Abstract

Pulmonary delivery of antibiotics represents an attractive strategy for the treatment of chronic respiratory infections, enabling high local drug concentrations while minimizing systemic exposure. Ciprofloxacin, a broad-spectrum fluoroquinolone, is considered a promising candidate for inhalation therapy; however, its crystalline structure and strong interparticle interactions can negatively influence powder dispersion and aerosolization performance in dry powder inhalers.

In this study, hot-melt extrusion (HME) was applied as a formulation strategy to produce ciprofloxacin–polymer solid dispersions designed for pulmonary administration. Binary mixtures composed of ciprofloxacin and selected pharmaceutical polymers were processed using a twin-screw extruder under controlled processing temperatures. The extruded strands were subsequently milled to obtain powders with particle characteristics appropriate for inhalation delivery. The obtained formulations were filled into hard gelatin capsules and aerosolized using a Cyclohaler® dry powder inhaler.

The solid-state properties of the systems were investigated using differential scanning calorimetry (DSC). Thermal analysis revealed a substantial reduction or disappearance of the melting endotherm associated with crystalline ciprofloxacin, suggesting a transition of the drug into an amorphous or partially amorphous state within the polymer matrices. These observations indicate successful incorporation and dispersion of ciprofloxacin during the extrusion process.

Aerodynamic behavior of the powders was assessed using a Next Generation Impactor (NGI) to determine aerodynamic particle size distribution. The emitted dose was quantified using a Dosage Unit Sampling Apparatus (DUSA), and drug deposition across impactor stages was determined using validated chromatographic analysis. The developed formulations exhibited efficient aerosol generation and consistent capsule emptying. Emitted dose values exceeded 65% of the nominal dose, while the recovered dose was greater than 85%. The fine particle dose surpassed 30%, indicating effective formation of respirable particles capable of reaching the lower respiratory tract. Deposition profiles showed predominant drug accumulation in NGI stages corresponding to aerodynamic diameters below 5 µm. Increased airflow conditions further improved powder dispersion and aerodynamic performance.

Overall, the results demonstrate that hot-melt extrusion is an effective approach for engineering ciprofloxacin solid dispersions suitable for dry powder inhalation systems. The extrusion process combined with polymer carriers enabled modification of the drug’s solid-state characteristics and generation of powders with favorable emission and deposition properties. This formulation strategy may support the development of advanced inhaled ciprofloxacin therapies for targeted treatment of respiratory infections.

Funding: levofloxacin, dry powder inhaler, lactose carrier, pulmonary delivery, NGI

Funding: This research is funded by a research grant from the Medical Research Agency (ABM), Poland, under the National Recovery and Resilience Plan, project number KPOD.07.07-IW.07-0216/24.

Keywords: ciprofloxacin, hot-melt extrusion, solid dispersion, pulmonary delivery, NGI

References:

1. Alshetaili, A.; Alshahrani, S.M.; Almutairy, B.K.; Repka, M.A. Hot Melt Extrusion Processing Parameters Optimization. Processes 2020, 8, 1516.

  1. Censi, R.; Gigliobianco, M.R.; Casadidio, C.; Di Martino, P. Hot Melt Extrusion: Highlighting Physicochemical Factors to Be Investigated While Designing and Optimizing a Hot Melt Extrusion Process. Pharmaceutics 2018, 10, 89.
  2. Li, S.; Tian, Y.; Jones, D.S.; Andrews, G.P. Optimising Drug Solubilisation in Amorphous Polymer Dispersions: Rational Selection of Hot-melt Extrusion Processing Parameters. AAPS PharmSciTech 2016, 17, 200-213.
 Biography:

Joanna Chałupka, PhD, is a pharmacist and senior researcher at the Department of Medicinal Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland. Her research is focused on the design, development, and physicochemical characterization of modern drug delivery systems, with particular emphasis on dry powder inhalers and amorphous solid dispersions prepared using hot-melt extrusion technology. She has extensive experience in solid-state characterization of pharmaceutical systems using thermal analysis, including differential scanning calorimetry, as well as advanced analytical techniques such as LC–MS/MS and high-resolution mass spectrometry (IT-TOF) for qualitative and quantitative drug analysis. Her work involves both formulation development and comprehensive evaluation of aerodynamic performance, emission characteristics, and stability of inhalation products. Her scientific interests include pulmonary drug delivery, pharmaceutical technology, and the application of advanced analytical tools in the development of innovative medicinal products.