INTRODUCTION: Oral administration of cannabinoids is a convenient route of administration in many cases. To enhance the poor and variable bioavailability of cannabinoids, selected strategies utilizing proper delivery systems have been designed. Low solubility in the GI aqueous media is the first and most critical barrier. Thereafter, cannabinoids can reach the systemic blood circulation via the portal vein that is associated with significant hepatic first pass metabolism (FPM) or bypass it via lymphatic absorption. AREAS COVERED: The solubility obstacle of cannabinoids is mainly addressed with lipid-based formulations such as self-nanoemulsifying drug delivery systems (SNEDDS). Certain lipids are used to overcome the solubility issue. Surfactants and other additives in the formulation have additional impact on several barriers, including dictating the degree of lymphatic bioavailability and hepatic FPM. Gastro-retentive formulation is also plausible. EXPERT OPINION: Comparison of the role of the same SNEDDS formulation, cyclosporine vs. cannabinoids, when used to elevate the oral bioavailability of different compounds, is presented. It illustrates some similarities and major mechanistic differences obtained by the same SNEDDS. Thus, the different influence over the absorption pathway illuminates the importance of understanding the absorption mechanism and its barriers to properly select appropriate strategies to achieve enhanced oral bioavailability.

Apomorphine (APO), a potent treatment for Parkinson's disease, is only administered parenterally either as intermittent injections or as an infusion. This is due to extensive hepatic “first pass” metabolism. Prolonged delivery through buccal mucosa may be potential substitute for parenteral infusions. To investigate this concept of buccal mucosal delivery, permeability ex vivo studies were performed through excised porcine buccal mucosa by utilizing Ussing diffusion chamber. Permeability rates were assessed for APO from simulated saliva medium at pH 7.4 as well as with utilization of different permeability modifying methods. Lowering the pH to 5.9 decreased permeability rate six-fold, while addition of ethanol: propylene glycol solution elevated it four-fold. Addition of nano-scale lipospheres to the donor compartment delayed the accumulation of APO at the receiver side, prolongating the lag-time from one to approx. three hours. These findings were strengthened by results obtained with co-administration of permeability markers (standards) atenolol and metoprolol. Simulation of the obtained permeability rates to in vivo setup in human showed therapeutically relevant plasma levels when using the outcomes of the current study. These findings verify the novel concept of APO prolonged release buccal administration as a noninvasive substitute for parenteral infusions in treating Parkinson's disease. © 2020

Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6), which is metabolically stable and has the potential to become a peripheral painkiller being a full μ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6), we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6). © Copyright © 2020 Talhami, Swed, Hess, Ovadia, Greenberg, Schumacher-Klinger, Rosenthal, Shalev, Hurevich, Lazarovici, Hoffman and Gilon.

The aim of this research was to investigate the effect of the lipid component in self-emulsifying drug delivery systems on the oral absorption of major cannabinoids Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD). The investigated lipids were either long chain triglycerides (LCT) or medium chain triglycerides (MCT) with different composition, fatty acid chain length, degree of saturation and their absorption pathway to the systemic circulation. Formulations were developed with the purpose of creating thermodynamically stable oil-in-water nano emulsions/suspensions with particle size of 50 nm or less which carry the lipophilic drug and increase water solubility. Following a methodic screening of suitable excipients in-vitro, leading formulations based on sesame oil or MIGLYOL® 812N (Type I LCT/MCT SNEDDS) and cocoa butter or tricaprin (Type II LCT/MCT SNEDDS) were investigated in the freely moving rat model. Results in rat model demonstrated that the effect of each type of lipid on bioavailability of cannabinoids is not straightforwardly anticipated. The differences in the effect of LCT and MCT on absorption was not substantial for Type I formulations, however, more prominent for Type II formulations. This unpredictable behavior in-vivo demonstrates the importance of investigating each vehicle pre-clinically, following the in-vitro development. © 2020 Elsevier B.V.

Piperine is an alkaloid naturally found in black pepper with a myriad of pharmacological attributes. Piperine's most far reaching indication is drug absorption enhancment, with supportive data regarding its ability to inhibit first pass effect mechanisms. However, alongside these findings, the role of piperine as an absorption enhancer is undermined with publications stating an apparent effect of a metabolic inducer. The aim of this work is to investigate the effect of repeated administration of piperine in a lipid-based formulation, on oral absorption of cannabidiol (CBD), compared to acute piperine dosing. The effect of piperine on CBD absorption was determined pre-clinically in the freely moving rat model. Results of this work demonstrated that there was no significant difference in piperine's effect, when given chronically or in a single dose regimen. Both groups resulted in approximate 2.5-fold increase in oral bioavailability of CBD compared to control group without piperine. © 2020 Elsevier B.V.

The cannabis plant has been widely researched for many therapeutic indications and found to be effective in many chronic conditions such as epilepsy, neuropathic or chronic pain and more. However, biased opinion against compounds of the plant, regulatory as well as compounding challenges have led to very few approved cannabinoid medicinal products. Those formulations which are approved are dosed several times a day, creating an unmet need for controlled release (CR) formulations of cannabinoids. Conventional CR formulations rely on prolonged absorption of the drug, including absorption from the colon. The purpose of this work is to investigate regional absorption of major cannabinoids THC and CBD from the colon and develop a suitable CR formulation. As hypothesized by researchers, THC and CBD have poor absorption from the colon compared to small intestine, suggesting that these compounds have a narrow absorption window. The suggested CR formulation examined in-vitro was a floating gastro retentive tablet based on egg albumin matrix, gas generating agents and surfactants. In-vivo investigation of CBD containing formulation in the freely moving rat model proved a prolonged absorption phase with a substantial increase in bioavailability compared to CBD solution. The findings of this paper answer a crucial question regarding potential application of CR dosage forms for cannabinoids and shed light on the regional intestinal absorption of these compounds. Ultimately, these results cement the way for future development of cannabinoid gastro retentive dosage forms. © 2020 Elsevier B.V.

Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of scientific research. The reasons behind this popularity is the compound's therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration. The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers. The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS). Administration of CBD in lipid-based vehicles resulted in a significant increase in Cmax and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile. Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid pharmacokinetics. © 2020 Elsevier B.V.

Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and “first pass“ metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract. © 2020 Elsevier B.V.

Lipid-based drug delivery systems have been vastly investigated as a pharmaceutical method to enhance oral absorption of lipophilic drugs. However, these vehicles not only affect drug bioavailability but may also have an impact on gastric emptying, drug disposition, lymphatic absorption and be affected by lipid digestion mechanisms. The work presented here compared the pharmacokinetic (PK) behavior of the non-intoxicating cannabinoid cannabidiol (CBD) in sesame oil vs. a self-nano emulsifying drug delivery system (SNEDDS). This investigation was conducted with a unique tool termed the "absorption cocktail approach". In this concept, selected molecules: metoprolol, THC, and ibuprofen, were coadministered with CBD in the SNEDDS and sesame oil. This method was used to shed light on the complex absorption process of poorly soluble drugs in vivo, specifically assessing the absorption kinetics of CBD. It was found that the concentration vs. time curve following CBD-sesame oil oral administration showed extended input of the drug with a delayed Tmax compared to CBD-SNEDDS. Using the "cocktail"approach, a unique finding was observed when the less lipophilic compounds (metoprolol and ibuprofen) exited the stomach much earlier than the lipophilic cannabinoids in sesame oil, proving differential absorption kinetics. Findings of the absorption cocktail approach reflected the physiological process of the GI, e.g., gastric retention, stomach content separation, lipid digestion, drug precipitation and more, demonstrating its utility. Nonetheless, the search for more compounds as suitable probes is underway. © 2020 American Chemical Society.

Introduction: Sativex® spray is clinically utilized to deliver delta9-tetrahydrocannabinol and cannabidiol to oral mucosa for systemic absorption. We challenge the consensus that the mechanism of absorption following the oro-mucosal application occurs via the buccal tissue. Areas covered: Correctness of the consensus of this absorption pathway arose when reviewing publications regarding the influence fed versus fasting states have on pharmacokinetics of these cannabinoids administered to the oral mucosa. This finding is more suitable for peroral administration, where stomach content affects the absorption profile. We hypothesize that these cannabinoids are ingested and absorbed in the gastrointestinal tract. Expert opinion: Although clinical importance of Sativex® is not disputed, the wide acceptance of its being a successful example of drug delivery through oral mucosa is questionable. Sativex® acts as an example for other drugs delivered to oral mucosa for systemic absorption and unintentionally washed by the saliva flow into the gastrointestinal tract. Delivery of each medicine through oral mucosa should be validated in-vivo to ensure this route to be the predominant one. Revealing the underlying absorption mechanisms would enable predicting the impact of different physiological parameters such as saliva flow and fed/fasting states on the pharmacokinetics of the delivered medication. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Myeloid differentiation primary response 88 (MyD88) is an intracellular adaptor protein central to the signaling of multiple receptors involved in inflammation. Since innate immune inflammation promotes autoimmunity, MyD88 is an attractive target in autoimmune disease. We previously developed c(MyD 4-4), a novel cyclic peptide competitive inhibitor of MyD88 dimerization that is metabolically stable. Parenteral administration of c(MyD 4-4) reduces disease severity in a mouse model of the human autoimmune disease multiple sclerosis. We now show that N-terminal myristoylation of c(MyD 4-4) enhances the competitive inhibition of MyD88 dimerization in living cells, leading to improved inhibition of the Toll-like receptor and IL-1 receptor signaling. Importantly, myristoylation converts c(MyD 4-4) to an orally bioavailable inhibitor of MyD88. Oral administration of c(MyD 4-4) significantly lowered the inflammatory cytokines secreted by peripheral autoimmune T cells in mice immunized with myelin antigens and ameliorated disease severity in the mouse model of multiple sclerosis. Taken together, we show the conversion of a protein active region to a metabolically stable, selective cyclic peptide that is orally bioavailable. © 2019 American Chemical Society.