Improved delivery through biological membranes. XXXL: Solubilization and stabilization of an estradiol chemical delivery system by modified beta-cyclodextrins.
A dihydropyridine in equilibrium pyridinium salt chemical delivery system (CDS) for estradiol (E2CDS) was complexed with various modified beta-cyclodextrins including hydroxyethyl-beta-cyclodextrin (HECD), hydroxypropyl-beta-cyclodextrin (HPCD), and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DMCD). Complex formation with all of these cyclodextrins resulted in dramatic increases in the water solubility of E2CDS. Studies on the complex of E2CDS and HPCD (E2CDS-CD) indicated that the encapsulated estrogen was approximately four times more stable than the unmanipulated CDS, producing an estimated half-life of degradation of 4 years compared with 1.2 years for the uncomplexed drug at room temperature. The complexation of E2CDS and HPCD also stabilized the dihydronicotinate in solutions containing potassium ferricyanide. This formulation was shown to be equivalent to E2CDS in dimethyl sulfoxide in delivering the oxidized, estradiol precursor (E2Q+) to the brain, and also produced similar biological responses; these included decreased luteinizing hormone (LH) secretion and a decrease in the rate of weight gain in castrated female rats.
Brewster
M E
ME
Center for Drug Design and Delivery, College of Pharmacy, J. Hillis Miller Health Center, University of Florida, Gainesville 32610.
Estes
K S
KS
Loftsson
T
T
Perchalski
R
R
Derendorf
H
H
Mullersman
G
G
Bodor
N
N
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004958:Estradiol / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology; D005260:Female; D005292:Ferricyanides / Q000494:pharmacology; D006207:Half-Life; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008567:Membranes, Artificial; D010052:Ovariectomy; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D005292:Ferricyanides; D008567:Membranes, Artificial; D047392:beta-Cyclodextrins; C007931:hexacyanoferrate III; D004958:Estradiol; D007986:Luteinizing Hormone; C031215:betadex; D004121:Dimethyl Sulfoxide