(T1230-11-71) Development of Cannabidiol-Loaded Nanostructured Lipid Carriers as an Approach for Potential Solubility Enhancement

Purpose: In the pharmaceutical field, Cannabidiol (CBD) has recently generated a lot of interest due to its various pharmacological activities and lack of psychoactive effects. However, developing CBD formulations is challenging due to its low aqueous solubility and susceptibility to first-pass metabolism, which negatively impact its bioavailability. The primary objective of this ongoing research is to enhance the aqueous solubility of CBD through the creation of nanostructured lipid carriers (NLCs). Two methods were used to prepare CBD NLCs: Hot Melt Extrusion (HME) and conventional hot homogenization (CHH). A comparative study was conducted to evaluate the two methods.

Methods: Lipid-based drug delivery systems have shown great potential as oral carriers for poorly water-soluble drugs, as they can enhance solubility and improve oral bioavailability. Nanostructured lipid carriers (NLCs) are developed by combining solid and liquid lipids, and offer advantages over solid lipid nanoparticles (SLNs), such as greater drug entrapment capacity, improved drug release properties, and requiring less stabilizers. In this study, CBD NLCs were developed using the conventional hot homogenization (CHH) method with 2% w/w CBD and different lipid/surfactant ratios. Compritol 888 ATO and sesame oil were used as the solid and liquid lipids, respectively, with tween 80 as the surfactant to decrease particle size and stabilize the system. The lead formulation (CBD NLC5), which also were prepared by HME, was selected based on the lowest particle size and stability over one month. . Probe sonication was used to decrease the particle size for both methods. To characterize the developed CBD NLCs, particle size (PS), polydispersity index (PDI), and zeta potential (ZP) were evaluated using light scattering (Malvern Instruments, Inc). HPLC was used to determine drug content (DC) and entrapment efficiency (EE), while drug release was assessed using dissolution USP apparatus II in pH 7.4 + 0.1% tween 80 media at 50 rpm and 37°C. Stability studies were conducted at two different temperatures (4°C and 25°C).

Results: Out of the nine CBD NLC formulations prepared using the CHH method, two formulations (CBD NLC5 and CBD NLC9) were deemed the most stable based on drug content (DC), entrapment efficiency (EE), particle size (PS), and polydispersiy index (PDI) (Table 1). Additionally, CBD NLC5 was produced using the Hot Melt Extrusion (HME) method as a continuous process. The results showed no significant difference between CBD NLC5 prepared using the HME and CHH techniques in terms of DC, EE, and PS (Table 2). The EE was 99.23% and 98.91% for CBD NLC5-CHH and CBD NLC5-HME, respectively. Both formulations released over 90% of the CBD within 30 minutes (Figure 1). NLC5-CHH remained stable at both 4°C and 25°C for 90 days, whereas NLC5-HME exhibited a decrease in DC from 96.5% to 93.5% and 88% at 4°C and 25°C, respectively, after 60 days. In NLC5 CHH, the quantity of CBD released remained constant for 60 days, while in NLC5 HME, the quantity of CBD released decreased by 7%. This decrease in the release percentage is linked to the decrease in EE in NLC5 HME, which dropped from 98.9% to 89.8%, while in NLC5 CHH, the EE remained unchanged. It was observed that CBD NLC prepared by HME coupled with probe sonication was more stable than the one with HME alone which may be due to the higher homogeneity of the emulsion after sonication., however it did not reduce the particle size anymore.

Conclusion: CBD NLCs were effectively produced using both CHH and HME methods, with no significant differences observed between the two methods on day zero. The release study demonstrated an improvement in CBD dissolution compared to pure CBD, which supports the hypothesis that CBD solubility can be enhanced. HME was utilized as a continuous and easily scalable method to create NLCs with small particle sizes. This finding holds promise for improving CBD's water solubility, and consequently its oral bioavailability by boosting the solubility as well as the potential of lymphatic absorption and preventing first-pass metabolism. More optimization for the HME process is needed to improve the long-term stability of the prepared CBD NLC.

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Acknowledgements: We would to thank Coy Waller lab in the University of Mississippi for the collaboration and providing CBD.

Table.1 Results of evaluation tests for NLC1, NLC2, NLC3, NLC4, NLC5, NLC6, NLC7, NLC8, and NLC9.

Table.2 Comparison between NLC5 prepared by CHH and HME in terms of DC, EE, PS, PDI, and ZP.

Figure.1 Drug release results for NLC5 prepare by CHH and HME compared to pure CBD showing no significant difference between both methods in increasing CBD dissolution.