By: DSM Pharma Solutions Editors
Cannabidiol (CBD) is emerging as an exciting potential therapeutic ingredient in the pharmaceutical market. This has been powered by increasing scientific research investigating the role of CBD across a number of health areas, including central nervous system diseases (CNS), pain management, cancer, mood disorders, and more. However, bioavailability remains a significant challenge in CBD-based formulations, especially for oral delivery – the preferred choice for most patients.
With the number of CBD developments expected to rise across the pharmaceutical industry, there is an ever more urgent drive for manufacturers to address the technical challenges CBD brings. Read on to discover why lipid-based systems may help to overcome bioavailability challenges and optimize the success of CBD-based formulations.
Watch our Ask-the-Expert interview with Alex Zabara – Technology Platform Director, DSM – to explore the benefits of lipid-based systems in CBD innovation.
The low oral bioavailability of CBD – which is affected by both poor solubility and the first pass effect – is creating new opportunities for formulation optimization in the CBD space. Cannabinoids – including CBD – are highly lipophilic molecules (with a logP 6.3) and therefore have very low solubility in water (12.6 mg/L). If these factors are not considered during the oral formulation process, the absorption of CBD can be lower than intended in the final product. One systematic review exploring the pharmacokinetic data of CBD in humans concluded that the bioavailability of CBD after oral intake can be as low as 6% if it is not addressed properly.1
The molecule is also subject to first pass metabolism. The first pass effect is a phenomenon of drug metabolism whereby the concentration of a drug – specifically when administered orally – is greatly reduced before it reaches the systemic circulation. First pass metabolism usually occurs in the gut or liver and means that a large proportion of the drug does not reach the desired site of action. It is estimated that up to 75% of orally absorbed CBD is removed by hepatic metabolism before reaching systemic circulation.2
The first pass effect is likely to result in the incomplete gastrointestinal absorption of CBD, and means that the active ingredient may be needed in a large quantity to have any real therapeutic effect. Alternative routes of administration have been explored to overcome this, but these present their own challenges too. For example, inhalation routes can require complex equipment and there are sometimes difficulties associated with patient self-administration, especially when the need is acute and rapid, whereas sublingual drops exhibit 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 specifically. Addressing intrinsic solubility, for instance, may help to tackle the solubility aspect of poor bioavailability.
Lipid-based systems are a natural way to improve the solubility of molecules with high lipophilicity and low water solubility, like CBD. In this approach, the solubility of CBD in the lipid creates an overall solubilized formulation that avoids solid-state limitations for absorption. However, bioavailability can remain low if a molecule is also susceptible to first pass metabolism. Using lipid formulations that contain long-chain polyunsaturated fatty acid (LCPUFA) components – like docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – can help promote intestinal lymphatic absorption, over the normal hepatic portal system. This is because long-chain fatty acids encourage chylomicron production. These chylomicrons are transported into the blood stream, offering a path to bypass first-pass metabolism in the liver altogether. If lipophilic drugs are co-administered with these lipids (e.g., via lipid-based nanoparticles), they are incorporated into chylomicrons and can be delivered to the lymphatic system.
This approach has been used previously for effective lutein delivery.3 Here, DHA and EPA omega-3 LCPUFAs offered a superior in-vitro sustained release profile compared to conventional nano-emulsions.
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 integral to multiple bodily functions. DHA and EPA can also react with existing endocannabinoids to create omega-3-derived endocannabinoid epoxides, which were shown in academic literature to have powerful anti-inflammatory properties.4
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.
With the right partner, manufacturers can enter the CBD market early and with confidence, to build a leading position. DSM is a leader in lipid manufacturing, with an extensive nutritional lipids portfolio that meets the highest safety and quality requirements for use in a range of pharmaceutical applications. Plus, through our recent strategic partnership with CBD pioneer – Brains Bioceutical – we now also offer an innovation platform to help customers explore the therapeutic potential of CBD. Our expertise can help customers to overcome CBD bioavailability issues in conjunction with other formulation challenges, to expand treatment strategies and support patient health globally.
Together, let’s discover the innovation potential of CBD-based pharmaceuticals. Visit www.dsm.com/cbd-api to start the conversation.
21 January 2022
4 min read
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