Improvement of nasal bioavailability of luteinizing hormone-releasing hormone agonist, buserelin, by cyclodextrin derivatives in rats.
The effects of chemically modified cyclodextrins on the nasal absorption of buserelin, an agonist of luteinizing hormone-releasing hormone, were investigated in anesthetized rats. Of the cyclodextrins tested, dimethyl-beta-cyclodextrin (DM-beta-CyD) was the most effective in improving the rate and extent of the nasal bioavailability of buserelin. Fluorescence spectroscopic studies indicated that the cyclodextrins formed inclusion complexes with buserelin, which may reduce the diffusibility of buserelin across the nasal epithelium and may participate in the protection of the peptide against enzymatic degradation in the nasal mucosa. Additionally, the cyclodextrins increased the permeability of the nasal mucosa, which was the primary determinant based on the multiple regression analysis of the nasal absorption enhancement of buserelin. Scanning electron microscopic observations revealed that DM-beta-CyD induced no remarkable changes in the surface morphology of the nasal mucosa at a minimal concentration necessary to achieve substantial absorption enhancement. The present results suggest that DM-beta-CyD could improve the nasal bioavailability of buserelin and is well-tolerated by the nasal mucosa of the rat.
Matsubara
K
K
Pharma Research Laboratories, Hoechst Japan Ltd., Saitama, Japan.
Abe
K
K
Irie
T
T
Uekama
K
K
D000042:Absorption; D000281:Administration, Intranasal; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002064:Buserelin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003505:Cyclodextrins / Q000494:pharmacology*; D005079:Excipients / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013050:Spectrometry, Fluorescence
D018931:Antineoplastic Agents, Hormonal; D003505:Cyclodextrins; D005079:Excipients; D007987:Gonadotropin-Releasing Hormone; D002064:Buserelin