Comparison of Phospholipid-Based Particles for Sustained Release of Ciprofloxacin Following Pulmonary Administration to Bronchiectasis Patients

Abstract

The rapid clearance of ciprofloxacin hydrochloride from the lungs following administration as an aerosol leads to poor efficacy in the treatment of pulmonary infections. The development of formulations capable of sustaining ciprofloxacin concentrations in the lungs has the potential to significantly improve antibacterial activity. The present review compares two approaches for sustaining levels of ciprofloxacin in the lungs, a liposomal formulation where ciprofloxacin is encapsulated in small unilamellar vesicles, and a dry powder formulation of the practically insoluble zwitterionic form of the drug. These two formulations recently completed large multicenter, phase 3 clinical studies in bronchiectasis patients. As such, they present a unique opportunity to examine the chemistry, manufacturing, and control of the dosage forms in addition to their tolerability and efficacy in more than 1000 bronchiectasis patients. Both formulations were generally well tolerated with most adverse events found to be mild to moderate in intensity. While the formulations were effective in reducing and/or eradicating infections, this did not lead to reductions in pulmonary exacerbations, the primary endpoint. The failures speak more to the heterogeneous nature of the disease and the difficulty in identifying bronchiectasis patients likely to exacerbate, rather than an inherent limitation of the formulations. While the formulations are similar in many respects, they also present some interesting differences. This review explores the implications of these differences on the treatment of respiratory infections.

In vivo efficacy of a dry powder formulation of ciprofloxacin-copper complex in a chronic lung infection model of bioluminescent Pseudomonas aeruginosa

“…administration, CIP half-life in rat lung ELF is higher than 2 h, while it is lower than 1 h after a CIP solution nebulization [2]. At the opposite, previous studies showed that CIP-HCl has poor lung targeting following oral inhalation; the drug is rapidly absorbed into the systemic circulation with a halflife of less than 1 h in the rat lungs, making CIP-HCl suboptimal for pulmonary delivery [5,13,28]. To improve the lung targeting of CIP by inhalation, Bayer AG also aimed at prolonging the residence time of CIP in the lungs.…”

Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler

“…Ciprofloxacin is a broad-spectrum antibiotic with activity against both gram-positive and gram-negative bacteria. Ciprofloxacin DPI (Bayer) was developed for the treatment of chronic infections in CF and non-CF bronchiectasis patients [54,55]. Ciprofloxacin DPI is prepared by the suspension-based PulmoSphere manufacturing process, using the poorly soluble zwitterionic form of the drug at neutral pH [51,55].…”

“…Ciprofloxacin DPI (Bayer) was developed for the treatment of chronic infections in CF and non-CF bronchiectasis patients [54,55]. Ciprofloxacin DPI is prepared by the suspension-based PulmoSphere manufacturing process, using the poorly soluble zwitterionic form of the drug at neutral pH [51,55]. This process results in small porous particles of micronized crystalline drug particles coated with porous shell comprising a 2:1 molar ratio of DSPC:CaCl2.…”

“…This process results in small porous particles of micronized crystalline drug particles coated with porous shell comprising a 2:1 molar ratio of DSPC:CaCl2. Formulation of the neutral form of the drug provides for dissolution-limited delivery in the lungs, enhancing the pharmacokinetic/pharmacodynamic metrics (e.g., the AUC/MIC ratio) and efficacy of the drug in the lungs [55]. The drug loading in the spray-dried drug product is 0.65 mg/mg.…”

Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

“…The most advanced is a liposomal formulation of CIP for inhalation branded Linhaliq ® in Europe and Apulmiq ® in the USA (previously called Pulmaquin ® ), which is now in the final stages of clinical testing [17,101]. Some good recent reviews [19,102,103] describe their development in detail and will therefore only be discussed briefly here: Linhaliq ® is a 80-100 nm liposome-encapsulated CIP delivered once daily through a jet nebulizer (PARI LC ® ). The liposomes are a mix of hydrogenated soy phosphatidylcholine and cholesterol, with a lipid/drug ratio of 2.…”