Semifluorinated alkanes--a new class of excipients suitable for pulmonary drug delivery.
BACKGROUND
Semifluorinated alkanes (SFAs) are considered as diblock molecules with fluorocarbon and hydrocarbon segments. Unlike Perfluorocarbons (PFCs), SFAs have the potential to dissolve several lipophilic or water-insoluble substances. This makes them possibly suitable as new excipients for inhalative liquid drug carrier systems.


OBJECTIVE
The aim of the study was to compare physico-chemical properties of different SFAs and then to test their respective effects in healthy rabbit lungs after nebulisation.


METHODS
Physico-chemical properties of four different SFAs, i.e. Perfluorobutylpentane (F4H5), Perfluorohexylhexane (F6H6), Perfluorohexyloctane (F6H8) and Perfluorohexyldodecane (F6H12) were measured. Based on these results, aerosol characteristics of two potential candidates suitable as excipients for pulmonary drug delivery, i.e. F6H8 and F4H5, were determined by laser light diffraction. Tracheotomised and ventilated New Zealand White rabbits were nebulised with either a high- or a low dose of SFAs (F6H8(low/high) and F4H5(low/high)) or saline (NaCl). Ventilated healthy animals served as controls (Sham). Arterial blood gases, lung mechanics, heart rate and blood pressure were recorded prior to nebulisation and in 30 min intervals during the 6-h study period.


RESULTS
Out of the four SFAs studied initially, no satisfactory behaviour as a solvent has to be expected because of low lipophilicity for F6H6. Output rate during aerosolisation was very low for F6H12. F6H8 and F4H5 presented comparable aerosolisation characteristics and lipophilicity and were therefore tested in the in vivo model. Aerosol therapy, either SFAs or saline, impaired paO2/FiO2 ratio, dynamic lung compliance and respiratory mechanics in all groups, except for F4H5(low) group which behaved like the control group (Sham). F4H5(low) had no adverse effects on gas exchange or pulmonary mechanics.


CONCLUSIONS
Perfluorobutylpentane (F4H5) in a low-dose application may be suitable as a new inhalable excipient in SFA-based pulmonary drug delivery systems for lipophilic or water-insoluble substances.
Tsagogiorgas
C
C
Dept. of Anaesthesiology and Intensive Care Medicine, University Medical Center Mannheim, Mannheim, Germany. charalambos.tsagogiorgas@umm.de
Krebs
J
J
Pukelsheim
M
M
Beck
G
G
Yard
B
B
Theisinger
B
B
Quintel
M
M
Luecke
T
T
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002245:Carbon Dioxide / Q000097:blood; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D005079:Excipients / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D005466:Fluorocarbons / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects; D009330:Nebulizers and Vaporizers; D010100:Oxygen / Q000097:blood; D010316:Particle Size; D011817:Rabbits; D015656:Respiratory Mechanics / Q000187:drug effects; D019141:Respiratory System Agents / Q000008:administration & dosage* / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors; D014140:Tracheotomy
D000336:Aerosols; D004337:Drug Carriers; D005079:Excipients; D005466:Fluorocarbons; D019141:Respiratory System Agents; C533290:perfluorobutylpentane; C519465:perfluorohexylhexane; D002245:Carbon Dioxide; C118616:perfluorohexyl-octan; D010100:Oxygen