Aradigm (United States)

The in vivo efficacy of liposomal encapsulated ciprofloxacin in two formulations, lipoquin and apulmiq, were evaluated against the causative agent of anthrax, Bacillus anthracis. Liposomal encapsulated ciprofloxacin is attractive as a therapy since it allows for once daily dosing and achieves higher concentrations of the antibiotic at the site of initial mucosal entry but lower systemic drug concentrations. The in vivo efficacy of lipoquin and apulmiq delivered by intranasal instillation was studied at different doses and schedules in both a post exposure prophylaxis (PEP) therapy model and in a delayed treatment model of murine inhalational anthrax. In the mouse model of infection, the survival curves for all treatment cohorts differed significantly from the vehicle control. Ciprofloxacin, lipoquin and apulmiq provided a high level of protection (87–90%) after 7 days of therapy when administered within 24 hours of exposure. Reducing therapy to only three days still provided protection of 60–87%, if therapy was provided within 24 hours of exposure. If treatment was initiated 48 hours after exposure the survival rate was reduced to 46–65%. These studies suggest that lipoquin and apulmiq may be attractive therapies as PEP and as part of a treatment cocktail for B. anthracis.

Introduction: ARD-3150 (ARD) is a once-daily 6 mL nebulized formulation of liposomal (135 mg) and free (54 mg) ciprofloxacin that was tested in two 48-week phase 3 trials (ORBIT-3 [NCT01515007]; ORBIT-4 [NCT02104245]) in NCFB patients with chronic P. aeruginosa infection over 6 cycles of 28 days on/off treatment. Patients (pts) completing the double-blind period (DBP) could enter a 28-day OLE with ARD treatment + 30-day follow-up. Aims: To evaluate responses to ARD in those previously receiving ARD or placebo (PB) treatment. Methods: All pts received ARD for 28 days. Pulmonary exacerbations (PE), microbiological outcomes, and adverse events (AE) were monitored. Results: In ORBIT-4 and ORBIT-3, 92%-97% of DBP completers entered the OLE. During the OLE, 11.1% (ORBIT-4) and 12.3% (ORBIT-3) pts had a PE. During DBP, ARD pts had PE rates of 0.98 and 1.09 and PB pts had rates of 1.47 and 1.31 PE/pt, respectively. When OLE PE rates were normalized to the 48-wk duration of the DBP, ARD rates were 0.53 and 0.55 PEs/pt and PB pts rates were 1.14 and 1.11 PE/pt. Both ARD and PB pts in DBP had a decline in PE rate during OLE. Entering OLE, 54.3% and 50.4%of ARD, and 66.7% and 75.8% of PB pts of ORBIT-4 and ORBIT-3, respectively, had ciprofloxacin MIC Conclusions: The efficacy and safety profile of ARD was maintained during the OLE.

The failure of chronic therapy with antibiotics to clear persistent respiratory infection is the key morbidity and mortality factor for patients with chronic lung diseases, primarily due to the presence of biofilm in the lungs. It is hypothesised that carbon sources, such as mannitol, could stimulate the metabolic activity of persister cells within biofilms and restore their susceptibility to antibiotics. The aims of the current study are to: (1) establish a representative in vitro model of Pseudomonas aeruginosa biofilm lung infection, and (2) investigate the effects of nebulised mannitol on antibiotic efficacy, focusing on ciprofloxacin, in the eradication of biofilm. Air interface biofilm was cultured onto Snapwell inserts incorporated into a modified pharmacopeia deposition apparatus, the Anderson Cascade Impactor (ACI). Three different formulations including mannitol only, ciprofloxacin only and combined ciprofloxacin and mannitol were nebulised onto the P. aeruginosa biofilm using the modified ACI. Antibacterial effectiveness was evaluated using colony-forming units counts, biofilm penetration and scanning electron microscopy. Nebulised mannitol promotes the dispersion of bacteria from the biofilm and demonstrated a synergistic enhancement of the antibacterial efficacy of ciprofloxacin compared to delivery of antibiotic alone. The combination of ciprofloxacin and mannitol may provide an important new strategy to improve antibiotic therapy for the treatment of chronic lung infections. Furthermore, the development of a representative lung model of bacterial biofilm could potentially be used as a platform for future new antimicrobial pre-clinical screening.

PurposeIn order to attenuate the drug release rate, a single freeze-thaw step was previously shown to convert encapsulated drug into a single nanocrystal within each liposome vesicle. The goal of this study was to alter the nanocrystalline character, and thus the drug encapsulation state and release profile, by addition of surfactant prior to freeze-thaw.MethodsA liposomal ciprofloxacin (CFI) formulation was modified by the addition of surfactant and frozen. After thawing, these formulations were characterized in terms of drug encapsulation by centrifugation-filtration, liposome structure by cryo-TEM imaging, vesicle size by dynamic light scattering, and in vitro release (IVR) performance.ResultsThe addition of increasing levels of polysorbate 20 (0.05 to 0.4%) or Brij 30 (0.05 to 0.3%) to the CFI preparations followed by subsequent freeze-thaw, resulted in a greater proportion of vesicles without drug nanocrystals and reduced the extent of growth of the nanocrystals thus leading to modified release rates including an increase in the ratio of non-encapsulated to sustained release of drug.ConclusionsThis study provides another lever to achieve the desired release rate profile from a liposomal formulation by addition of surfactant and subsequent freeze-thaw, and thus may provide a personalized approach to treating patients.

A study was designed to compare differences in insulin aerosol deposition profiles in healthy male and female subjects, as well as examine the effect of mouthpiece cross-sectional shape, volume, and taper on deposition profiles using a developmental AERx pulmonary delivery system. Six mouthpieces were screened in the laboratory, and three were selected for clinical investigation: a cylindrical mouthpiece with constant-cross-sectional area, an elliptical mouthpiece with constant-cross-sectional area, and a tapered elliptical mouthpiece with an exit cross-sectional area equal to one half the entrance cross-sectional area. There was no significant difference in the lung dose or in the deposition pattern between males and females (p > 0.05, by ANOVA). The cross-sectional shape of the mouthpiece had no significant effect on the clinical lung dose or the deposition pattern (p > 0.05, by ANOVA), although in vitro testing showed lower emitted dose values with the tapered elliptical mouthpiece (by ANOVA and Duncan's multiple range test, alpha = 0.05). Using the tapered mouthpiece in the clinic resulted in significantly more deposition on the mouthpiece itself when compared to the nontapered mouthpieces. Inhalation of insulin using the AERx system was insensitive to differences in male and female respiratory tract geometry across all mouthpiece designs examined.

The AERx insulin Diabetes Management system (AERx iDMS) is a liquid aerosol device that enables insulin to be administered to the peripheral parts of the lung. This study aimed to compare the pharmacokinetic and pharmacodynamic properties of insulin which is inhaled using AERx iDMS with insulin which is subcutaneously administered. In total, 18 C-peptide negative patients with Type I (insulin-dependent) diabetes mellitus participated in this randomised, open-label, 5-period crossover trial. Human regular insulin was administered subcutaneously (0.12 U/kg body weight) or inhaled by means of the AERx iDMS (dosages 0.3, 0.6, 1.2, and 1.8 U/kg body weight). Thereafter plasma glucose was kept constant at 7.2 mmol/l for a 10-h period (glucose clamp technique). Inhaled insulin provided a dose-response relation that was close to linear for both pharmacokinetic (AUC-Ins(0-10 h); Cmax-Ins) and pharmacodynamic (AUC-GIR(0-10 h); GIRmax) parameters. Time to maximum insulin concentration (Tmax-Ins) and time to maximum glucose infusion rate (TGIRmax) were shorter with inhaled insulin than with subcutaneous administration. The pharmacodynamic system efficiency of inhaled insulin (AUC-GIR(0-6 h) was 12.7% (95% C.I.: 10.2-15.6). The inhalation of soluble human insulin using the AERx iDMS is feasible and provides a clear dose response. Further long-term studies are required to investigate safety aspects, HbA1c values, incidence of hypoglycaemic events and the quality of life.

We have used rhDNase to investigate the feasibility of developing a dry protein powder aerosol for inhalation delivery. Powders of rhDNase alone and with sodium chloride were prepared by spray drying. Powder blends were obtained by mixing (tumbling and sieving) pure rhDNase powder with 'carrier' materials (lactose, mannitol or sodium chloride). The weight percent of drug in the blends was between 5 and 70%. The particle size distributions and crystallinity of the spray dried powders were obtained by laser diffraction and X-ray powder diffraction, respectively. Particle morphology was examined by scanning electron microscopy. The ability of the powders and powder blends to be dispersed into respirable aerosols was measured using a Rotahaler connected to a multistage liquid impinger operating at 60 L/min. Pure rhDNase powder was quite cohesive with a fine particle fraction (FPF or "respirable fraction': % wt. of particles < 7 microns in the aerosol cloud) of about 20%. When particles also contained NaCl, the powders were dispersed better to form aerosols. A linear relationship was observed between the NaCl content and FPF for a similar primary size (approximately 3 microns volume median diameter) of particles. The particle morphology of these powders varied systematically with the salt content. For the blends, SEM revealed a monolayer-like adhesion of the fine drug particles to the carriers at drug contents > or = 50% wt. An overall 2-fold increase in FPF of rhDNase in the aerosol cloud was obtained for all the blends compared to the pure drug aerosols. The aerosol properties of spray dried rhDNase powders can be controlled by incorporation of a suitable excipient, such as NaCl, and its relative proportion. Coarse carriers can also enhance the performance of rhDNase dry powder aerosols.