Dry powder inhaler of colistimethate sodium for lung infections in cystic fibrosis: optimization of powder construction

Abstract

Colistimethate sodium (CMS) for treatment of lung infections in cystic fibrosis patient was transformed into a dry powder for inhalation by spray drying. Design of Experiment was applied for understanding the role of the spray-drying process parameters on the critical quality attributes of the CMS spray-dried (SD) powders and agglomerates thereof. Eleven experimental SD microparticle powders were constructed under different process conditions according to a central composite design. The SD microparticles were then agglomerated in soft pellets. Eleven physico-chemical characteristics of SD CMS microparticle powders or agglomerates thereof were selected as critical quality attributes. The yield of SD process was higher than 75%. The emitted fraction of agglomerates from RS01 inhaler was 75–84%, and the fine particle fraction (particles <5?µm) was between 58% and 62%. The quality attributes of CMS SD powders and respective agglomerates that were significantly influenced by spray-drying process parameters were residual solvent and drug content of the SD microparticles as well as bulk density and respirable dose of the agglomerates. These attributes were also affected by the combination of the process variables. The air aspiration rate was found as the most positively influential on drug and solvent content and respirable dose. The residual solvent content significantly influenced the powder bulk properties and aerodynamic behavior of the agglomerates, i.e. quality attributes that govern drug metering in the device and the particles lungs deposition. Agglomerates of CMS SD microparticles, in combination with RS01?DPI, showed satisfactory results in terms of dose emitted and fine particle fraction.     

Deposition of Nacystelyn from a Dry Powder Inhaler in Healthy Volunteers and Cystic Fibrosis Patients

The aim of this study was to compare, using gamma scintigraphy, the lung deposition of a novel mucoactive agent, Nacystelyn (NAL), administered as a dry powder inhaler (DPI) in six healthy volunteers, six adult patients with cystic fibrosis (CF), and six children and adolescents patients with CF. The correlation between in vitro and in vivo results was also tested. It was first demonstrated that the method of labeling of NAL with ^99mTc was reliable as tested by three in vitro methods (multistage liquid impinger, multistage cascade impactor, and 2-stage glass impinger). The deposition of unlabeled NAL, labeled NAL, and the radiolabel was similar in all stages of each device. Furthermore, the fine particle fraction (FPF) was the same on all apparatuses. The mean lung deposition obtained in volunteers was 27.5 ± 13.5%. The results are approximately three times higher than the results obtained previously in healthy volunteers with NAL metered-dose inhalers (MDIs). As expected, the lung deposition observed in patients with CF was lower, e.g., 23.5 ± 7.0% for adults and 16.5 ± 5.9% for children and adolescents. A significant correlation was found between lung deposition and both the patient weight (p < 0.02) and height (p < 0.04). Surprisingly, the peripheral:central (P:C) ratio was similar for the three populations, indicating that the presence of mucus in moderately ill patients with CF does not modify the lung distribution of NAL. The FPF measured in vitro was similar to that obtained in volunteers but higher than that found in both patient populations. The DPI formulation of NAL developed will probably improve patient compliance and comfort in future clinical trials and postmarketing use of the drug.     

Long-term effect of chronic intravenous and inhaled nephrotoxic antibiotic treatment on the renal function of patients with cystic fibrosis

Cystic fibrosis (CF) patients have numerous infectious exacerbations requiring prolonged antibiotic treatments, some of which are nephrotoxic. Inhaled antibiotics can reach detectable serum levels. We studied the impact of chronic nephrotoxic antibiotic exposure on kidney function in CF population. We collected data retrospectively for 113 adult CF patients followed for 8.5 years. Fifty‐seven (50.4%) were males and 56 (49.5%) females (mean age 31.7 years [SD 9.9]), of which 31% had diabetes and 9.7% had hypertension. Over 8.5 years follow up, there were no significant changes in blood urea nitrogen (BUN; P = 0.92) or creatinine (P = 0.2) in the whole group. 22% of patients had ≥1 episodes of acute kidney injury (AKI). The presence of AKI was associated with increased BUN (P = 0.002) and creatinine (P = 0.056) at the end of follow up. Use of intravenous colistin, gentamicin, tobramycin, or vancomycin did not correlate with increased BUN (P = 0.64; P = 0.49; P = 0.51; P = 0.47) or creatinine (P = 0.43; P = 0.49; P = 0.17; P = 0.2) after 8.5 years. Elevated tobramycin peak and trough levels did not correlate with increased BUN or creatinine. Inhaled colistin and gentamicin correlated with increased BUN (P = 0.009; P = 0.02) but not creatinine (P = 0.45; P = 0.46). Inhaled tobramycin did not correlate with increased BUN (P = 0.17) or creatinine (P = 0.58). Only inhaled colistin correlated with AKI episodes (P = 0.03). Chronic inhaled colistin and gentamicin are associated with an increase in BUN but not creatinine at the end of follow up. Inhaled colistin was associated with episodes of AKI. Well‐managed intravenous use of nephrotoxic antibiotics in CF population is associated with no major long‐term renal toxicity.     

Ethanol combined with heparin as a locking solution for the prevention of catheter related blood stream infections in hemodialysis patients: A prospective randomized study

Introduction: Ethanol lock solution has been mainly administered in paediatric and home parenteral nutrition patients in order to prevent catheter related blood stream infections (CRBSI). Its utility in hemodialysis (HD) patients with non‐tunneled‐uncuffed catheter (NTC) has been poorly explored. Methods: We conducted a prospective randomized study in chronic HD patients requiring a newly inserted NTC‐while awaiting for the maturation of an already established arteriovenous fistula (AVF) or arteriovenous graft (AVG) or tunneled‐cuffed catheter insertion. Patients were randomized in two groups: Group A, where the lock solution was ethanol 70% + unfractionated heparin 2000 U/mL and group B, that received only unfractionated heparin 2000 U/mL. Primary end point was CRBSIs whereas exit site infections, thrombotic and bleeding episodes were the secondary end points. Findings: One hundred three HD patients were enrolled in the study (group A, n = 52; group B, n = 51). The median number of catheter days was 32 for group A (range: 23–39) and 34 (range: 27–40) for group B with no statistically significant difference between the two groups. Group A (ethanol + heparin) demonstrated 4/52 episodes (7.69%) of CRBSI whereas Group B (heparin) 11/51 episodes (21.57%) (P = 0.04). CRBSI rates per 1000 catheter days were 2.53/1000 catheter days for group A and 6.7/1000 catheter days for group B (P = 0.04). Mean cumulative infection‐free catheter survival in the ethanol group did not differ significantly compared to the heparin group (log‐rank test = 2.99, P = 0.08). Thrombotic episodes did not differ between the two groups. Discussion: Locking of NTCs in HD patients with ethanol 70% + unfractionated heparin reduces CRBSI rates without increasing the thrombotic episodes.