用于治疗慢性阻塞性肺疾病的可吸入大麻二酚干粉的制备及体外特性研究
Preparation and in vitro characterization of inhalable cannabidiol dry powder for treating chronic obstructive pulmonary disease.
作者信息
Komal Komal, Chen Shuli, Hanton Lyall R, Glass Michelle, Das Shyamal C
机构信息
School of Pharmacy, University of Otago, Dunedin, New Zealand.
Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
出版信息
Int J Pharm. 2025 Jun 25;682:125892. doi: 10.1016/j.ijpharm.2025.125892.
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, pIC 4.5 ± 0.3 and 4.2 ± 0.2. Interestingly, the CBD dry powder formulations significantly reduced inflammation (pEC = 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.
大麻二酚(CBD)是一种无精神活性的大麻素,已显示出治疗炎性呼吸道疾病(如慢性阻塞性肺疾病和哮喘)的潜力。然而,CBD的治疗效果受到广泛肝脏代谢和低口服生物利用度(约20%)的限制。通过选择合适的靶向药物递送系统可以克服这些问题。通过干粉制剂将CBD递送至肺部可能是实现足够浓度和治疗效果的有效方法。本研究旨在使用喷雾干燥法开发一种含有菊粉(INU)和L-亮氨酸(LEC)的CBD干粉制剂,并表征其物理化学和空气动力学性质。采用实验设计(DOE)方法,通过改变进料浓度(0.2% w/v至0.8% w/v)、LEC浓度(5% w/w至20% w/w)和CBD浓度(5% w/w至20% w/w)来优化制剂。所得的CBD干粉制剂呈现出皱纹形态,粒径范围为1至5 µm,并通过粉末X射线衍射确定显示出晶体结构。响应面法(RSM)表明,进料浓度的增加与CBD制剂的更高产率相关。具体而言,进料浓度为0.8% w/v的制剂产率达到61%。雾化数据表明细颗粒分数(FPF)与LEC浓度之间存在直接关系,表明随着LEC浓度的增加FPF增加。在LEC浓度为20% w/w且进料浓度为0.2% w/v时,实现了最高62%的FPF。基于此,LEC在提高雾化效率方面起着关键作用。虽然进料浓度对FPF有负面影响,但较低的进料浓度会导致FPF增加。细颗粒剂量(FPD)随CBD浓度而变化,较高浓度导致更高的FPD。在不同湿度条件(<15%和53%)下进行的28天稳定性研究证实了CBD制剂的稳定性。INU和LEC对A549细胞表现出最小的细胞毒性,而原料CBD和CBD制剂表现出相当水平的细胞毒性,pIC分别为4.5±0.3和4.2±0.2。有趣的是,CBD干粉制剂显著降低了脂多糖(LPS)诱导的炎症(pEC = 4.9)。这些发现表明,已成功开发出一种包含LEC和INU的可吸入CBD制剂。这些制剂表现出改善的雾化性质、稳定性和有前景的抗炎作用,可能使其成为炎性肺病的一种可行治疗选择。