Direct lung delivery of a dry powder formulation of DTPA with improved aerosolization properties: effect on lung and systemic decorporation of plutonium.
DTPA, an actinide chelating agent, has demonstrated its ability to complex plutonium (Pu) and to facilitate its urinary excretion after internal contamination. This process, known as decorporation is crucial to diminish the burden of Pu in the body. The ability to deliver a chelating agent directly to the alveolar region may increase its local concentration as compared to systemic delivery and therefore increase the extent of decorporation. Second, inhalation offers the potential for needle-free, systemic delivery of small molecules and would be convenient in case of nuclear accident as a first pass emergency treatment. To benefit from the improvement of inhalation technology, we have formulated DTPA into porous particles by spray-drying with dl-Leucine, DPPC and ammonium bicarbonate. The optimized particles possess a volume mean geometric diameter around 4.5 mum and crumpled paper morphology. The in vitro aerodynamic evaluation shows that about 56% of the powder should deposits in the lungs, with about 27% in the alveolar region, an improvement as compared with the micronized powder available with the Spinhaler. After pulmonary administration to rats contaminated with PuO(2), a 3-fold increase of the Pu urinary excretion was observed, but the dissolution of PuO(2) in the lungs was not enhanced.
Gervelas
C
C
Univ Paris-Sud, CNRS UMR 8612, Physico-chimie-Pharmacotechnie-Biopharmacie, F-92296, Châtenay-Malabry, France.
Serandour
A-L
AL
Geiger
S
S
Grillon
G
G
Fritsch
P
P
Taulelle
C
C
Le Gall
B
B
Benech
H
H
Deverre
J-R
JR
Fattal
E
E
Tsapis
N
N
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D002614:Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D008168:Lung / Q000187:drug effects*; D008297:Male; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D004369:Pentetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D011005:Plutonium / Q000493:pharmacokinetics* / Q000652:urine; D016062:Porosity; D011208:Powders / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D014961:X-Ray Diffraction
D000336:Aerosols; D002614:Chelating Agents; D011208:Powders; D011005:Plutonium; D004369:Pentetic Acid