Ciprofloxacin Dry Powder for Inhalation (ciprofloxacin DPI): Technical design and features of an efficient drug–device combination

Abstract

Bronchiectasis is a chronic respiratory disease with heterogeneous etiology, characterized by a cycle of bacterial infection and inflammation, resulting in increasing airway damage. Exacerbations are an important cause of morbidity and are strongly associated with disease progression. Many patients with bronchiectasis suffer from two or more exacerbations per year. However, there are no approved therapies to reduce or delay exacerbations in this patient population. Ciprofloxacin DPI is in development as a long-term, intermittent therapy to reduce exacerbations in patients with non-cystic fibrosis (CF) bronchiectasis and evidence of respiratory pathogens. Ciprofloxacin DPI combines drug substance, dry powder manufacturing technology, and an efficient, pocket-sized, dry powder inhaler to deliver an effective antibiotic directly to the site of infection, with minimal systemic exposure and treatment burden. Here we review the drug substance and particle engineering (PulmoSphere™) technology used, and key physical properties of Ciprofloxacin Inhalation Powder, including deposition, delivered dose uniformity, consistency, and stability. Design features of the T-326 Inhaler are described in relation to lung targeting, safety and tolerability of inhalation powders, as well as treatment burden and adherence. If approved, Ciprofloxacin DPI may provide a valuable treatment option for those with frequent exacerbations and respiratory pathogens.

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

“…Bayer HealthCare in collaboration with Nektar Therapeutics and Novartis companies developed a CIP-based DPI as a therapy to reduce exacerbations due to respiratory bacterial pathogens (mainly PA) in adults with NCFB. The advantage of CIP-DPI over established liquid inhalation systems for antibiotics is the high and reproducible deposition of CIP in the lungs, the reduced application time (seconds compared to several minutes), and the reduced handling for the device compared to nebulizers (requiring cleaning and sterilization) [20]. This DPI combines three advances in the field of inhalation.…”

“…First, the selection of the solid state of the CIP, crystallized in a neutral hydrate form (CIP·3.5 H 2 O) with low aqueous solubility and a slow dissolution rate, allows a favorable pulmonary PK (elimination rate from the lung controlled by the dissolution rate) [14,74]. CIP contains two ionizable groups, a carboxylic acid (pka1 = 6.2), and a piperazine group (pka2 = 8.6), conferring a pH-dependent solubility (Figure 3) [20,75]. In solution, at a pH two units lower than the pKa of the carboxylic acid (pH~4), approximately 99% of the CIP molecules have a positive charge.…”

“…At the physiological pH of the lungs (pH~7.4), the carboxylic acid group is deprotonated, and CIP exists as a zwitterion (CIP ± with a net neutral charge). This zwitterion is often referred to as the betaine form, having a solubility around 70 µg/mL [20,74]. As pKa1 and pKa2 are separated by less than three units, CIP can also be present in the uncharged ampholytic form CIP 0 [75].…”

“…The betaine form of CIP is the form used to formulate the CIP-DPI and its slower dissolution rate compared to CIP-HCl, the usually used solid salt form of CIP, increases its lung targeting. Indeed, A half-life of 13.5 h in rat lungs following oral inhalation has been demonstrated with the neutral form while CIP-HCl is rapidly absorbed into the systemic circulation, with a half-life in rat lungs of less than 1 h [14,20]. Additionally, following IT administration of a 7.5 mg/kg suspension, the AUC for the neutral form was increased 40-fold and the C max is increased 8-fold in rat lungs relative to CIP-HCl [14].…”

“…There are several ways to increase the FQ lung residence time after inhalation, such as lowering their P app through the lungs or controlling their release rate from formulations. In this sense, metal cation complexes, liposomal formulations, dry-powder microparticles, and lipid nanocarriers have received much interest in recent years as promising technologies for the administration of FQs by inhalation [16][17][18][19][20][21][22][23][24][25]. In the following sections, these two aspects-the control of dissolution rate and the control of permeability-will be discussed with regard to obtaining high and stable concentrations of drugs in the lungs after the inhalation of molecules with high permeability, such as FQs.…”