betadex and oridonin

Chemotherapy via oral route of anticancer drugs offers much convenience and compliance to patients. However, oral chemotherapy has been challenged by limited absorption due to poor drug solubility and intestinal efflux. In this study, we aimed to develop a nanosuspension formulation of oridonin (Odn) using its cyclodextrin inclusion complexes to enhance oral bioavailability. Nanosuspensions containing Odn/2 hydroxypropyl-β-cyclodextrin inclusion complexes (Odn-CICs) were prepared by a solvent evaporation followed by wet media milling technique. The nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and dissolution. The resulting nanosuspensions were approximately 313.8 nm in particle size and presented a microcrystal morphology. Nanosuspensions loading Odn-CICs dramatically enhanced the dissolution of Odn. Further, the intestinal effective permeability of Odn was markedly enhanced in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and poloxamer. Bioavailability studies showed that nanosuspensions with Odn-CICs can significantly promote the oral absorption of Odn with a relative bioavailability of 213.99% (Odn suspensions as reference). Odn itself possesses a moderate permeability and marginal intestinal metabolism. Thus, the enhanced bioavailability for Odn-CIC nanosuspensions can be attributed to improved dissolution and permeability by interaction with absorptive epithelia and anti-drug efflux. Nanosuspensions prepared from inclusion complexes may be a promising approach for the oral delivery of anticancer agents.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Oral; Animals; beta-Cyclodextrins; Biological Availability; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Diterpenes, Kaurane; Drug Compounding; Male; Microscopy, Electron, Scanning; Nanoparticles; Particle Size; Permeability; Rats; Rats, Sprague-Dawley; Solubility; Spectroscopy, Fourier Transform Infrared; Suspensions

Complexations between three oridonin derivatives and β-cyclodextrin (βCD) were studied by nuclear magnetic resonance (NMR) method. Job's plots for complexes were depicted by (1)H NMR spectra chemical shifts, which proved the 1:1 stoichiometry inclusion complex formation between each derivative and βCD. Two-dimensional rotating frame overhauser effect spectroscopy (2D ROESY) support the above conclusion and also proved that ring A of each oridonin derivative deeply enters into hydrophobic cavity from the wider rim and the other parts are outside the cavity. Apparent formation constants (Ka) of complexes between three oridonin derivatives and two CDs are calculated according to Scott's equation.

Topics: beta-Cyclodextrins; Diterpenes, Kaurane; Hydrophobic and Hydrophilic Interactions; Kinetics; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Stereoisomerism

Oridonin, a diterpenoid, is a sparingly soluble compound and its aqueous solubility can't meet the requirement of clinical intravenous administration. This study was, accordingly, to prepare an inclusion complex of oridonin and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) by lyophilization to improve its apparent solubility. The solubility enhancement of oridonin was evaluated by phase solubility method, and the phase solubility curve displayed a typical A(L)-type, indicating the formation of 1:1 inclusion complex. The formation of inclusion complex was confirmed by DSC, XRD, FTIR, and NMR, and thereby two possible inclusion modes were inferred. In vivo studies demonstrated that HP-beta-CD had no significant effect on the plasma pharmacokinetic behaviors of oridonin following i.v. administration to rats, but the inclusion complex tended to decrease the distribution of oridonin in heart, spleen, and kidney and increase that in lung in mice, compared to that of free drug.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Area Under Curve; beta-Cyclodextrins; Biological Availability; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Diterpenes, Kaurane; Excipients; Freeze Drying; Injections, Intravenous; Magnetic Resonance Spectroscopy; Male; Mice; Rats; Rats, Wistar; Solubility; Spectroscopy, Fourier Transform Infrared; Tissue Distribution; X-Ray Diffraction

The inclusion compound of Oridonin-beta-cyclodextrin was prepared by the liquid-phase method in aqueous solution. And it was confirmed by thin layer chromatography, differential thermal analysis and specific rotation. The change (A) of ultraviolet spectrum was determined. The composition ratio of inclusion compound between Oridonin and beta-CD was obtained by the continuous variation method.

Topics: beta-Cyclodextrins; Calorimetry, Differential Scanning; Chromatography, Thin Layer; Cyclodextrins; Diterpenes; Diterpenes, Kaurane; Drug Carriers; Isodon; Plants, Medicinal