alpha-cyclodextrin and hydroxypropyl-gamma-cyclodextrin

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.. 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).. 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.. Complexation of beta-lap with HPbeta-CD offers a major improvement in drug solubility and bioavailability.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adjuvants, Pharmaceutic; alpha-Cyclodextrins; Animals; beta-Cyclodextrins; Biological Availability; Cyclodextrins; gamma-Cyclodextrins; Humans; Injections, Intraperitoneal; Lethal Dose 50; Mice; Mice, Inbred C57BL; Naphthoquinones; Solubility; Tumor Cells, Cultured

The interaction of cyclodextrins (CDs) with dipalmitoylphosphatidylcholine (DPPC) liposomes has been studied using differential scanning calorimetry (DSC). The phase transition temperature and the enthalpy change due to the gel-to-liquid crystalline phase transition of the liposomes were measured in the presence of alpha-CD, beta-CD, gamma-CD, heptakis (2,6-di-O-methyl)-beta-CD (DOM-beta-CD), heptakis (2,3,6-tri-O-methyl)-beta-CD (TOM-beta-CD) and 2-hydroxylpropyl beta-CD, respectively. The effects on the change of enthalpy of the transition temperature were remarkable in the order of DOM-beta-CD > alpha-CD > TOM-beta-CD. The residual CDs caused scarcely detectable changes in the enthalpy changes and the transition temperatures. In order to clarify the DSC curves in the presence of the CDs mentioned above, the type of interactions which occurred between CDs and DPPC liposomes were studied. Consequently, it was found that DOM-beta-CD forms a soluble complex and alpha-CD forms an insoluble complex with DPPC liposomes, whereas only a slight amount of TOM-beta-CD was suggested to penetrate the matrix of the liposomes.

Topics: 1,2-Dipalmitoylphosphatidylcholine; 2-Hydroxypropyl-beta-cyclodextrin; alpha-Cyclodextrins; beta-Cyclodextrins; Calorimetry, Differential Scanning; Cyclodextrins; gamma-Cyclodextrins; Liposomes; Thermodynamics