits and therapeutic uses, especially in pain, inflammation, and anxiety. CBD has high hydrophobicity and very low solubility in water. CBD has also shown exceptionally low oral-gastrointestinal (oral-GI) bioavailability. In this study, we aimed to examine the oral gastrointestinal absorption and subsequent bioavailability of CBD in a nanoemulsion formulation prepared by Pressure BioSciences’ UltraShearTM technology. Methods: CBD nanoemulsion (2%) was provided by Pressure BioSciences, Inc. (South Easton, MA), and CBD pharmacokinetic parameters were evaluated in male Sprague-Dawley rats using LC-MS/MS technology. Results: Bioavailability of orally delivered CBD UltraShear nanoemulsion was calculated to be 18.6% at 6 h and 25.4% at 24 h. While oral-GI bioavailability is unsurprisingly limited by first-pass metabolism, it is nonetheless notable that CBD bioavailability for oral-GI UltraShear nanoemulsion CBD is roughly 3–4x higher than the typical bioavailability for oral-GI CBD delivered in oil solution or conventional edible formats. Conclusion: This study has provided a compelling demonstration of unprecedented speed and efficiency of oral-GI CBD absorption of CBD UltraShear nanoemulsions, achieving 10% of levels achieved for direct IV injection within 30 min and 80% of IV levels in 24 h. Notably, within just the first hour post-administration, the bioavailability of oral CBD from UltraShear nanoemulsion formulation exceeded the typical 6% total CBD oral bioavailability benchmarks reported for CBD edibles and ultimately achieved 3–4X these levels within 6–24 h.

Current Challenges and Opportunities for Improved Cannabidiol Solubility.

Cannabidiol (CBD), derived from the cannabis plant, has gained significant attention due to its potential therapeutic benefits. However, one of the challenges associated with CBD administration is its low bioavailability, which refers to the fraction of an administered dose that reaches systemic circulation. This limitation necessitates the exploration of various approaches to enhance the bioavailability of CBD, thus helping to maximize its therapeutic potential. A variety of approaches are now emerging, including nanoemulsion-based systems, lipid-based formulations, prodrugs, nanocarriers, and alternative routes of administration, which hold promise for improving the bioavailability of CBD and pave the way for novel formulations that maximize the therapeutic potential of CBD in various medical conditions. This opinion piece presents the current understanding surrounding CBD bioavailability and considers strategies aimed at improving both its absorption and its bioavailability.

Archaeosomes facilitate storage and oral delivery of cannabidiol

Cannabidiol (CBD) has received great scientific interest due to its numerous therapeutic applications. Degradation in the gastrointestinal (GI) tract, first-pass metabolism, and low water solubility restrain bioavailability of CBD to only 6% in current oral administration. Lipid-based nanocarriers are delivery systems that may enhance accessibility and solubility of hydrophobic payloads, such as CBD. Conventional lecithin-derived liposomes, however, have limitations regarding stability in the GI tract and long-term storage. Ether lipid-based archaeosomes may have the potential to overcome these problems due to chemical and structural uniqueness. In this study, we compared lecithin-derived liposomes with archaeosomes in their applicability as an oral delivery system of CBD. We evaluated drug load, storage stability, stability in a simulated GI tract, and in vitro particle uptake in Caco-2 cells. Loading capacity was 6-fold higher in archaeosomes than conventional liposomes while providing a stable formulation over six months after lyophilization. In a simulated GI tract, CBD recovery in archaeosomes was 57 ± 3% compared to only 34 ± 1% in conventional liposomes and particle uptake in Caco-2 cells was enhanced up to 6-fold. Our results demonstrate that archaeosomes present an interesting solution to tackle current issues of oral CBD formulations due to improved stability and endocytosis.

Trial of a Novel Oral Cannabinoid Formulation in Patients with Hypertension: A Double-Blind, Placebo-Controlled Pharmacogenetic Study.

Cannabidiol (CBD) is a non-psychoactive cannabinoid, and available evidence suggests potential efficacy in the treatment of many disorders. DehydraTECH™2.0 CBD is a patented capsule formulation that improves the bioabsorption of CBD. We sought to compare the effects of CBD and DehydraTECH™2.0 CBD based on polymorphisms in CYP P450 genes and investigate the effects of a single CBD dose on blood pressure. In a randomized and double-blinded order, 12 females and 12 males with reported hypertension were given either placebo capsules or DehydraTECH™2.0 CBD (300 mg of CBD, each). Blood pressure and heart rate were measured during 3 h, and blood and urine samples were collected. In the first 20 min following the dose, there was a greater reduction in diastolic blood pressure (p = 0.025) and mean arterial pressure MAP (p = 0.056) with DehydraTECH™2.0 CBD, which was probably due to its greater CBD bioavailability. In the CYP2C9*2*3 enzyme, subjects with the poor metabolizer (PM) phenotype had higher plasma CBD concentrations. Both CYP2C19*2 (p = 0.037) and CYP2C19*17 (p = 0.022) were negatively associated with urinary CBD levels (beta = -0.489 for CYP2C19*2 and beta = -0.494 for CYP2C19*17). Further research is required to establish the impact of CYP P450 enzymes and the identification of metabolizer phenotype for the optimization of CBD formulations.

Cannabidiol-Loaded Poly Lactic-Co-Glycolic Acid Nanoparticles with Improved Bioavailability as a Potential for Osteoarthritis Therapeutic.

Cannabidiol (CBD) is a non-intoxicating cannabinoid from cannabis sativa that has demonstrated efficacious against inflammation, which can be considered as a potential drug for arthritis treatment. However, the poor solubility and low bioavailability limit its clinical application. Here, we report an effective strategy to fabricate Cannabidiol-loaded poly(lactic-co-glycolic acid) copolymer (CBD-PLGA) nanoparticles (NPs), with a spherical morphology and an average diameter of 238 nm. CBD was sustained release from CBD-PLGA-NPs, which improved the bioavailability of CBD. The CBD-PLGA-NPs effectively protect the damage of LPS to cell viability. We observed that CBD-PLGA-NPs significantly suppressed LPS-induced primary rat chondrocyte expression of inflammatory cytokines, including interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase 13 (MMP-13). Remarkably, CBD-PLGA-NPs also showed better therapeutic effects of inhibiting the degradation of the extracellular matrix of chondrocytes than equivalent CBD solution. In general, the fabrication CBD-PLGA-NPs showed good protection of primary chondrocytes in vitro and is a promising system for osteoarthritis treatment.

Digestion behavior, in vitro and in vivo bioavailability of cannabidiol in emulsions stabilized by whey protein-maltodextrin conjugate: Impact of carrier oil

An emulsion delivery system may be affected significantly by oil phase composition in terms of digestion behavior and bioavailability of the delivered substance. In this study, emulsions loaded with cannabidiol (CBD) were prepared with medium chain triglyceride (MCT), long chain triglyceride (LCT) or MCT/LCT(1:1) as carrier oil and whey protein-maltodextrin conjugate as emulsifier, and the digestion behavior of emulsion and bioavailability of CBD were assessed in vitro and in vivo. The particle size of emulsions throughout the in vitro digestion process was in the order of MCT < MCT/LCT < LCT, and three emulsions showed consistent particle size changes: stable in oral phase, sharply increased in gastric phase, and decreased in small intestine. After intestinal digestion, about 90% of free fatty acids (FFA) was released in MCT emulsion, followed by MCT/LCT (76%) and then LCT (45%). CBD was degraded during gastrointestinal digestion and the transformation stability of CBD in oil phase was in the order of LCT > MCT/LCT > MCT. Although CBD had higher bioaccessibility in MCT and MCT/LCT emulsions, the bioavailability of CBD in LCT was the highest (43%), followed by MCT/LCT (39%), MCT (33%). In vivo pharmacokinetic study showed that MCT/LCT and LCT were more favorable for CBD transport and absorption. The results may provide useful information for the construction of delivery systems, protecting CBD molecules, and improving their bioavailability.

Cannabidiol in canine epilepsy

The anticonvulsant effect of cannabidiol (CBD), which has been confirmed by findings from animal models and human trials, has attracted the interest of veterinary practitioners and dog owners. Moreover, social media and public pressure has sparked a renewed awareness of cannabinoids, which have been used for epilepsy since ancient times. Unfortunately, at this moment veterinarians and veterinary neurologists have difficulty prescribing cannabinoids because of the paucity of sound scientific studies. Pharmacokinetic studies in dogs have demonstrated a low oral bioavailability of CBD and a high first-pass effect through the liver. Administering CBD in oil-based formulations and/or with food has been shown to enhance the bioavailability in dogs, rats and humans. Tolerability studies in healthy dogs and dogs with epilepsy have demonstrated that CBD was safe and well tolerated with only mild to moderate adverse effects. In this context, it should be noted that the quality of available CBD varies widely, underscoring the importance of pharmaceutical quality and its control. One clinical trial in dogs with drug-resistant idiopathic epilepsy failed to confirm a difference in response rates between the CBD group and the placebo group, while in another cross-over trial a ≥ 50 % reduction in epileptic seizure frequency was found in six of 14 dogs in the treatment phase, a reduction that was not observed during the placebo phase. Based on the current state of knowledge it is not possible to provide clear-cut recommendations for the use of CBD in canine epilepsy. Randomized controlled canine trials with large sample sizes are needed to determine the range of therapeutic plasma concentrations, develop evidence-based dosing regimens, determine the efficacy of cannabidiol in drug-refractory epilepsy, and explore potential associations between treatment effects and different etiologies, epilepsy types, and drug combinations.

Pharmacokinetics of cannabidiol in a randomized crossover trial in senior horses.

To determine the pharmacokinetics, bioavailability, and pharmacological effects of cannabidiol (CBD) in senior horses. 8 university-owned senior horses. In this randomized, crossover study, horses were assigned to receive either a single oral dose of 2 mg/kg CBD in oil or a single IV dose of 0.1 mg/kg CBD in DMSO between August 10 and September 4, 2020. Blood samples were collected before and then 0.5, 1, 4, 8, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, and 264 hours after CBD administration. Serum biochemical analyses and CBCs were performed. Plasma concentrations of CBD and its metabolites were determined with the use of liquid chromatography-tandem mass spectrometry. Concentrations of CBD and metabolites (7-COH CBD and 7-COOH CBD) were detected in all plasma samples up to 8 hours after dosing (oral and IV), with 7-COOH CBD being the most predominant metabolite. Pharmacokinetic results for CBD oral dosing at 2 mg/kg were mean ± SD half-life of 7.22 ± 2.86 hours, maximum concentration of 18.54 ± 9.80 ng/mL, and time to maximum concentration of 2.46 ± 1.62 hours. For both oral and IV administrations, 7-COOH CBD did not fall below the limit of quantification for the times reported. Oral bioavailability for CBD was 7.92%. There was no meaningful effect of CBD on results for CBC, serum biochemical analyses, or vital signs for any horse. Pharmacokinetics and bioavailability of CBD in senior horses were determined, and there were no adverse effects of administering either the oral or IV dose of CBD evaluated.

Vegetable oils composition affects the intestinal lymphatic transport and systemic bioavailability of co-administered lipophilic drug cannabidiol

Although natural sesame oil has been shown to facilitate the lymphatic delivery and oral bioavailability of the highly lipophilic drug cannabidiol (CBD), considerable variability remains an unresolved challenge. Vegetable oils differ substantially in composition, which could lead to differences in promotion of intestinal lymphatic transport of lipophilic drugs. Therefore, the differences in composition of sesame, sunflower, peanut, soybean, olive and coconut oils and their corresponding role as vehicles in promoting CBD lymphatic targeting and bioavailability were investigated in this study. The comparative analysis suggests that the fatty acids profile of vegetable oils is overall similar to the fatty acids profile in the corresponding chylomicrons in rat lymph. However, arachidonic acid (C20:4), was introduced to chylomicrons from endogenous nondietary sources. Overall, fatty acid composition of natural vegetable oils vehicles affected the intestinal lymphatic transport and bioavailability of CBD following oral administration in this work. Olive oil led to the highest concentration of CBD in the lymphatic system and in the systemic circulation in comparison to the other natural vegetable oils following oral administration in rats.

Enhanced Intramuscular Bioavailability of Cannabidiol Using Nanocrystals: Formulation, In Vitro Appraisal, and Pharmacokinetics.

Cannabidiol (CBD) has poor water solubility and is subjected to extensive first-pass metabolism. These absorption obstacles are responsible for low and variable oral bioavailability of CBD. This study endeavored to improve CBD bioavailability by intramuscular (IM) injection of CBD nanocrystals (CBD-NC). The nanocrystals were prepared by antisolvent precipitation method and were characterized in terms of the particle size, polydispersity index (PDI), zeta potential, morphology, and crystalline status. CBD-NC displayed a particle size of 141.7±1.5 nm, a PDI of 0.18±0.01, and a zeta potential of -25.73 mV. CBD-NC freeze-dried powder using bovine serum albumin (BSA) as cryoprotectant had good redispersibility, and the average particle size was 139.1±1.4 nm after reconstitution. Moreover, these freeze-dried powders were characterized for drug loading and pH and were evaluated for in vitro dissolution and in vivo studies in a rat model. The in vivo results showed that AUC0-24 h and Cmax of CBD by IM injection of CBD nanocrystals increased significantly compared with that of oral (P.O) administration of CBD nanocrystals and CBD oil solution. This underlines the nano-sized CBD could be suggested as a practical and simple nanosystem for IM delivery with improved bioavailability. More importantly, these results pave the way for future development of CBD-NC retentive dosage forms. Graphical abstract.

Natural sesame oil is superior to pre-digested lipid formulations and purified triglycerides in promoting the intestinal lymphatic transport and systemic bioavailability of cannabidiol

Lipid-based formulations play a significant role in oral delivery of lipophilic drugs. Previous studies have shown that natural sesame oil promotes the intestinal lymphatic transport and oral bioavailability of the highly lipophilic drug cannabidiol (CBD). However, both lymphatic transport and systemic bioavailability were also associated with considerable variability. The aim of this study was to test the hypothesis that pre-digested lipid formulations (oleic acid, linoleic acid, oleic acid with 2-oleoylglycerol, oleic acid with 2-oleoylglycerol and oleic acid with glycerol) could reduce variability and increase the extent of the intestinal lymphatic transport and oral bioavailability of CBD. The in vivo studies in rats showed that pre-digested or purified triglyceride did not improve the lymphatic transport and bioavailability of CBD in comparison to sesame oil. Moreover, the results suggest that both the absorption of lipids and the absorption of co-administered CBD were more efficient following administration of natural sesame oil vehicle compared with pre-digested lipids or purified trioleate. Although multiple small molecule constituents and unique fatty acid compositions could potentially contribute to a better performance of sesame oil in oral absorption of lipids or CBD, further investigation will be needed to identify the mechanisms involved.

Comparison of Five Oral Cannabidiol Preparations in Adult Humans: Pharmacokinetics, Body Composition, and Heart Rate Variability

Data supporting the physiological effects of cannabidiol (CBD) ingestion in humans are conflicting. Differences between CBD preparations and bioavailability may contribute to these discrepancies. Further, an influence of body composition on CBD bioavailability is feasible, but currently undocumented. The aims of this study were to: (1) compare the pharmacokinetics of five oral CBD preparations over 4 h; (2) examine the relationship between body composition and CBD pharmacokinetics; and, (3) explore the influence of CBD on heart rate variability. In total, five preparations of CBD, standardized to 30 mg, were orally administered to 15 healthy men and women (21–62 years) in a randomized, crossover design. Prior to and 60 min following CBD ingestion, heart rate variability was determined. Body composition was assessed using dual energy X-ray absorptiometry. Peak circulating CBD concentration, time to peak concentration, and area under the curve was superior in a preparation comprising 5% CBD concentration liquid. Fat free mass was a significant predictor (R2 = 0.365, p = 0.017) of time to peak concentration for this preparation. Several heart rate variability parameters, including peak frequency of the high frequency band, were favorably, but modestly modified following CBD ingestion. These data confirm an influence of CBD preparation and body composition on CBD bioavailability, and suggest that acute CBD ingestion may have a modest influence on autonomic regulation of heart rate.