DSM CBD lab copy

Scientist pipetting samples into micro centrifuge tubes ready for automated analysis. Image courtesy of DSM.

Cannabidiol (CBD) is fast emerging as an exciting ingredient across the pharmaceutical market, powered by increasing scientific research investigating its potential benefits in a number of disease states, including central nervous system (CNS) disorders, pain management, cancer and more. While there is a remarkable opportunity for the development of CBD-based solutions in the field, formulation can be challenging at times, especially when the focus is on increasing the oral bioavailability of the molecule. There are new and emerging ways to address the technical challenges associated with CBD bioavailability and enable the molecule to fulfill its full potential as a therapeutic agent. Here, we explore how lipid-based systems may hold the key to success in this space.

Understanding the complexity of CBD formulation

Oral bioavailability — simply defined — is a measure of the quantity of drug absorbed into the systemic (blood) circulation following oral administration of the drug. The oral bioavailability of CBD has been shown to be very low in humans, as a result of incomplete absorption in the gut and significant presystemic elimination in the liver. It is paramount to understand and control these inherent obstacles to address the challenge of bioavailability when formulating with the molecule.

1. Incomplete gastrointestinal absorption

The very low solubility of CBD in water (12.6 mg/L) is largely due to the fact that cannabinoids – including CBD – are highly lipophilic molecules with a logP of 6.3. Consequently, they cannot be readily absorbed when taken orally. To prevent a CBD-based solution not reaching market because of its compromised absorption, and therefore poor bioavailability and ineffectiveness, it is vital that a high percentage of the dose is absorbed in the gut and reaches the blood circulation. From there, the drug can travel to its site(s) of action, where it will have a therapeutic effect.

2. Extensive presystemic metabolism 

Like most drugs, CBD passes through the liver when administered orally before reaching the systemic circulation. Many molecules undergo some extent of enzymatic metabolism in the liver – also known as the first pass effect. Because of this process, a proportion of the drug is eliminated prematurely and does not reach the desired site of action. However, CBD is subject to significant pre-systemic metabolism in the liver. In fact, it is estimated that up to 75% of orally absorbed CBD is removed by hepatic metabolism before reaching systemic circulation. This means that a large concentration of CBD is removed before it even reaches its site(s) of action.

There is currently no available published data demonstrating the absolute oral bioavailability of the only FDA/EMA-approved CBD formulation (a 100mg/mL oral solution in a sesame-oil based vehicle). However, one systematic review exploring the pharmacokinetic data of CBD in humans concluded that absolute oral bioavailability of the molecule after intake is approximately only 6%. This is similar to the oral bioavailability of tetrahydrocannabinol (THC) – the most abundant cannabinoid in the cannabis plant well-known for producing a ‘high’ sensation.

As a result of its complex pharmacokinetics, CBD is classified as a BCS (Biopharmaceutics classifications system) class 2 drug, i.e. a poorly water-soluble and highly permeable pharmaceutical. Additionally, CBD is categorized as a BDDCS (Biopharmaceutics Drug Disposition classification system) class 2 compound, indicating it is a poorly water-soluble drug that is eliminated by metabolism.

How does CBD bioavailability influence formulation?

Since 70-75% of CBD is thought to be metabolized by the liver and the absolute bioavailability of the drug is around 6%, it can be concluded with high certainty that gastrointestinal absorption of CBD is significantly insufficient.

Alex Zabara, technology platform director at DSM explains: “This means that the active ingredient is needed in a large quantity to have any real therapeutic effect. Increasing the dose might help overcome these issues, but even though CBD has a favourable toxicity profile, this approach could potentially result in increased drug-drug interactions and undesirable side effects. Alternative routes of administration have been explored too, but these present their own challenges. For example, inhalation routes can require complex equipment and there are sometimes difficulties associated with patient self-administration. Sublingual drops are an option too, but this format exhibits challenges related to taste.”

As such, formulators continue to seek solutions that will help to improve the bioavailability of CBD, and ultimately minimize the overall quantity of drug substance required in oral formulations. In simple terms, an optimal formulation strategy will address CBD bioavailability in multiple ways:

  • Improve dissolution in the gut.
  • Increase the absorption across the gut wall.
  • Reduce the extent of first-pass metabolism.

The potential role of lipid-based solutions

Lipid-based drug delivery systems offer a natural approach to improving the bioavailability of molecules with low water solubility, like CBD. This well-established technology works by transporting active ingredients through the gastrointestinal tract, into the lymphatic or blood circulation and to the target area(s) in the body without the drug degrading; thus, increasing its bioavailability.

For example, lipid encapsulation and liposomal delivery of fat-soluble actives are already well-established strategies for enhancing the bioavailability of poorly soluble compounds because they create an overall solubilized formulation that protects the active ingredient until it reaches systemic circulation. However, bioavailability can still remain low if a molecule is susceptible to first pass metabolism.

“Using lipid formulations that contain long-chain unsaturated fatty acid (LCPUFA) components – like docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – can help promote intestinal lymphatic absorption, over the normal hepatic portal system, because long-chain fatty acids encourage chylomicron production. Simply put, the chylomicrons are transported into the bloodstream, offering a path to bypass first-pass metabolism in the liver altogether,” continues Alex. “Additionally, the use of long chain saturated and unsaturated lipids was recently proposed by McClements, whose paper states that solubilization capacity increases as the chain length of the fatty acid increases, enhancing the bio-accessibility of hydrophobic bioactives by modulating the size of the mixed micelles formed during digestion.”

Although they need to be tested in CBD formulations specifically, lipid-based delivery systems could therefore help improve the solubility and absorption of the drug. This approach has been used previously for effective lutein delivery. It is interesting to note that in the study, DHA and EPA LCPUFAs offered a superior in-vitro sustained release profile compared to conventional nano-emulsions.

Benefits of LCPUFAs beyond bioavailability

The benefits of DHA and EPA in CBD-based innovation extend beyond bioavailability too. Omega-3 LCPUFAs are also involved in the synthesis of endocannabinoids – cannabinoids that are naturally produced in the body. These endocannabinoids send signals between nerve cells and are involved in multiple bodily functions. DHA and EPA act as precursors of omega-3-derived endocannabinoid epoxides, which have powerful anti-inflammatory properties.

Successful formulations begin with quality raw ingredients

Alex Zabara

Alex Zabara

CBD research is full of promise in the pharmaceutical industry, and there are many opportunities for novel developments in the space. However, the market is still in its infancy and significant technical challenges are facing formulators looking to innovate with the ingredient.

Before beginning any product development with CBD, it is critical to start with ingredients and raw materials that have been thoroughly tested and validated to be of the highest purity and quality. To guarantee this, it is essential for developers to partner with suppliers that are knowledgeable in CBD extraction and testing methods, the variability the molecule brings and that have the formulation and technical expertise to overcome any challenges that arise.

Alex Zabara is the technology platform director at DSM.