(W1130-11-72) Formulation Development and Evaluation of Cannabidiol Hot Melt Extruded Solid Self-Emulsifying Drug Delivery System for Oral Applications

Purpose: CBD is a phytocannabinoid used globally for a variety of indications but with few approved medicinal applications. CBD is only approved in treatment-resistant, rare pediatric forms of epilepsy. It is a highly lipophilic compound with poor oral bioavailability, due to poor aqueous solubility and extensive first pass metabolism. Delivery of CBD to the site of action depends on the individual’s physiology and the drug’s physiochemical properties like solubility, dissolution and permeability. All these factors directly affect its bioavailability and lead to insufficient therapeutic efficacy and variable pharmacokinetic profiles. Hence, using lipid-based delivery systems, such as self-emulsifying drug delivery systems (SEDDS), is a viable strategy for highly lipophilic drugs such as CBD. The aim of this study was to explore the potential of employing Hot Melt Extrusion (HME) technology for the continuous production of Self Emulsifying Drug Delivery Systems (SEDDS) to improve the solubility and in vitro dissolution performance of CBD.

Methods: A series of different placebos were processed through Haake Mini Lab II hot melt extruder in order to obtain solid SEDDS formulation. Two selected SEDDS formulations (F1 and F2) were prepared with CBD, sesame oil, Poloxamer 188, Gelucire 59/14, PEO N80 and Soluplus^® mixed in predefined ratios (Table 1). The total batch size was 10 grams. The barrel temperature used was 90°C, and 100°C for F1 and F2 respectively and the screw speed was set at 50rpm. The SEDDS were examined visually for their emulsification time, droplet size, polydispersity index (PDI) and zeta potential measurements were used to assess homogeneity. To evaluate the physical state of CBD in the formulations, differential scanning calorimetry (DSC) was used.FTIR analysis of pure CBD, the physical mixtures, F1, and F2 was performed to evaluate the compatibilities between the excipients and CBD. PXRD was performed for the identification of crystallinity of the prepared SEDD’s. Tests for content uniformity and in vitro drug release were performed. Furthermore, the formulations were subjected to stability studies for 60 days at 25 °C and 40 °C. Samples were observed for physical appearance and analyzed for droplet size measurement, drug content, and in vitro drug release.

Results: The CBD-loaded SEDDS were prepared using a 10% w/w drug load in the final formulations. The extrudates produced from HME were frozen using liquid nitrogen and then milled to be used for the different studies. Emulsification time for relative emulsification of the formulations indicated that F1(9.19±0.02 minutes) showed shorter emulsification time compared to F2(9.30±0.03). The formulations had a particle size of 366±4.5 nm and 185.0±3.1nm for F1and F2. The small particle size (20–500 nm) of the final emulsions would allow for effective drug absorption via the lymphatic route. DSC analysis showed that pure CBD exhibited a sharp endothermic peak at 67 °C due to the crystallinity of the CBD. Further verification of CBD conversion from the crystalline state to the amorphous state was confirmed using PXRD. The extruded CBD filaments did not show the characteristic peaks of CBD, suggesting the transformation of the crystalline state of the drug into the amorphous state. Moreover, both formulations demonstrated CBD content, 99.9±1.1 for F1 and 96.3±1.3 for F2(Table 2). These results indicated that the mixing and HME processing conditions helped in the preparation of uniform formulations. The in vitro dissolution test showed CBD release with F1 and F2 releasing 90% and 83% of their content in the first hour, respectively while the pure drug showed only 14.7% release(Figure 1). Although both the formulations showed signs of physical degradation during the accelerated stability testing, the formulation F1 had drug content within the acceptable limits and the dissolution profile for F1 remained unaffected.

Conclusion: CBD loaded SEDDS were prepared by HME. SEDDS formulation showed enhanced physiochemical characteristics. In addition, all developed formulations improved the CBD dissolution rate compared to the pure drug. The formulation(F2) showed physical degradation as well decrease in dissolution rate when tested for stability at 30- and 60-day time point. Further investigation is required to optimize the formulation and asses the stability of the formulation. In conclusion, the study demonstrated that SEDDS could be a promising oral drug delivery vehicle for CBD.

References: 1.Salehi, A.; Puchalski, K.; Shokoohinia, Y.; Zolfaghari, B.; Asgary, S. Differentiating Cannabis Products: Drugs, Food, and Supplements. Front Pharmacol 2022, 13, 906038, doi:10.3389/fphar.2022.906038.
2. Morozowich, W.; Gao, P. Chapter 19 - Improving the Oral Absorption of Poorly Soluble Drugs Using SEDDS and S-SEDDS Formulations. In Developing Solid Oral Dosage Forms; Qiu, Y., Chen, Y., Zhang, G.G.Z., Liu, L., Porter, W.R., Eds.; Academic Press: San Diego, 2009; pp. 443–468 ISBN 978-0-444-53242-8.
3. Wagh, M.P.; Singh, P.K.; Chaudhari, C.S.; Khairnar, D.A. Solid Self-emulsifying Drug Delivery System: Preparation Techniques and Dosage Forms.

Acknowledgements: We are grateful to Dr. Mahmoud A. ElSohly for providing the CBD and Dr. Mohamed M. Radwan for his valuable advice and guidance.

Table 1.Formulation Composition of CBD Loaded SEDDS

Table 2.Stability Drug Content Analysis for F1 and F2.

Figure 1.Stability Dissolution Studies; (A) F1, F2 and CBD at Day 0; (B) F1 and F2 at 25°C, Day 30; (C) F1 and F2 at 40°C, Day 30; (D) F1 at 25°C and 40°C, Day 60