Design and in vivo testing of 17 beta-estradiol-HP beta CD sublingual tablets.
17 beta-Estradiol is almost insoluble in water. The effect of various cyclodextrins and two different polymers, polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC), on the aqueous solubility of 17 beta-estradiol was investigated. 17 beta-Estradiol was dissolved in aqueous 50% w/v 2-hydroxypropyl-beta- cyclodextrin (HP beta CD) solution containing 0.25% (w/v) CMC and the dry 17 beta-estradiol-HP beta CD complex formed by lyophilisation of the solution. Sublingual tablets from the dry complex were produced by direct compression. The dissolution of 17 beta-estradiol from tablets containing the drug in a lyophilised HP beta CD complex was determined. For reference the dissolution of 17 beta-estradiol was determined from tablets containing physical mixture of 17 beta-estradiol and HP beta CD or tablets containing 17 beta-estradiol without HP beta CD. Sublingual tablets containing 17 beta-estradiol-HP beta CD in the lyophilised complex demonstrated the fastest dissolution profile and those tablets were selected for further studies in humans. Six postmenopausal women received a sublingual tablet containing 17 beta-estradiol-HP beta CD complex equivalent to 100 micrograms 17 beta-estradiol. Blood samples were collected over a 12 h period and the 17 beta-estradiol plasma concentration was determined. 17 beta-Estradiol was rapidly absorbed from the sublingual tablets, resulting in a peak 17 beta-estradiol plasma concentration of 568 +/- 97 pmol/l 15 min after administration of the tablets, followed by a biphasic elimination.
Fridriksdóttir
H
H
Department of Pharmacy, University of Iceland, Reykjavik.
Loftsson
T
T
Gudmundsson
J A
JA
Bjarnason
G J
GJ
Kjeld
M
M
Thorsteinsson
T
T
D000286:Administration, Sublingual; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015195:Drug Design; D004958:Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013607:Tablets; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D013607:Tablets; D047392:beta-Cyclodextrins; D004958:Estradiol; C031215:betadex