(M1230-05-29) Employing Hot Melt Extrusion and Vacuum Compression Molding to Develop Cannabidiol Solid Sedds for Improved Solubility

Purpose: Cannabidiol (CBD) is a highly lipophilic drug, with extensive first pass metabolism and poor aqueous solubility, meaning it has low bioavailability when ingested orally. Other factors that affect the delivery of CBD to the site of action include the patient’s physiology and the drugs inherent physiochemical properties including dissolution and permeability. Lipid based drug delivery systems, such as self-emulsifying drug delivery systems (SEDDS) can be used as a viable option for highly lipophilic drugs such as CBD. These systems provide several advantages when taken orally, including enhanced permeability, reduced first pass metabolism, and greater drug solubility. SEDDS are multicomponent systems consisting of an oil, a surfactant, and a co-surfactant. SEDDS spontaneously transform into emulsions upon slight agitation - caused by peristaltic movement of the stomach - when they encounter the digestive fluids in the gastrointestinal tract, thereby increasing the solubility of the drug. The purpose of the current study was to investigate the applications of two advanced processing techniques - hot melt extrusion and vacuum compression molding - to produce solid SEDDS for improving the solubility of CBD.

Methods: The selection of excipients was done by performing a preliminary screening study, in which the solubility of CBD was evaluated in different oils, lipids and surfactants, by adding 100 mg of CBD to 1000 mg of excipients. The mixtures were heated and cooled to room temperature and examined visually for precipitated drug particles. The drug excipient mixtures that did not show any signs of precipitation were selected for the saturation solubility study. The saturation solubility study was performed on separately for the solid and liquid excipients. DSC analysis was used for the solid excipients and HPLC analysis was used for the liquid excipients. The oil and surfactants having the highest amount of solubility were selected for the final formulation. Central composite design was used to prepare a series of placebo formulations having different concentrations of oil surfactant and co-surfactant, which were then processed through HME and VCM. The formulation having the shortest particle size and emulsification time was selected as the lead formulation and 10% drug loading was done for the same formulation. The solid SEDDS obtained were examined visually for their emulsification time. Particle size (PS), polydispersity index (PDI) and zeta potential measurements were carried out using a Zetasizer (Nano ZS Zen3600, Malvern Panalytical Inc., Westborough, MA, USA) to assess homogeneity of the emulsion formed. Moreover, various characterization tests were performed to evaluate the solid SEEDS formulations. The physical state of CBD in the SEDDS formulations was evaluated using differential scanning calorimetry (DSC). To assess the compatibility of the excipients and CBD, FTIR analysis was done on pure CBD, the physical mixture and the formulations. Tests for content uniformity and in vitro drug release were conducted on the formulations prepared using HME and VCM.

Results: The CBD loaded SEDDS produced from HME and VCM were allowed to cool at room temperature before used for further testing. The emulsification test revealed that the HME formulation had a shorter emulsification time of 53±1.4 seconds as compared to 80±0.8 seconds for the VCM formulation (Table 1). This result can be attributed to the smaller particle size of the HME formulation (537.2±16.2 nm) as comparted to the VCM formulation (847±20.83 nm). DSC analysis revealed that pure CBD had an endothermic peak at 67°C due to its crystalline nature, however in both the formulations this peak was absent indicating that the CBD was miscible with other excipients (Figure 1). The drug content in both formulations was, 99.8%±2.0 for HME and 97.6%±1.5 for VCM formulation (Table 1). The in vitro dissolution test demonstrated that both the processing methods enhanced the release rate of the drug. While the VCM formulation had 80±1.8% release in three hours the HME formulation had 76±3.6% release, as compared to the pure drug which only had 26±0.9% release in 3 hours (Figure 2).

Conclusion: In conclusion both processing methods, HME and VCM were used successfully to develop solid SEDDS for CBD. The formulated solid SEDDS showed improved physiochemical characteristics. In addition, both HME and VCM SEDDS formulations improved the dissolution rate of CBD by at least 2-fold as compared to the pure drug. Therefore, the study demonstrated that both processing methods could be used to develop solid SEDDS for CBD with enhanced solubility.

References: 1. Khan AA, Mudassir J, Mohtar N, Darwis Y. Advanced drug delivery to the lymphatic system: lipid-based nanoformulations. IJN. 2013 Jul 26;8(1):2733–44.
2. Shadambikar G, Kipping T, Di-Gallo N, Elia AG, Knüttel AN, Treffer D, et al. Vacuum Compression Molding as a Screening Tool to Investigate Carrier Suitability for Hot-Melt Extrusion Formulations. Pharmaceutics. 2020 Nov;12(11):1019.
3. Uttreja, P.; Youssef, A.A.A.; Karnik, I.; Sanil, K.; Narala, N.; Wang, H.; Elkanayati, R.M.; Vemula, S.K.; Repka, M.A. Formulation Development of Solid Self-Nanoemulsifying Drug Delivery Systems of Quetiapine Fumarate via Hot-Melt Extrusion Technology: Optimization Using Central Composite Design. Pharmaceutics 2024, 16, 324. https://doi.org/10.3390/pharmaceutics16030324


Figure 1. DSC thermogram of CBD, Gelucire® 50/13, Physical mixture, HME and VCM formulation.


Figure 2. In vitro Dissolution profile of pure CBD, HME and VCM formulation.


Table 1. Data for Emulsification time, DS,PDI, ZP and Drug Content for HME and VCM formulation (mean±SD, n=3).