Effects of Emulsion Composition on Pulmonary Tobramycin Delivery During Antibacterial Perfluorocarbon Ventilation

Background: The effectiveness of inhaled aerosolized antibiotics is limited by poor ventilation of infected airways. Pulmonary delivery of antibiotics emulsified within liquid perfluorocarbon [antibacterial perfluorocarbon ventilation (APV)] may solve this problem through better airway penetration and improved spatial uniformity. However, little work has been done to explore emulsion formulation and the corresponding effects on drug delivery during APV. This study investigated the effects of emulsion formulation on emulsion stability and the pharmacokinetics of antibiotic delivery via APV. Methods: Gravity-driven phase separation was examined in vitro by measuring emulsion tobramycin concentrations at varying heights within a column of emulsion over 4 hours for varying values of fluorosurfactant concentration (Cfs?=?5?48?mg/mL H2O). Serum and pulmonary tobramycin concentrations in rats were then evaluated following pulmonary tobramycin delivery via aerosol or APV utilizing sufficiently stable emulsions of varying aqueous volume percentage (Vaq?=?1%?5%), aqueous tobramycin concentration (Ct?=?20?100?mg/mL), and Cfs (15 and 48?mg/mL H2O). Results: In vitro assessment showed sufficient spatial and temporal uniformity of tobramycin dispersion within emulsion for Cfs?≥15?mg/mL H2O, while lower Cfs values showed insufficient emulsification even immediately following preparation. APV with stable emulsion formulations resulted in 5?22 times greater pulmonary tobramycin concentrations at 4 hours post-delivery relative to aerosolized delivery. Concentrations increased with emulsion formulations utilizing increased Vaq (with decreased Ct) and, to a lesser extent, increased Cfs. Conclusions: The emulsion stability necessary for effective delivery is retained at Cfs values as low as 15?mg/mL H2O. Additionally, the pulmonary retention of antibiotic delivered via APV is significantly greater than that of aerosolized delivery and can be most effectively increased by increasing Vaq and decreasing Ct. APV has been further proven as an effective means of pulmonary drug delivery with the potential to significantly improve antibiotic therapy for lung disease patients.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140106/1/jamp.2015.1235.pd

Characterization of a Reverse-Phase Perfluorocarbon Emulsion for the Pulmonary Delivery of Tobramycin

Background: Aerosolized delivery of antibiotics is hindered by poor penetration within distal and plugged airways. Antibacterial perfluorocarbon ventilation (APV) is a proposed solution in which the lungs are partially or totally filled with perfluorocarbon (PFC) containing emulsified antibiotics. The purpose of this study was to evaluate emulsion stability and rheological, antibacterial, and pharmacokinetic characteristics. Methods: This study examined emulsion aqueous droplet diameter and number density over 24?hr and emulsion and neat PFC viscosity and surface tension. Additionally, Pseudomonas aeruginosa biofilm growth was measured after 2-hr exposure to emulsion with variable aqueous volume percentages (0.25, 1, and 2.5%) and aqueous tobramycin concentrations (Ca=0.4, 4, and 40?mg/mL). Lastly, the time course of serum and pulmonary tobramycin concentrations was evaluated following APV and conventional aerosolized delivery of tobramycin in rats. Results: The initial aqueous droplet diameter averaged 1.9±0.2??m with little change over time. Initial aqueous droplet number density averaged 3.5±1.7?109 droplets/mL with a significant (p<0.01) decrease over time. Emulsion and PFC viscosity were not significantly different, averaging 1.22±0.03?10?3 Pa·sec. The surface tensions of PFC and emulsion were 15.0±0.1?10?3 and 14.6±0.6?10?3 N/m, respectively, and the aqueous interfacial tensions were 46.7±0.3?10?3 and 26.9±11.0?10?3 N/m (p<0.01), respectively. Biofilm growth decreased markedly with increasing Ca and, to a lesser extent, aqueous volume percentage. Tobramycin delivered via APV yielded 2.5 and 10 times larger pulmonary concentrations at 1 and 4?hr post delivery, respectively, and significantly (p<0.05) lower serum concentrations compared with aerosolized delivery. Conclusions: The emulsion is bactericidal, retains the rheology necessary for pulmonary delivery, is sufficiently stable for this application, and results in increased pulmonary retention of the antibiotic.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140105/1/jamp.2013.1058.pd

Antibacterial Perfluorocarbon Ventilation: A Novel Treatment Method for Bacterial Respiratory Infections.

Bacterial respiratory infections significantly contribute to the morbidity and mortality associated with lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and bronchiectasis. These patients feature abnormal mucus production and rheology that can impair host immune defenses, ultimately leading to chronic lung infection. Inhaled antibiotic delivery is currently used to treat these patients; however, its effectiveness is limited by an intrinsic dependence on airflow within the lung. Poor ventilation due to mucus plugging and lung damage restricts antibiotic delivery to the most burdened regions of the lung. In order to address these shortcomings, this research proposes a novel method of treatment entitled antibacterial perfluorocarbon ventilation (APV). During APV the lungs are filled with a breathable liquid [perfluorocarbon (PFC)] containing emulsified, micron-scale droplets of aqueous antibiotic. Such delivery has removed dependence on airflow and is thus capable of achieving more spatially uniform delivery. APV should also be able to actively remove infected mucus from the airways as well as promote a return to normal lung function via anti-inflammatory properties of PFC. This work represents an in-depth analysis and characterization of the emulsions used during APV. Initial efforts evaluated the feasibility of the emulsion’s use during liquid ventilation as well as its ability to effectively kill the tenacious bacterial biofilms found in the airways during infection. Following studies utilized both in vitro and in vivo methods to better understand the effects of emulsion formulation on the pharmacokinetics and availability of delivered drug and any potential cytotoxicity associated with the emulsion. A rat model of bacterial respiratory infection was developed and used at multiple points throughout this work to assess the potential treatment benefits of APV. Great strides were made in developing and optimizing the emulsion. The emulsions have been shown to be an adequate ventilation medium and a viable means of pulmonary drug delivery during APV. Final efforts resulted in a promising emulsion formulation that exhibited no cytotoxic effects and drastically improved drug availability relative to those previously assessed in vivo. Further in vivo work is required to determine if this optimized emulsion formulation provides a treatment benefit over inhaled antibiotics.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/116728/1/raoriz_1.pd

Thoracic artificial lung impedance studies using computational fluid dynamics and in vitro models.

Current thoracic artificial lungs (TALs) possess blood flow impedances greater than the natural lungs, resulting in abnormal pulmonary hemodynamics when implanted. This study sought to reduce TAL impedance using computational fluid dynamics (CFD). CFD was performed on TAL models with inlet and outlet expansion and contraction angles, θ, of 15°, 45°, and 90°. Pulsatile blood flow was simulated for flow rates of 2-6 L/min, heart rates of 80 and 100 beats/min, and inlet pulsatilities of 3.75 and 2. Pressure and flow data were used to calculate the zeroth and first harmonic impedance moduli, Z(0) and Z(1), respectively. The 45° and 90° models were also tested in vitro under similar conditions. CFD results indicate Z(0) increases as stroke volume and θ increase. At 4 L/min, 100 beats/min, and a pulsatility of 3.75, Z(0) was 0.47, 0.61, and 0.79 mmHg/(L/min) for the 15°, 45°, and 90° devices, respectively. Velocity band and vector plots also indicate better flow patterns in the 45° device. At the same conditions, in vitro Z (0) were 0.69 ± 0.13 and 0.79 ± 0.10 mmHg/(L/min), respectively, for the 45° and 90° models. These Z(0) are 65% smaller than previous TAL designs. In vitro, Z(1) increased with flow rate but was small and unlikely to significantly affect hemodynamics. The optimal design for flow patterns and low impedance was the 45° model.</p

Characterization of a reverse-phase perfluorocarbon emulsion for the pulmonary delivery of tobramycin.

<p>BACKGROUND: Aerosolized delivery of antibiotics is hindered by poor penetration within distal and plugged airways. Antibacterial perfluorocarbon ventilation (APV) is a proposed solution in which the lungs are partially or totally filled with perfluorocarbon (PFC) containing emulsified antibiotics. The purpose of this study was to evaluate emulsion stability and rheological, antibacterial, and pharmacokinetic characteristics.</p> <p>METHODS: This study examined emulsion aqueous droplet diameter and number density over 24 hr and emulsion and neat PFC viscosity and surface tension. Additionally, Pseudomonas aeruginosa biofilm growth was measured after 2-hr exposure to emulsion with variable aqueous volume percentages (0.25, 1, and 2.5%) and aqueous tobramycin concentrations (Ca=0.4, 4, and 40 mg/mL). Lastly, the time course of serum and pulmonary tobramycin concentrations was evaluated following APV and conventional aerosolized delivery of tobramycin in rats.</p> <p>RESULTS: The initial aqueous droplet diameter averaged 1.9±0.2 μm with little change over time. Initial aqueous droplet number density averaged 3.5±1.7×10(9) droplets/mL with a significant (p</p> <p>CONCLUSIONS: The emulsion is bactericidal, retains the rheology necessary for pulmonary delivery, is sufficiently stable for this application, and results in increased pulmonary retention of the antibiotic.</p