Nasal administration of an ACTH(4–9) peptide analogue with dimethyl‐β‐cyclodextrin as an absorption enhancer: pharmacokinetics and dynamics

Abstract

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 P-cyclodextrin derivative, dimethyl-p-cyclodextrin (DMPCD) 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 DMPCD 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 DMPCD, in spite of the fact that Org2766 was well absorbed. I.v. injection of Org2766 was also ineffective.

Targeted Drug Delivery to Bone: Pharmacokinetic and Pharmacological Properties of Acidic Oligopeptide-Tagged Drugs

“…Therefore, we have suggested an alternative route, intranasal administration, to increase the bioavailability of tagged molecules. The bioavailability of E 2 -17 D 6 after intranasal administration was increased to 75% when the formulation was changed by incorporating 2,6-di-O-methyl--cyclodextrin, with which E 2 -17 D 6 formed an inclusion compound that could achieve prolonged residence in the nasal cavity [67][68][69][70]. These results support the potential clinical usefulness of acidic oligopeptide-tagged drugs.…”

Cyclodextrins in non-viral gene delivery

“…A similar absorption-enhancing effect of CDs was shown by using dimentylb-CD, which, at a concentration of 5% (w/v), elevated the permeability of the nasal mucosa to the intranasally administered neurotrophic peptide, Org2766, and enhanced the absorption in rabbits 1to 2-fold from 10 AE 6% (mean AE s.d.) for administration of the peptide alone to 17 AE 8%, and in rats 5-fold from 13 AE 4% to 65 AE 21% [32]. All these evidenced the absorption-enhancing property of CDs, and it is this property that may also facilitate gene delivery.…”

Cell Transfection with a β-Cyclodextrin-PEI-Propane-1,2,3-Triol Nanopolymer

“…Since current advances in applications of cyclodextrins to non-viral gene delivery have been reviewed by a recent article [4] , readers are referred to that article for details [4] . In general, cyclodextrins have high potential in gene transfer because of their binding affinity to nucleic acids [20] , [21] , their ability to attenuate the cytotoxicity of other gene vectors [22] , and their absorption-enhancing property in therapeutics delivery [23] , [24] . Given this fact, the performance of PEA in gene delivery is expected to be augmented upon cross-linking with β-CD.…”