Percutaneous absorption of physiologically active peptides, ebiratide and elcatonin, in rats.
This study was designed to evaluate the percutaneous absorption of physiologically active peptides, ebiratide (a behaviorally potent adrenocorticotropic analog) and elcatonin (a hypocalcemic peptide) in an attempt to develop an efficient transdermal therapeutic system for the treatment of diseases. The [125I]ebiratide penetration through rat skin from gel formulations could be described fairly well by a zero-order kinetic profile. Skin penetration was the greatest when EDTA, n-octyl-beta-D-thioglucoside (OTG, 1.5%) and taurocholate (1.0%) were combined in a gel formulation. The order of flux was: EDTA, OTG and taurocholate (formulation 3) > OTG and taurocholate (formulation 2) > glucosyl-beta-cyclodextrin and OTG (formulation 4). When the transdermal systems of [125I]ebiratide prepared using a corresponding gel formulation were applied to rat abdomen, the plasma levels of radioactivity after formulations 3 and 2 were much higher than those after formulation 1 without enhancers, and the radioactivity was observed in the brain, although in a very small quantity. The hypocalcemic effect of elcatonin was measured in vivo after application of the transdermal systems. The plasma calcium levels decreased comparatively rapidly and low levels were maintained for a long period, indicating the effectively percutaneous absorption of elcatonin. Formulation 7 containing D-limonen and taurocholate as enhancers and/or inhibitors showed much higher hypocalcemic effect than two other formulations combined with laurocapram or N,N-diethyl-m-toluamide, consequently giving the highest pharmacological availability (8.7 +/- 1.0%). These results clearly demonstrated that the peptides were effectively absorbed through rat skin in the presence of enhancers.
Ogiso
T
T
Faculty of Pharmaceutical Sciences, Kinki University, Osaka, Japan.
Paku
T
T
Iwaki
M
M
Tanino
T
T
Nishioka
S
S
D000279:Administration, Cutaneous; D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000595:Amino Acid Sequence; D000818:Animals; D002116:Calcitonin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002118:Calcium / Q000097:blood; D005079:Excipients / Q000494:pharmacology; D005782:Gels; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012869:Skin Absorption / Q000502:physiology*; D014018:Tissue Distribution
D005079:Excipients; D005782:Gels; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D011480:Protease Inhibitors; D000324:Adrenocorticotropic Hormone; D002116:Calcitonin; C057139:ebiratide; D002118:Calcium; C012755:elcatonin