Search

Pseudomonas aeruginosais the predominant pathogen in the persistent lung infections of cystic fibrosis (CF) patients among other diseases. One of the mechanisms of resistance of P. aeruginosainfections is the formation and presence of biofilms. Previously, we demonstrated that PEGylated-tobramycin (Tob-PEG) had superior antimicrobial activity against P. aeruginosabiofilms compared to tobramycin (Tob). The goal of this study was to optimize the method of PEGylation of Tob and assess its activity in an in vitro CF-like mucus barrier biofilm model. Tob was PEGylated using three separate chemical conjugation methods and analyzed by 1H NMR. A comparison of the Tob-PEG products from the different conjugation methods showed significant differences in the reduction of biofilm proliferation after 24 h of treatment. In the CF-like mucus barrier model, Tob-PEG was significantly better than Tob in reducing P. aeruginosaproliferation after only 5 h of treatment (p< 0.01). Finally, Tob-PEG caused a reduction in the number of surviving P. aeruginosabiofilm colonies higher than that of Tob (p< 0.0001). We demonstrate the significantly improved antimicrobial activity of Tob-PEG against P. aeruginosabiofilms compared to Tob using two PEGylation methods. Tob-PEG had better in vitro activity compared to that of Tob against P. aeruginosabiofilms growing in a CF-like mucus barrier model.

Effective targeting of nasal spray deposition could improve local, systemic, and CNS drug delivery; however, this has proven to be difficult due to the anatomical features of the nasal cavity, including the nasal valve and turbinate structures. Furthermore, nasal cavity geometries and dimensions vary between individuals based on differences in their age, gender, and ethnicity. The effect of patient-specific administration parameters was evaluated for their ability to overcome the barriers of targeted nasal drug delivery. The nasal spray deposition was evaluated in 10 3D-printed nasal cavity replicas developed based on the CT-scans of five pediatric and five adult subjects. Cromolyn sodium nasal solution, USP, modified with varying concentrations of hypromellose was utilized as a model nasal spray to evaluate the deposition pattern from formulations producing a variety of plume angles. A central composite design of experiments was implemented using the formulation with the narrowest plume angle to determine the patient-specific angle for targeting the turbinate region in each individual. The use of the patient-specific angle with this formulation significantly increased the turbinate deposition efficiency compared to that found for all subjects using an administration angle of 30°, around 90% compared to about 73%. Generally, we found turbinate deposition increased with decreases in the administration angle. Deposition to the upper regions of the replica was poor with any formulation or administration angle tested. Effective turbinate targeting of nasal sprays can be accomplished with the use of patient-specific administration parameters in individuals. Further research is required to see if these parameters can be device-controlled for patients and if other regions can be effectively targeted with other nasal devices.