Machine Learning-Guided Prediction of Formulation Performance in Inhalable Ciprofloxacin-Bile Acid Dispersions with...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Respiratory Medicine

Background:

• Ciprofloxacin (CFX) is vital for respiratory infections but faces challenges in dry powder inhaler (DPI) delivery due to poor solubility and high crystallinity.
• Soluble CFX forms risk systemic absorption, compromising targeted lung delivery.

Purpose of the Study:

• To create controlled-release solid dispersions of CFX with primary bile acids (cholic acid - CA, chenodeoxycholic acid - CDA) for enhanced DPI efficacy.
• To improve CFX solubility and lung deposition while retaining antimicrobial activity and assessing safety.

Main Methods:

• Spray drying and ball milling were used to formulate CFX-bile acid solid dispersions.
• Characterization included differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and dissolution studies.
• Aerodynamic performance was assessed using an Andersen cascade impactor, and antimicrobial activity was tested in vitro.
• In vivo toxicology studies in rats and machine learning models were employed to predict performance and identify critical variables.

Main Results:

• CFX-bile acid dispersions exhibited enhanced solubility and partially amorphous structures.
• Chenodeoxycholic acid (CDA) dispersions showed superior lung deposition (higher fine particle fraction, lower MMAD) and emitted dose compared to cholic acid (CA) dispersions.
• Formulations maintained CFX's antimicrobial efficacy, with mild, dose-dependent hepatic effects observed in vivo, particularly with CDA.

Conclusions:

• Primary bile acid-based solid dispersions offer a promising strategy for developing effective inhalable ciprofloxacin therapies.
• Chenodeoxycholic acid (CDA) demonstrated superior performance for lung deposition and emission in DPI formulations.
• Machine learning effectively predicted formulation performance, identifying key variables like bile acid type and processing parameters.