Abstract
Cannabidiol (CBD), a non-psychoactive cannabinoid, has shown therapeutic potential for treating inflammatory respiratory diseases such as chronic obstructive pulmonary disease and asthma. However, the therapeutic efficacy of CBD is limited by extensive hepatic metabolism and low oral bioavailability (approximately 20 %). These problems can be overcome by choosing an appropriate targeted drug delivery system. Delivering CBD to the lungs via a dry powder formulation could be an effective method to achieve adequate concentration and therapeutic efficacy. This study aims to develop a dry powder formulation of CBD with Inulin (INU) and L-leucine (LEC) using spray drying and to characterize its physicochemical and aerodynamic properties. A design of experiments (DOE) approach was used to optimize the formulation by varying feed concentration (0.2 % w/v to 0.8 % w/v), LEC concentration (5 % w/w to 20 % w/w), and CBD concentration (5 % w/w to 20 % w/w). The resulting CBD dry powder formulations exhibited a wrinkled morphology with particle sizes ranging from 1 to 5 µm and displayed a crystalline structure, as determined by powder X-ray diffraction. The response surface method (RSM) showed that increasing the feed concentration correlated with higher yields of the CBD formulations. Specifically, the formulation with a feed concentration of 0.8 % w/v achieved a yield of 61 %. The aerosolization data demonstrated a direct relationship between the Fine Particle Fraction (FPF) and LEC concentration, indicating that FPF increases as the LEC concentration increases. The highest FPF of 62 % was achieved with a 20 % w/w LEC concentration and a feed concentration of 0.2 % w/v. Based on this, LEC plays a crucial role in enhancing aerosolization efficiency. While feed concentration negatively affects FPF, lower feed concentrations lead to an increase in FPF. The Fine Particle Dose (FPD) varied with the concentration of CBD, with higher concentrations resulting in a higher FPD. A 28 days stability study under different humidity conditions (<15 % and 53 %) confirmed the stability of the CBD formulations. INU and LEC exhibited minimal cytotoxicity on A549 cells, while the raw CBD and CBD formulations showed comparable levels of cytotoxicity, pIC50 4.5 ± 0.3 and 4.2 ± 0.2. Interestingly, the CBD dry powder formulations significantly reduced inflammation (pEC50 = 4.9) induced by lipopolysaccharide (LPS). These findings suggest that an inhalable formulation of CBD, incorporating LEC and INU, has been successfully developed. The formulations demonstrated improved aerosolization properties, stability, and promising anti-inflammatory effects, potentially making them a viable therapeutic option for inflammatory lung diseases.