Enhancement of solubility and bioavailability of beta-lapachone using cyclodextrin inclusion complexes.
OBJECTIVE
To explore the use of cyclodextrins (CD) to form inclusion complexes with beta-lapachone (beta-lap) to overcome solubility and bioavailability problems previously noted with this drug.


METHODS
Inclusion complexes between beta-lap and four cyclodextrins (alpha-, beta-, gamma-, and HPbeta-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and 1H-NMR spectroscopy. Biologic activity and bioavailability of beta-lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g).


RESULTS
Phase solubility studies showed that beta-lap solubility increased in a linear fashion as a function of alpha-, beta-, or HPbeta-CD concentrations but not gamma-CD. Maximum solubility of beta-lap was achieved at 16.0 mg/ml or 66.0 mM with HPbeta-CD. Fluorescence and 1H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between beta-CD and HPbeta-CD with beta-lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of beta-lap in beta-CD or HPbeta-CD inclusion complexes (TD50 = 2.1 microM). Animal studies in mice showed that the LD50 value of beta-lap in an HPbeta-CD inclusion complex is between 50 and 60 mg/kg.


CONCLUSIONS
Complexation of beta-lap with HPbeta-CD offers a major improvement in drug solubility and bioavailability.
Nasongkla
Norased
N
Department of Macromolecular Science and Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Wiedmann
Andy F
AF
Bruening
Andrew
A
Beman
Meghan
M
Ray
Dale
D
Bornmann
William G
WG
Boothman
David A
DA
Gao
Jinming
J
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000277:Adjuvants, Pharmaceutic / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D003505:Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D051379:Mice; D008810:Mice, Inbred C57BL; D009285:Naphthoquinones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D012995:Solubility; D014407:Tumor Cells, Cultured; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins
D000277:Adjuvants, Pharmaceutic; D003505:Cyclodextrins; D009285:Naphthoquinones; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins; C479658:hydroxypropyl-alpha-cyclodextrin; C479659:hydroxypropyl-gamma-cyclodextrin; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C014638:beta-lapachone; C031215:betadex; C023792:gamma-cyclodextrin; C032613:alpha-cyclodextrin