Enhancement of Solubility and Bioavailability of β-Lapachone Using Cyclodextrin Inclusion Complexes Journal Article
| Authors: | Nasongkla, N.; Wiedmann, A. F.; Bruening, A.; Beman, M.; Ray, D.; Bornmann, W. G.; Boothman, D. A.; Gao, J. |
| Article Title: | Enhancement of Solubility and Bioavailability of β-Lapachone Using Cyclodextrin Inclusion Complexes |
| Abstract: | Purpose. To explore the use of cyclodextrins (CD) to form inclusion complexes with β-lapachone (β-lap) to overcome solubility and bioavailability problems previously noted with this drug. Methods. Inclusion complexes between β-lap and four cyclodextrins (α-, β-, γ-, and HPβ-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and 1 H-NMR spectroscopy. Biologic activity and bioavailability of β-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 β-lap solubility increased in a linear fashion as a function of α-, β-, or HPβ-CD concentrations but not γ-CD. Maximum solubility of β-lap was achieved at 16.0 mg/ml or 66.0 mM with HPβ-CD. Fluorescence and 1 H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between β-CD and HPβ-CD with β-lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of β-lap in β-CD or HPβ-CD inclusion complexes (TD50 = 2.1 μM). Animal studies in mice showed that the LD50 value of β-lap in an HPβ-CD inclusion complex is between 50 and 60 mg/kg. Conclusions. Complexation of β-lap with HPβ-CD offers a major improvement in drug solubility and bioavailability. |
| Keywords: | controlled study; unclassified drug; human cell; drug activity; nonhuman; mouse; animals; mice; complex formation; fluorescence; analytic method; animal experiment; in vivo study; cytotoxicity; in vitro study; tumor cells, cultured; cell assay; mice, inbred c57bl; drug bioavailability; mouse strain; cell strain mcf 7; aqueous solution; concentration response; lethality; bioavailability; biological availability; proton nuclear magnetic resonance; solubility; drug solubility; beta-cyclodextrins; injections, intraperitoneal; beta lapachone; adjuvants, pharmaceutic; cyclodextrins; ld 50; cyclodextrin; lethal dose 50; humans; human; female; priority journal; article; naphthoquinones; β-lapachone; inclusion complex; alpha cyclodextrin; beta cyclodextrin; gamma cyclodextrin; hp beta cyclodextrin; alpha-cyclodextrins; gamma-cyclodextrins |
| Journal Title: | Pharmaceutical Research |
| Volume: | 20 |
| Issue: | 10 |
| ISSN: | 0724-8741 |
| Publisher: | Springer Science + Business Media, LLC |
| Date Published: | 2003-10-01 |
| Start Page: | 1626 |
| End Page: | 1633 |
| Language: | English |
| DOI: | 10.1023/a:1026143519395 |
| PUBMED: | 14620518 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
