UCL-School of Pharmacy, London University, 29-39 Brunswick Square, London WC1N1AX, UK; Faculty of Pharmacy, Ain Shams University, P.O. Box:11566, Cairo, Egypt.
Pulm Pharmacol Ther. 2013 Dec;26(6):700-9. doi: 10.1016/j.pupt.2013.07.010. Epub 2013 Aug 8.
Highly viscous mucus poses a big challenge for the delivery of particulates carrying therapeutics to patients with cystic fibrosis. In this study, surface modifying DNase I loaded particles using different excipients to achieve better lung deposition, higher enzyme stability or better biological activity had been exploited. For the purpose, controlled release microparticles (MP) were prepared by co-spray drying DNase I with the polymer poly-lactic-co-glycolic acid (PLGA) and the biocompatible lipid surfactant 1,2-dipalmitoyl-Sn-phosphatidyl choline (DPPC) using various hydrophilic excipients. The effect of the included modifiers on the particle morphology, size, zeta potential as well as enzyme encapsulation efficiency, biological activity and release had been evaluated. Powder aerosolisation performance and particle phagocytosis by murine macrophages were also investigated. The results showed that more than 80% of enzyme activity was recovered after MP preparation and that selected surface modifiers greatly increased the enzyme encapsulation efficiency. The particle morphology was greatly modified altering in turn the powders inhalation indices where dextran, ovalbumin and chitosan hydrochloride increased considerably the respirable fraction compared to the normal hydrophilic carriers lactose and PVP. Despite of the improved aerosolisation caused by chitosan hydrochloride, yet retardation of chitosan coated particles in artificial mucus samples discouraged its application. On the other hand, dextran and polyanions enhanced DNase I effect in reducing cystic fibrosis mucus viscosity. DPPC proved good ability to reduce particles phagocytic uptake even in the presence of the selected adjuvants. The prepared MP systems were biocompatible with lung epithelial cells. To conclude, controlled release DNase I loaded PLGA-MP with high inhalation indices and enhanced mucolytic activity on CF sputum could be obtained by surface modifying the particles with PGA or dextran.
高粘度的黏液给将携带治疗剂的颗粒递送给囊性纤维化患者带来了巨大的挑战。在这项研究中，通过使用不同的赋形剂对负载有 DNase I 的颗粒进行表面修饰，以实现更好的肺部沉积、更高的酶稳定性或更好的生物活性。为此，通过共喷雾干燥法将 DNase I 与聚合物聚乳酸-羟基乙酸共聚物（PLGA）和生物相容性脂质表面活性剂 1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱（DPPC）一起负载到各种亲水性赋形剂中，制备了控制释放微球（MP）。评价了包含的修饰剂对颗粒形态、粒径、Zeta 电位以及酶包封效率、生物活性和释放的影响。还研究了粉末气溶胶化性能和鼠巨噬细胞对颗粒的吞噬作用。结果表明，MP 制备后可回收超过 80%的酶活性，并且选择的表面修饰剂大大提高了酶的包封效率。改变颗粒形态极大地改变了粉末的吸入指数，其中葡聚糖、卵清蛋白和盐酸壳聚糖与正常亲水性载体乳糖和 PVP 相比，明显增加了可吸入部分。尽管盐酸壳聚糖可改善气溶胶化，但壳聚糖涂层颗粒在人工黏液样品中的延迟释放却阻碍了其应用。另一方面，葡聚糖和多阴离子增强了 DNase I 降低囊性纤维化黏液粘度的效果。DPPC 证明了即使在选择的佐剂存在下，仍具有降低颗粒吞噬作用的良好能力。所制备的 MP 系统与肺上皮细胞生物相容。总之，通过用 PGA 或葡聚糖对颗粒进行表面修饰，可以获得具有高吸入指数和增强对 CF 痰液溶粘液活性的载有 DNase I 的 PLGA-MP 控释系统。
