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<p>Cystic fibrosis (CF) is a genetic disorder characterized by thick mucus accumulation in the lungs, leading to chronic infections and inflammation. Ivacaftor, a CFTR potentiator, requires frequent dosing in its conventional form, reducing patient compliance. This study aims to develop ivacaftor-loaded nanoparticles for pulmonary drug delivery using poly(lactic acid) (PLA) and chitosan. Preformulation studies, such as solubility and melting point, as well as drug-excipient compatibility (FTIR, XRD, DSC), were performed. Nanoparticles were formulated via solvent evaporation and ionic gelation, followed by PEG surface modification for enhanced stability. A Plackett-Burman design was used to screen key formulation variables. First, a suite of ivacaftor-loaded nanoparticles were prepared using different formulation parameters to study the effects of these parameters on size, drug loading, encapsulation efficiency, and morphology (SEM). In-vitro release profiles were also conducted along with an In-vitro lung deposition study using a cascade impactor. Further optimization using a three-level factorial design yielded optimized batches. Prepared nanoparticles were spherical with size ranging from 110 to 763&#xa0;nm for PLA nanoparticles and 149 –1165&#xa0;nm for chitosan nanoparticles, respectively. The percentage encapsulation efficiency (%EE) of 80.96–91.5% for PLA nanoparticles and 63.14–91.42% for chitosan nanoparticles. Optimized formulations achieved particle sizes below 300&#xa0;nm, good entrapment efficacy of 89.44%, drug loading from 3 to 5.6%, and lower PDI values enabling deeper lung penetration. In vitro studies demonstrated sustained drug release for 24&#xa0;h (chitosan) and 36&#xa0;h (PLA), significantly reducing dosing frequency compared to marketed ivacaftor tablets (Kalydeco 150&#xa0;mg), which require administration 2–3 times daily. The freeze-dried NPs Powder of PLA and Chitosan showed the required mass median aerodynamic diameter of 5.39&#xa0;μm and 4.75&#xa0;μm, respectively, and greater fine particle fraction (39.4965% and 24.9471% ). These findings underscore the potential of ivacaftor-loaded nanoparticles as an effective pulmonary delivery system, prolonging drug release and improving patient adherence for CF management.</p>

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Formulation and Evaluation of Surface Engineered CFTR Modulator Nanoparticles for the Treatment of Cystic Fibrosis

  • 期刊论文

  • 发表日期：

    2026年3月10日

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  • Himanshu Patel,
  • Sushma Kandukuri,
  • Meenakshi Patel,
  • Akansha Tamboli

摘要

Cystic fibrosis (CF) is a genetic disorder characterized by thick mucus accumulation in the lungs, leading to chronic infections and inflammation. Ivacaftor, a CFTR potentiator, requires frequent dosing in its conventional form, reducing patient compliance. This study aims to develop ivacaftor-loaded nanoparticles for pulmonary drug delivery using poly(lactic acid) (PLA) and chitosan. Preformulation studies, such as solubility and melting point, as well as drug-excipient compatibility (FTIR, XRD, DSC), were performed. Nanoparticles were formulated via solvent evaporation and ionic gelation, followed by PEG surface modification for enhanced stability. A Plackett-Burman design was used to screen key formulation variables. First, a suite of ivacaftor-loaded nanoparticles were prepared using different formulation parameters to study the effects of these parameters on size, drug loading, encapsulation efficiency, and morphology (SEM). In-vitro release profiles were also conducted along with an In-vitro lung deposition study using a cascade impactor. Further optimization using a three-level factorial design yielded optimized batches. Prepared nanoparticles were spherical with size ranging from 110 to 763 nm for PLA nanoparticles and 149 –1165 nm for chitosan nanoparticles, respectively. The percentage encapsulation efficiency (%EE) of 80.96–91.5% for PLA nanoparticles and 63.14–91.42% for chitosan nanoparticles. Optimized formulations achieved particle sizes below 300 nm, good entrapment efficacy of 89.44%, drug loading from 3 to 5.6%, and lower PDI values enabling deeper lung penetration. In vitro studies demonstrated sustained drug release for 24 h (chitosan) and 36 h (PLA), significantly reducing dosing frequency compared to marketed ivacaftor tablets (Kalydeco 150 mg), which require administration 2–3 times daily. The freeze-dried NPs Powder of PLA and Chitosan showed the required mass median aerodynamic diameter of 5.39 μm and 4.75 μm, respectively, and greater fine particle fraction (39.4965% and 24.9471% ). These findings underscore the potential of ivacaftor-loaded nanoparticles as an effective pulmonary delivery system, prolonging drug release and improving patient adherence for CF management.