In vitro and in vivo characterisation of PEG-lipid-based micellar complexes of salmon calcitonin for pulmonary delivery.
OBJECTIVE
To investigate DSPE-PEG(2000)-based micellar formulations of salmon calcitonin (sCT) for their ability to improve pulmonary delivery.


METHODS
Micelles were characterised by DLS and (31)P-NMR spectroscopy. Stability against sCT degrading peptidases, trypsin, α-chymotrypsin and neutrophil elastase as well as their influence on transepithelial absorption was investigated in vitro. In vivo performance of sCT micelles was studied in an experimental model of intratracheal aerosolisation into rats.


RESULTS
Micelles with a mean hydrodynamic diameter of 12 nm spontaneously assembled, when a total concentration of 0.02 mM of PEG-lipid and sCT (at 1:1 molar ratio) was exceeded. Nuclear magnetic resonance confirmed the presence of small micellar structures. The micellar formulation showed increased stability against enzymatic digestion. In vitro studies also showed that sCT micelles were able to enhance transepithelial absorption. Data obtained from in vivo experiments provided evidence of significantly (P < 0.05) higher mean plasma concentrations of sCT, after inhalation of micelles compared to sCT solution, at 60 and 90 min, a significantly higher AUC (inf) and a relative bioavailability of 160 ± 55% when compared to plain sCT solution.


CONCLUSIONS
The herein described PEG-lipid micelles are promising carriers for enhanced pulmonary delivery of sCT.
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Dublin, Ireland.
Leonie
L
Baginski
Oliviero L
OL
Gobbo
Frederic
F
Tewes
Johanna J
JJ
Salomon
Anne Marie
AM
Healy
Udo
U
Bakowsky
Carsten
C
Ehrhardt
D000042:Absorption; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002116:Calcitonin / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D002918:Chymotrypsin / Q000378:metabolism; D004337:Drug Carriers; D004339:Drug Compounding; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008027:Light; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008823:Micelles; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D020545:Respiratory Mucosa / Q000378:metabolism; D012542:Scattering, Radiation; D013678:Technology, Pharmaceutical / Q000379:methods; D014357:Trypsin / Q000378:metabolism
C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000336:Aerosols; D050071:Bone Density Conservation Agents; D004337:Drug Carriers; D008823:Micelles; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; C028815:salmon calcitonin; D002116:Calcitonin; D002918:Chymotrypsin; D019272:Leukocyte Elastase; D014357:Trypsin