Movellan Julie, Murgia Xabier, Gracia Raquel, Marradi Marco, Miranda José Ignacio, Aizpurua Jesús María, Grande Hans-Jürgen, Dupin Damien, Loinaz Iraida
CIDETEC, Basque Research and Technology Alliance (BRTA), Parque Científico y Tecnológico de Gipuzkoa, Donostia-San Sebastián, Spain.
Kusudama Therapeutics SA, Parque Científico y Tecnológico de Gipuzkoa, Donostia-San Sebastián, Spain.
Int J Pharm. 2025 Feb 25;671:125241. doi: 10.1016/j.ijpharm.2025.125241. Epub 2025 Jan 23.
Cystic fibrosis (CF) is characterized by abnormal mucus hydration due to a defective CF Transmembrane Regulator (CFTR) protein, leading to the production of difficult-to-clear mucus. This causes airflow obstruction, recurrent infections, and respiratory complications. Chronic lung infections are the leading cause of death for CF patients and inhaled tobramycin is the first-in-line antibiotic treatment against these infections, mainly caused by Pseudomonas aeruginosa in adult patients. KuDa-tob, a nanoformulation of tobramycin (tob) as the active ingredient and dextran single chain nanoparticles, a drug carrier platform (KuDa) as an excipient, has been developed. The neutralization of the positive charges of the drug by KuDa nanoparticles facilitates its diffusion through the mucus and biofilm, reaching the bacteria. The polar interactions existing between tobramycin and KuDa have been thoroughly characterized by electrophoresis (ζ-potential) and diffusion experiments (diffusion ordered spectroscopy and Taylor dispersion analysis) demonstrating that up to 40 wt% tobramycin could be loaded into the KuDa-tob nanoformulation. The drug product was developed following Quality by Design (QbD) principles. Critical quality attributes (CQAs), critical process parameters (CPPs) and critical material attributes (CMAs) have been defined to obtain a robust production process that was then scaled-up to 40 g, allowing the production of KuDa-tob for further preclinical evaluation. Finally, the final pharmaceutical form of KuDa-tob was defined based on stability studies, and nebulization assays showed that the aerosols generated by reconstituted KuDa-tob were in the ideal range size for lung deposition (Median Mass Aerodynamic Diameter - MMAD - 2.2 μm).
囊性纤维化（CF）的特征是由于囊性纤维化跨膜调节因子（CFTR）蛋白缺陷导致黏液水合异常，从而产生难以清除的黏液。这会导致气流阻塞、反复感染和呼吸并发症。慢性肺部感染是CF患者的主要死因，吸入妥布霉素是针对这些感染的一线抗生素治疗药物，在成年患者中主要由铜绿假单胞菌引起。已经开发出了KuDa-妥布霉素，它是以妥布霉素（tob）为活性成分的纳米制剂，以及作为辅料的药物载体平台葡聚糖单链纳米颗粒（KuDa）。KuDa纳米颗粒对药物正电荷的中和促进了其在黏液和生物膜中的扩散，从而到达细菌。通过电泳（ζ电位）和扩散实验（扩散有序光谱法和泰勒色散分析）对妥布霉素和KuDa之间存在的极性相互作用进行了全面表征，结果表明，高达40wt%的妥布霉素可以负载到KuDa-妥布霉素纳米制剂中。该药品是按照质量源于设计（QbD）原则开发的。已经定义了关键质量属性（CQA）、关键工艺参数（CPP）和关键物料属性（CMA），以获得稳健的生产工艺，然后将其扩大规模至40克，从而能够生产KuDa-妥布霉素用于进一步的临床前评估。最后，根据稳定性研究确定了KuDa-妥布霉素的最终剂型，雾化试验表明，复溶后的KuDa-妥布霉素产生的气溶胶粒径处于肺部沉积的理想范围内（质量中值空气动力学直径-MMAD-2.2μm）。
