(W0930-03-14) A Journey Through the Development of Cannabidiol Solid Oral Dosage Forms: Balancing API Loading, Physico-Chemical Stability and In Vivo Pharmacokinetic Performance

Purpose: In the rapidly growing and evolving cannabinoid space, crafting more patient-centric pharmaceuticals that meet therapeutic needs and convenience is at the forefront of drug developers’ minds. The sector has a high potential for innovation, but there remains much to learn about cannabinoid ingredients and how to formulate them. Pharmaceutical manufacturers continue to face challenges due to the lipophilic nature of cannabinoid molecules and their limited solubility – attributes which significantly restrict the tools available for formulating this class of molecules. In addition to physical and chemical stability challenges, the oral bioavailability of crystalline CBD has been shown to be very low in humans (approx. 6%), due to incomplete absorption in the gut and significant pre-systemic elimination in the liver. The objective of this work was to systematically explore a number of drug delivery technologies, previously claimed to possess the ability to enhance the bioavailability of poorly soluble drugs and assess their effectiveness in increasing the pharmacokinetic profile of CBD, whilst ensuring a good physical and chemical stability of the API and sufficient drug loading to allow for a patient-compliant solution.

Methods: Initial use of standard oils (e.g., sesame oil, corn oil), needed to solubilize the crystalline API prior to subsequent formulation, revealed not only a solubility limit (typically around 40%) which limits the CBD loading in the finished drug product, but also a tendency of the API to recrystallize after the drying process. Therefore, to develop a patient-centric, stable CBD formulation (API loading > >10wt%) we screened many formulation technologies: encapsulation of a CBD nano-emulsion into a solid matrix, formation of amorphous dispersions by either hot melt extrusion or spray drying and encapsulation of CBD into liposomes and lipid nanoparticles. By using a combination of characterization techniques (e.g. DSC, XRD, DLS), in-vitro assays (Caco-2 cell assays) and animal models (Sprague-Dawley rat model) we strived to balance the physical properties of the formulated API with its in-vitro bioaccessibility profile and its in-vivo pharmacokinetic performance.

Results: Preliminary stability data (5°C, 25°C and 40°C) revealed that the formulated API is both chemically and physically stable for at least 6 months for all the evaluated technologies. Using in-vitro cell data, we were able to evaluate the effects of particle size, excipient choice/formulation method on the CBD bioaccessibility and implicitly select the optimal candidates for in-vivo bioavailability assessment. Finally, based on the in-vivo blood plasma levels, we were able to compare the pharmacokinetic behaviour of the CBD-containing solid dosage forms with a commercially available CBD oil and select the optimal candidates for further development and clinical testing.

Conclusion: The end results of our research will not only help improve the patient-centricity of CBD drug products, but also inform the pharmaceutical industry on the appropriate formulation for their intended applications, thereby enabling the industry to explore and expand upon the established therapeutic benefits of CBD more effectively.

References: 1. Koch, N. et al. Production challenges of tablets containing lipid excipients: Case study using cannabidiol as drug model, Int. J. Pharm. 633, 122639 (2013).
2. Fraguas-Sánchez, A.I. et al. Stability characteristics of cannabidiol for the design of pharma-cological, biochemical and pharmaceutical studies, J. Chromatogr. B, 1150, 122188 (2020).
3. Millar, S.A.; Maguire, R.F.; Yates, A.S.; O'Sullivan, S.E. Towards better delivery of cannabidiol (CBD), Pharmaceuticals (Basel), 3(9), 219 (2020).