PDF(Pubmed)
Abstract：
Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 µm (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4-4.5 µm), fine particle fraction (56-71%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations.
摘要：
慢性阻塞性肺疾病和囊性纤维化等肺部炎症普遍存在，可能致命，特别是当它们的特征是异常的粘液积累。吸入的皮质类固醇通常用于肺部炎症，尽管它们有相当大的副作用。通过利用粒子工程技术，开发了包含纳米尺寸的酮洛芬包埋的甘露醇包衣的微粒的组合干粉吸入器(DPI)。纳米嵌入的微粒系统通过增强局部肺部沉积同时避免清除机制，意味着肺部递送的新进步。酮洛芬,一种难溶于水的抗炎药，分散在稳定剂溶液中，然后用ultraturrax均化。在此之后,含酮洛芬的纳米悬浮液是通过湿介质研磨生产的。此外，用L-亮氨酸(分散增强剂)和甘露醇(包衣和粘膜活性剂)进行共喷雾干燥。粒度,形态学,溶出度,渗透，粘度,体外和硅沉积，细胞毒性，和抗炎作用进行了研究。含酮洛芬的纳米悬浮液的粒度为〜230nm。喷雾干燥粉末的SEM图像显示出皱纹，涂层,和接近球形的颗粒，最终尺寸为〜2μm（纳米在微米），这是肺部分娩的最佳选择。含甘露醇的样品降低了10%粘蛋白溶液的粘度。质量中值空气动力学直径（2.4-4.5µm）的结果，细颗粒分数（56-71％），渗透(五倍增强)，和溶出度（5分钟内释放80％）证实该系统是局部吸入的理想选择。所有样品对具有低细胞毒性的LPS处理的U937细胞系显示出显著的抗炎作用和降低的IL-6。因此，通过采用纳米微方法开发包含酮洛芬和甘露醇的创新组合DPI是治疗肺部炎症的潜在方法。
