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 μm with little change over time. Initial aqueous droplet number density averaged 3.5±1.7×10(9) 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.
1 Department of Biomedical Engineering, University of Michigan , Ann Arbor, MI.
Ryan A
RA
Orizondo
Charlene Irvin
CI
Babcock
Mario L
ML
Fabiilli
Leonid
L
Pavlovsky
J Brian
JB
Fowlkes
John G
JG
Younger
Keith E
KE
Cook
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods / Q000592:standards*; D005466:Fluorocarbons / Q000592:standards*; D008168:Lung / Q000382:microbiology*; D008297:Male; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013500:Surface Tension; D013997:Time Factors; D014031:Tobramycin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D014783:Viscosity
D000900:Anti-Bacterial Agents; D005466:Fluorocarbons; D014031:Tobramycin
liquid ventilation; pulmonary antibiotic delivery; respiratory infection