Strategies for enhancing the oral bioavailability of cannabinoids

ABSTRACT

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.

KEYWORDS:

• Absorption enhancer
• bioavailability
• cannabinoids
• CBD
• chylomicrons
• cyclosporine
• first pass metabolism
• LBDDS
• lymphatic absorption
• piperine
• SNEDDS
• THC

Article highlights

• A set of absorption barrier must be tackled to enhance the bioavailability of cannabinoids. The major obstacles include the low water solubility of the cannabinoids, as well as being highly subjected to the hepatic first pass metabolism.

• The main strategy to overcome the solubility issue is by using lipid-based formulations. One of the most promising types of these formulations is the self-micro/nano emulsifying drug delivery system (SMEDDS/SNEDDS).

• To overcome the metabolism barrier, addition of an ‘absorption enhancer’ such as piperine to enhance the bioavailability of cannabinoids as an improving strategy is discussed.

• The cannabinoids CBD and THC are subjected to unique interplay within the enterocytes that dictates that a certain percentage will be delivered via the lymphatic absorption pathway. It evolves from their affinity for chylomicrons that are produced in the enterocytes.

• The interplay between the lymphatic absorption pathway and the portal vein-hepatic pathway is influenced by the fed/fasting state and by the content of the meal. Piperine-SNEDDS formulations of these cannabinoids have elevated bioavailability in both states.

• Understating of the absorption barriers cascade is crucial for the development and selection of the delivery system for lipophilic drugs, such as cannabinoids, to enhance their bioavailability.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.