Nasal administration of an ACTH(4-9) peptide analogue with dimethyl-beta-cyclodextrin as an absorption enhancer: pharmacokinetics and dynamics.
1. The systemic absorption and the neurotrophic effect of the metabolically stabilized ACTH (4-9) analogue, Org2766, were investigated following intranasal (i.n.) administration. 2. Without additives the nasal bioavailability of the peptide was in the order of 15 and 10% in rats and rabbits, respectively. The absorption could be improved by addition of a variety of absorption enhancers to the nasal preparation. The beta-cyclodextrin derivative, dimethyl-beta-cyclodextrin (DM beta CD) at a concentration of 5% (w/v) improved the absorption in rats about 5 fold from 13 +/- 4% (mean +/- s.d.) for administration of the peptide alone to 65 +/- 21%, and in rabbits 1 to 2 fold, from 10 +/- 6% to 17 +/- 8%. 3. The increased permeability of the rat nasal mucosa for Org2766 caused by DM beta CD in rats reversed substantially within 1 h. However, the nasal absorption had not yet completely returned to the level without enhancer. 4. S.c. administered Org2766 accelerated the functional recovery from peripheral nerve damage in rats. However, the peptide did not facilitate nerve repair following i.n. administration with DM beta CD, in spite of the fact that Org2766 was well absorbed. I.v. injection of Org2766 was also ineffective.
Schipper
N G
NG
Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Verhoef
J C
JC
De Lannoy
L M
LM
Romeijn
S G
SG
Brakkee
J H
JH
Wiegant
V M
VM
Gispen
W H
WH
Merkus
F W
FW
D000042:Absorption; D000281:Administration, Intranasal; D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D003505:Cyclodextrins / Q000494:pharmacology; D004347:Drug Interactions; D008297:Male; D009297:Nasal Mucosa / Q000378:metabolism*; D009416:Nerve Regeneration / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010525:Peripheral Nerves / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D010446:Peptide Fragments; D047392:beta-Cyclodextrins; C013765:Org 2766; C038119:heptakis(2,6-O-dimethyl)beta-cyclodextrin; D000324:Adrenocorticotropic Hormone